Targeting Mitochondrial Dysfunction and Reactive Oxygen Species for Neurodegenerative Disease Treatment.

Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative diseases, and they affect millions of people worldwide, particularly older individuals. Therefore, there is a clear need to develop novel drug targets for the treatment of age-related neurodegenerative diseases. Emerging evidence suggests that mitochondrial dysfunction and reactive oxygen species (ROS) generation play central roles in the onset and progression of neurodegenerative diseases. Mitochondria are key regulators of respiratory function, cellular energy adenosine triphosphate production, and the maintenance of cellular redox homeostasis, which are essential for cell survival. Mitochondrial morphology and function are tightly regulated by maintaining a balance among mitochondrial fission, fusion, biogenesis, and mitophagy. In this review, we provide an overview of the main functions of mitochondria, with a focus on recent progress highlighting the critical role of ROS-induced oxidative stress, dysregulated mitochondrial dynamics, mitochondrial apoptosis, mitochondria-associated inflammation, and impaired mitochondrial function in the pathogenesis of age-related neurodegenerative diseases, such as AD and PD. We also discuss the potential of mitochondrial fusion and biogenesis enhancers, mitochondrial fission inhibitors, and mitochondria-targeted antioxidants as novel drugs for the treatment of these diseases.

Abies holophylla Leaf Essential Oil Alleviates Allergic Rhinitis Based on Network Pharmacology.

Abies holophylla is an evergreen coniferous species that has been widely used for treating pulmonary diseases and colds. Previous research has demonstrated the anti-inflammatory effect of Abies species and the anti-asthmatic activities of Abies holophylla leaf essential oil (AEO). As asthma and allergic rhinitis (AR) share pathophysiology and pharmacotherapeutic interventions, AEO inhalation can also ameliorate upper respiratory allergic diseases. This study explored the protective effects of AEO on AR with network pharmacological pathway prediction. The potential target pathways of AEO were analyzed by a network pharmacological approach. The BALB/c mice were sensitized by ovalbumin (OVA) and 10 µm particular matter (PM10) to induce allergic rhinitis. Aerosolized AEO 0.0003% and 0.03% were delivered by nebulizer for 5 min a day, 3 times a week for 7 weeks. Nasal symptoms (sneezing and rubbing), histopathological changes in nasal tissues, serum IgE, and zonula occludens-1 (ZO-1) expressions on nasal tissues were analyzed. After AR induction with OVA+PM10 and inhalation of AEO 0.0003% and 0.03% treatment, AEO significantly decreased allergic symptoms (sneezing and rubbing), hyperplasia of nasal epithelial thickness, goblet cell counts, and serum IgE level. The network analysis demonstrated that the possible molecular mechanism of AEO is highly associated with the IL-17 signaling pathway and tight junction. The target pathway of AEO was investigated in RPMI 2650 nasal epithelial cells. Treatment of AEO on PM10-treated nasal epithelial cells significantly reduced the production of inflammatory mediators related to the IL-17 signaling pathway, NF-κB, and the MAPK signaling pathway and prevented the reduction in TJ-related factors. When taken together, AEO inhalation may be considered as a potential treatment for AR by alleviating nasal inflammation and recovering the tight junction.

Exploring the Potential Effects and Mechanisms of Asarum sieboldii Radix Essential Oil for Treatment of Asthma.

Asthma, a common chronic pulmonary disorder characterized by airway remodeling, hyperresponsiveness and obstruction, can be aggravated by repeated exposure to particulate matter (PM). The potential effect and mechanisms of Asarum sieboldii Radix essential oil (AEO) against asthma were explored based on network pharmacology. AEO was pre-treated using a nebulizer for 3 weeks and the mice were sensitized to ovalbumin (OVA) and PM10 with the co-treatment of AEO for 4 weeks. In addition, A549 lung epithelial cells were sensitized with PM10 to investigate the underlying mechanisms of AEO regarding the lung-fibrosis-related mediators. The target genes of methyl eugenol, a main compound of AEO, were highly matched by 48% with the gene set of asthma. AEO markedly inhibited the increase in epithelial thickness through the accumulation of goblet cells in the airways. Collagen deposition in the lung tissues of OVA+PM10-challenged asthmatic mice was significantly decreased by AEO. AEO also inhibited the influx of inflammatory cells in the bronchoalveolar lavage fluid, as well as the increases in serum IgE and IgG2a and cytokines in the lung tissues. Furthermore, AEO regulated the expressions of fibrotic mediators, especially POSTN and TGF-ß. In conclusion, we expect that AEO can be one of the effective alternative therapeutics to relieve asthma.

Efficacy and mechanism of essential oil from Abies holophylla leaf on airway inflammation in asthma: Network pharmacology and in vivo study.

BACKGROUND: Asthma is one of the most common chronic inflammatory diseases of the airways. Essential oil from Abies holophylla leaf (EOA) has been reported to have anti-inflammatory property. This study aimed to predict the inhibitory effect of EOA against asthma by network analysis and to confirm the underlying mechanism of EOA on airway inflammation. PURPOSE AND STUDY DESIGN: The effects and underlying mechanisms of EOA on asthma were investigated by in silico network pharmacology and an experimental in vivo study. METHODS: To define the effectiveness of EOA on asthma, the network pharmacology was constructed using major components of EOA. EOA (0.0003 and, 0.03 v/v%) was aerosolized by nebulizer 3 times a week for 5 min for 7 weeks. After 3 weeks of treating the mice with EOA, asthma was induced by sensitizing them with ovalbumin (OVA) and PM10. The effects of EOA on the IL-17 related signaling pathway was confirmed using an asthmatic model. RESULTS: The network analysis showed that EOA is highly associated with the IL-17-related signaling pathway. EOA inhibited respiratory epithelium hyperplasia, collagen deposition and goblet cell activation in the lung and trachea tissues. In addition, EOA reduced the number of eosinophils, lymphocytes and macrophages in BALF. Furthermore, in the asthmatic model of mice, we showed that EOA inhibited IL-17-related cytokines, increased Treg-related cytokines and decreased the TRAF6 and MAPK and, suppressed the nuclear transcriptional activities of NF-kB. CONCLUSIONS: The network pharmacology and in vivo study indicated that EOA may have an inhibitory effect on airway inflammation in asthma exposure through the IL-17-related signaling pathway.

Network Pharmacology Study and Experimental Confirmation Revealing the Ameliorative Effects of Decursin on Chemotherapy-Induced Alopecia.

Decursin, a pyranocoumarin compound from the root of Angelica gigas Nakai as a main constituent, has been reported to have various biological activities, including anti-inflammatory, anticancer, and antioxidant effects. This study aimed to predict and confirm the pharmacological relevance of Decursin on chemotherapy-induced alopecia (CIA) with the underlying molecular mechanisms. Decursin-targeted genes were compared with the gene set of alopecia and investigated through functional enrichment analysis. CIA was induced in C57BL/6J mice by injection of cyclophosphamide, and 1, 10, and 100 µM of Decursin were topically treated to depilated dorsal skin. KGF+ expression was detected in the dorsal skin tissues. Based on the predicted results, caspase, PIK3/AKT, and MAPKs protein expressions by Decursin were analyzed in the TNF-α-induced keratinocytes. The Decursin network had 60.20% overlapped genes with the network of alopecia. Biological processes, such as cellular response to chemical stimulus, apoptosis, PI3K-AKT signaling pathway, and MAPK signaling pathway, were derived from the Decursin network. In the Decursin-treated skin, there was morphological hair growth and histological restoration of hair follicles in the CIA mice. The KGF+ fluorescence and protein expressions were significantly increased by Decursin treatment. In addition, caspase-3, -7, and -8 expressions, induced by TNF-α, were dose-dependently decreased along with the inhibition of PI3K, AKT, ERK, and p38 expressions in Decursin-treated keratinocytes. These findings indicated that Decursin would be a potent therapeutic option for hair loss, in response to chemotherapy.

Promotion of osteogenesis by Sweroside via BMP2-involved signaling in postmenopausal osteoporosis.

Phlomis umbrosa has been traditionally used for bone diseases in traditional Korean Medicine. Sweroside (SOS), marker compounds of P. umbrosa, has been known to promote osteoblast differentiation. In this study, ameliorative effects of SOS on osteoporosis and potential target pathway were investigated. Ovariectomized mice were administered three doses of SOS three times a week for 4 weeks after inducing osteoporosis. Bone mineral content (BMC) and bone mineral density (BMD) were analyzed by dual energy X-ray absorptiometry. A human osteosarcoma cell line (SaOS-2) was differentiated to clarify the promoting effects of SOS on osteoblast differentiation and bone formation. Osteoblastic bone-forming markers were evaluated in lumbar vertebrae (LV) and mineralized SaOS-2 cells. SOS markedly elevated BMC and BMD levels and attenuated the bone marrow adipocytes in the femoral shaft. SOS increased the formation of bone matrix in SaOS-2 cells. Bone morphogenetic protein-2 (BMP2) and runt-related transcription factor 2 (CBFA1) in LV and SaOS-2 cells were up-regulated by SOS. SOS increased alkaline phosphatase (ALPL), osteopontin (SPP1), and bone sialoprotein-1 (BSPH1). In conclusion, SOS induced the formation of mineralized bone matrix by regulating BMP2/CBFA1-mediated molecules. Therefore, SOS could be a therapeutic compound of treatment for osteoporosis by producing the new bone matrix.

Macrophage peroxiredoxin 5 deficiency promotes lung cancer progression via ROS-dependent M2-like polarization.

Strategies for cancer treatment have traditionally focused on suppressing cancer cell behavior, but many recent studies have demonstrated that regulating the tumor microenvironment (TME) can also inhibit disease progression. Macrophages are major TME components, and the direction of phenotype polarization is known to regulate tumor behavior, with M2-like polarization promoting progression. It is also known that reactive oxygen species (ROS) in macrophages drive M2 polarization, and M2 polarization promote lung cancer progression. Lung cancer patients with lower expression of the antioxidant enzyme peroxiredoxin 5 (Prx5) demonstrate poorer survival. This study revealed that Prx5 deficiency in macrophages induced M2 macrophage polarization by lung cancer. We report that injection of lung cancer cells produced larger tumors in Prx5-deficit mice than wild-type mice independent of cancer cell Prx5 expression. Through co-culture with lung cancer cell lines, Prx5-deficient macrophages exhibited M2 polarization, and reduced expression levels of the M1-associated inflammatory factors iNOS, TNFα, and Il-1ß. Moreover, these Prx5-deficient macrophages promoted the proliferation and migration of co-cultured lung cancer cells. Conversely, suppression of ROS generation by N-acetyl cysteine (NAC) inhibited the M2-like polarization of Prx5-deficient macrophages, increased expression levels of inflammatory factors, inhibited the proliferation and migration of co-cultured lung cancer cells, and suppressed tumor growth in mice. These findings suggest that blocking the M2 polarization of macrophages may promote lung cancer regression.

Fat regulatory mechanisms of pine nut oil based on protein interaction network analysis.

BACKGROUND: Pine nut oil (PNO), a standardized and well-defined extract of Pinus koraiensis (Korean pine), has beneficial effects on wound healing, inflammatory diseases, and cancer. However, the explanation for the mechanism by which PNO reduces body fat remains uncertain. We performed a protein-protein interaction network (PPIN) analysis to explore the genes associated with pinolenic acid using the MEDILINE database from PubChem and PubMed. It was concluded through the PPIN analysis that PNO was involved in a neutral lipid biosynthetic process. PURPOSE: This study evaluated the effects of PNO predicted by the network analysis of fat accumulation in chronic obesity mouse models established by feeding a high fat diet (HFD) to C57BL/6J mice and explored potential mechanisms. METHODS: HFD mice were fed only HFD or HFD with PNO at 822 and 1644 mg/kg. After an oral administration of 7 weeks, several body weight and body fat-related parameters were examined, including the following: adipose weight, adipocyte size, serum lipid profiles, adipocyte expression of PPAR-γ, sterol regulatory element binding protein (SREBP)-1c, lipoprotein lipase (LPL) and leptin. RESULTS: We showed that oral administration of PNO to HFD mice reduces body fat weight, fat in tissue, white adipose tissue weight, and adipocyte size. The serum cholesterol was improved in the HFD mice treated with PNO. Additionally, PNO has significantly attenuated the HFD-induced changes in the adipose tissue expression of PPAR-γ, SREBP-1c, LPL, and leptin. CONCLUSIONS: The findings from this study based on the PPIN analysis suggest that PNO has potential as drug to reduce body fat through fat regulatory mechanisms by PPAR-γ and SREBP-1c.

Zanthoxylum piperitum alleviates the bone loss in osteoporosis via inhibition of RANKL-induced c-fos/NFATc1/NF-κB pathway.

BACKGROUND: The fruit of Zanthoxylum piperitum (ZP) is an herbal medicine as well as a spice agent in Asia to treat carminative, stomachic, anthelmintic and degenerative diseases. Z. piperitum was reported to have anti-oxidant, anti-inflammatory, anti-osteoarthritic and osteosarcoma proliferation-control effects. PURPOSE AND STUDY DESIGN: This study was conducted to determine the anti-osteoporotic effects and mechanisms of action of ZP. METHODS: Female ICR mice underwent ovariectomies (OVX) and were orally administered ZP at 1, 10 and 100 mg/kg for 6 weeks. The femoral and tibial bones were assessed by dual-energy X-ray absorptiometry and histology to analyze the bone mineral density (BMD) and the number of osteoclasts. Raw 264.7 cells were stimulated by 100 ng/ml receptor activator of nuclear factor-κB ligand (RANKL) for 7 days in the presence of ZP. RANKL-induced signaling molecules were analyzed in osteoclasts. RESULTS: The levels of femoral and tibial BMD were significantly increased by ZP administration. Serum biomarkers such as osteocalcin, calcium, alkaline phosphatase and bone-specific alkaline phosphatase concentrations were markedly recovered to normal levels in ZP-treated osteoporotic mice. In addition, the number of osteoclasts in the head, trochanter and body of the femur was obviously decreased in the ZP treatment groups. Moreover, ZP treated-cells showed a reduction in the number of TRAP-positive multinuclear cells in RANKL-stimulated Raw 264.7 cells. ZP decreased the RANKL-activated NFATc1 and c-fos, transcription factors of osteoclast formation. The nuclear translocation of NF-κB and phosphorylation of ERK42/44 were inhibited by the ZP treatment in RANKL-induced osteoclasts. CONCLUSION: Collectively, ZP exerts its inhibitory effect against bone resorption by regulating RANKL-mediated c-fos/NFATc1/NF-κB in osteoclast. ZP may prove to be a therapeutic agent for osteoporosis.

Inhalation of Essential Oil from Mentha piperita Ameliorates PM10-Exposed Asthma by Targeting IL-6/JAK2/STAT3 Pathway Based on a Network Pharmacological Analysis.

Fine particulate matter (PM) exposure exhibits a crucial risk factor to exacerbate airway epithelial remodeling, fibrosis, and pulmonary destruction in asthma. Based on the use of essential oils from aromatic plants on pain relief and anti-inflammatory properties, we investigated the inhibitory effects of essential oil derived from the Mentha species (MEO) against asthma exposed to PM10. The MEO (0.1 v/v %) was aerosolized by a nebulizer to ovalbumin and PM10-induced asthmatic mice. Histological changes were confirmed in the lung tissues. To define the mode of action of the MEO on asthma, a protein-protein interaction network was constructed using menthol and menthone as the major components of the MEO. Cytokine expression and the JAK2/STAT3 signaling pathway were analyzed in lung epithelial A549 cells co-treated with MEO and PM10. Inhalation of MEO by nebulization inhibited respiratory epithelium hyperplasia, collagen deposition, and goblet cell activation in asthmatic mice. Through a network pharmacological analysis, cytokine-cytokine receptor interaction and JAK/STAT was expected to be underlying mechanisms of MEO on asthma. Treatment with MEO significantly reduced the IL-6 levels with a decrease in pro-inflammatory and T helper 2-specific cytokines. PM10-induced phosphorylation of JAK2 and STAT3 was significantly decreased by MEO. Collectively, MEO may have an inhibitory effect on asthma under the condition of PM10 exposure through the IL-6/JAK2/STAT3 signaling pathway.

Human placenta induces hair regrowth in chemotherapy-induced alopecia via inhibition of apoptotic factors and proliferation of hair follicles.

BACKGROUND: The human placenta (HP) is a complex organ used to alleviate tiredness and promote wound healing. Previous research showed the hair growth-promoting effect of HP. However, no reports have addressed the effects of HP on hair regrowth in chemotherapy-induced alopecia. In this study, we investigated the effects of HP on the apoptosis and proliferation of hair follicles in chemotherapy-induced alopecia. METHODS: Male C57BL/6 mice in telogen were depilated to enter anagen. After 9 days, dystrophic catagen was induced by the intraperitoneal injection of 150 mg/kg cyclophosphamide. During 9 to 16 days, 0.1 and 1 mg/mL HP were topically applied to depilated dorsal skin. RESULTS: Dystrophic hair follicles by cyclophosphamide were recovered by HP treatment. New hair shafts containing hair fibers appeared to be straight after HP treatment. Immunohistological staining revealed a significant increase of Ki67-positive cells in hair follicles treated with 1 mg/mL HP. Topical HP treatment increased the ratio of Bcl-2/Bax, while it attenuated the expression of pro-apoptotic Bax, p53, and cytochrome c with caspase-9 and -3. In addition, the expression of KGF and the phosphorylation of AKT were upregulated by HP treatment. CONCLUSION: These results suggest that HP treatment induced hair growth by inhibiting apoptosis and promoting the proliferation of hair follicles. HP may be useful for treating chemotherapy-induced alopecia.

Gumiganghwal-tang ameliorates cartilage destruction via inhibition of matrix metalloproteinase.

ETHNOPHARMACOLOGICAL RELEVANCE: Kyung-Bang Gumiganghwal-tang tablet (GMGHT) is a standardized Korean Medicine that could treat a cold, headache, arthralgia and fever. Although GMGHT has been used for arthritis-related diseases including a sprain, arthralgia, unspecified arthritis and knee arthritis, there is no pre-clinical evidence to treat osteoarthritis (OA). This study determined the drug dosage and the mechanisms of GMGHT for OA. METHODS: OA was induced by intra-articular monoiodoacetic acid (MIA) injection in Sprague-Dawley rats. As calculated from the human equivalent dose formula, GMGHT was orally administered at the doses of 9.86, 98.6 and 986 mg/kg for 4 weeks. The arthritis score was performed by a blind test, and histological changes in articular cartilage were indicated by hematoxylin and eosin, Safranin O and toluidine blue staining. SW1353 chondrocytes were stimulated by interleukin (IL)-1ß recombinant to analyze the expressions of Type II collagen, matrix metalloproteinases (MMPs) and nuclear factor (NF)-κB. RESULTS: Rough and punctate surfaces of the femoral condyle induced by MIA, were recovered by the GMGHT treatment. The arthritis score was significantly improved in the 968 mg/kg of GMGHT-treated cartilage. Loss of chondrocytes and proteoglycan were ameliorated at the deep zone of the subchondral bone plate by the GMGHT administration in OA rats. The expression of Type II collagen was increased, while MMP-1, -3 and -13 levels were decreased in the GMGHT-treated SW1353 chondrocytes. In addition, the GMGHT treatment regulated NF-κB activation along with IL-6, transforming growth factor-ß and IL-12 production. CONCLUSIONS: GMGHT promoted the recovery of articular cartilage damage by inhibiting MMPs, accompanied with its anti-inflammatory effects in OA. GMGHT might be an alternative therapeutic treatment for OA.

Effects of Processed Polygonum multiflorum with KIOM Patent on Bone Remodeling-Related Protein Expression in Human Osteoblast-Like SaOS-2 Cells.

This present study evaluated the effects of processed P. multiflorum on osteogenesis using Sarcoma osteogenic (SaOS-2) cell lines and osteoclastogenesis of bone marrow-derived macrophage cells (BMM) and to elucidate differences in effect on the expression of bone-related proteins between commercially sold P. multiflorum and patented, in vitro-propagated Korea Institute of Oriental Medicine (KIOM) P. multiflorum. Raw P. multiflorum and P. multiflorum that were stir-baked and steamed in black bean juice were compared, and western blotting analysis was performed to investigate the expression of bone remodeling-related proteins in SaOS-2 cells. In the cells treated with P. multiflorum steamed in black bean juice, the expression of RANKL was decreased, whereas that of osteoprotegerin, alkaline phosphatase, Runx2, and osterix was increased. Owing to these results, we conclude that processed P. multiflorum can be used as an alternative treatment for bone diseases such as osteoporosis, osteopenia, periodontitis, and Paget's disease.

Peroxiredoxin 5 ameliorates obesity-induced non-alcoholic fatty liver disease through the regulation of oxidative stress and AMP-activated protein kinase signaling.

Non-alcoholic fatty liver disease (NAFLD) is becoming the most common chronic liver disease globally. NAFLD-which can develop into liver fibrosis, nonalcoholic steatohepatosis, cirrhosis, and hepatocellular carcinoma-is defined as an excess accumulation of fat caused by abnormal lipid metabolism and excessive reactive oxygen species (ROS) generation in hepatocytes. Recently, we reported that Peroxiredoxin 5 (Prx5) plays an essential role in regulating adipogenesis and suggested the need to further investigation on the potential curative effects of Prx5 on obesity-induced fatty liver disease. In the present study, we focused on the role of Prx5 in fatty liver disease. We found that Prx5 overexpression significantly suppressed cytosolic and mitochondrial ROS generation. Additionally, Prx5 regulated the AMP-activated protein kinase pathway and lipogenic gene (sterol regulatory element binding protein-1 and FAS) expression; it also inhibited lipid accumulation, resulting in the amelioration of free fatty acid-induced hepatic steatosis. Silence of Prx5 triggered de novo lipogenesis and abnormal lipid accumulation in HepG2 cells. Concordantly, Prx5 knockout mice exhibited a high susceptibility to obesity-induced hepatic steatosis. Liver sections of Prx5-deletion mice fed on a high-fat diet displayed Oil Red O-stained dots and small leaky shapes due to immoderate fat deposition. Collectively, our findings suggest that Prx5 functions as a protective regulator in fatty liver disease and that it may be a valuable therapeutic target for the management of obesity-related metabolic diseases.

Peroxiredoxin 5 Inhibits Glutamate-Induced Neuronal Cell Death through the Regulation of Calcineurin-Dependent Mitochondrial Dynamics in HT22 Cells.

Glutamate is an essential neurotransmitter in the central nervous system (CNS). However, high glutamate concentrations can lead to neurodegenerative diseases. A hallmark of glutamate toxicity is high levels of reactive oxygen species (ROS), which can trigger Ca2+ influx and dynamin-related protein 1 (Drp1)-mediated mitochondrial fission. Peroxiredoxin 5 (Prx5) is a well-known cysteine-dependent peroxidase enzyme. However, the precise effects of Prx5 on glutamate toxicity are still unclear. In this study, we investigated the role of Prx5 in glutamate-induced neuronal cell death. We found that glutamate treatment induces endogenous Prx5 expression and Ca2+/calcineurin-dependent dephosphorylation of Drp1, resulting in mitochondrial fission and neuronal cell death. Our results indicate that Prx5 inhibits glutamate-induced mitochondrial fission through the regulation of Ca2+/calcineurin-dependent dephosphorylation of Drp1, and it does so by scavenging cytosolic and mitochondrial ROS. Therefore, we suggest that Ca2+/calcineurin-dependent mitochondrial dynamics are deeply associated with glutamate-induced neurotoxicity. Consequently, Prx5 may be used as a potential agent for developing therapies against glutamate-induced neurotoxicity and neurodegenerative diseases where it plays a key role.

Chrysophanol, an anthraquinone from AST2017-01, possesses the anti-proliferative effect through increasing p53 protein levels in human mast cells.

OBJECTIVE: Natural products are well known as the source of drugs in the treatment of allergic inflammation. Chrysophanol, an anthraquinone from the AST2017-01 extract, showed a beneficial anti-inflammatory effect on activated human mast cells in our previous study. However, a regulatory effect of AST2017-01 and chrysophanol on mast cell proliferation induced by thymic stromal lymphopoietin (TSLP) remains unclear. The present study determined the anti-proliferative effect and the fundamental mechanism of AST2017-01 and chrysophanol in mast cells. METHODS: We evaluated an anti-proliferative effect of AST2017-01 and chrysophanol in TSLP-stimulated human mast cell line, HMC-1. RESULTS: Without cytotoxicity, AST2017-01 and chrysophanol decreased mast cells growth and Ki67 mRNA expression increased by TSLP. AST2017-01 and chrysophanol enhanced expressions of p53 and Bax, whereas inhibited expression of Bcl-2. AST2017-01 and chrysophanol restored caspase-3 activity which was decreased by TSLP. AST2017-01 and chrysophanol suppressed expressions of murine double minute-2 protein and phosphorylated-signal transducer and activator of transcription six which are associated with the regulation of p53 protein. AST2017-01 and chrysophanol decreased levels of interleukin (IL)-13, IL-6, and tumor necrosis factor-α. Moreover, AST2017-01 and chrysophanol reduced mRNA expressions of TSLP receptor and IL-7 receptor α. CONCLUSIONS: Therefore, this study proposes that AST2017-01 and chrysophanol may be promising candidates for the development of potent anti-inflammatory or health functional foods.

Anemarrhena asphodeloides Bunge ameliorates osteoporosis by suppressing osteoclastogenesis.

Anemarrhena asphodeloides Bunge has been traditionally used in Korean medicine for its antipyretic, diuretic, sedative, and antitussive effects. In the present study, the effects of an ethanol extract of A. asphodeloides Bunge (AAB) on osteoporosis and its underlying mechanisms on bone remodeling were investigated. Osteoporosis was induced in ICR strain mice by ovariectomy. The mice were divided into four groups: sham, ovariectomized, 17ß­estradiol and 100 mg/kg AAB. The treatment was continued for 4 weeks. Bone mineral density (BMD) and bone mineral content (BMC) were measured using dual­energy X­ray absorptiometry. In addition, Raw 264.7 cells were treated in the presence of 0.1, 1 and 10 µg/ml AAB with 100 ng/ml receptor activator of nuclear factor κΒ ligand (RANKL) to induce osteoclast formation and stained with tartrate resistant acid phosphatase. In addition, levels of osteoclast­related factors were analyzed to investigate the signaling cascades in osteoclasts. The results demonstrated that AAB treatment reversed the decreases of both BMD and BMC in osteoporotic femurs. Additionally, the formation of osteoclasts was significantly suppressed by the AAB treatment in RANKL­stimulated Raw 264.7 cells. Compared with cells treated with RANKL alone, the AAB­treated osteoclasts had significantly decreased tumor necrosis factor­α and interleukin­6. The protein levels of c­fos were also decreased in the AAB­treated osteoclasts. Furthermore, the RANKL­induced nuclear translocation of nuclear factor­κB was attenuated in osteoclasts by the AAB treatment compared with cells treated with RANKL alone. Finally, AAB treatment downregulated the phosphorylation of mitogen­activated protein kinases. The present results demonstrated that AAB exhibited ameliorative effects on osteoporosis by inhibiting osteoclastogenesis, and suggested that AAB may be a potential candidate for the treatment of osteoporosis.

Inhibition of RANKL-stimulated osteoclast differentiation by Schisandra chinensis through down-regulation of NFATc1 and c-fos expression.

BACKGROUND: Schisandra chinenesis (SC) has been reported to have ameliorative effect on osteoporosis. However, the mechanisms underlying the anti-osteoporosis activity of SC have not been clearly elucidated. In the present study, we determined the effects of SC on The receptor activator of NF-kB ligand (RANKL)-induced osteoclastogenesis and its potential mechanism. METHODS: Raw 264.7 cells were treated with 0.6, 6 and 60 µg/mL SC in the presence of 100 ng/mL RANKL for 7 days. RANKL-induced osteoclast formation was analyzed by tartrate resistant acid phosphatase (TRAP) staining. The osteoclast differentiation-related factors were confirmed along with TNF-α. RESULTS: SC inhibits the RANKL-induced osteoclast differentiation in dose-dependent manner within non-toxic concentrations. The supernatant concentrations of TNF-α were significantly decreased by SC treatment. In addition, osteoclastogenesis-related factors, TRAP6 and NF-κB, were markedly decreased by SC in RANKL-induced osteoclasts. Mechanistically, SC reduced the RANKL-triggered NFATc1 and c-fos expressions. CONCLUSIONS: Taken together, our data suggest that SC can modulate bone metabolism by suppressing RANKL-induced osteoclast differentiation.

Peroxiredoxin 5 regulates adipogenesis-attenuating oxidative stress in obese mouse models induced by a high-fat diet.

Elevated levels of reactive oxygen species (ROS) are a hallmark of obesity. Peroxiredoxin 5 (Prx5), which is a cysteine-dependent peroxidase enzyme, has an intensive ROS scavenging activity because it is located in the cytosol and mitochondria. Therefore, we focused on the role of Prx5 in regulating mitochondrial ROS and adipogenesis. We demonstrated that Prx5 expression was upregulated during adipogenesis and Prx5 overexpression suppressed adipogenesis by regulating cytosolic and mitochondrial ROS generation. Silencing Prx5 promoted preadipocytes to differentiate into adipocytes accumulating lipids by activating adipogenic protein expression. Prx5-deletion mice fed on a high-fat diet (HFD) exhibited significant increase in body weight, enormous fat pads, and adipocyte hypertrophy in comparison to wild type mice. Prx5 deletion also remarkably induced adipogenesis-related gene expression in white adipose tissue. These phenotypic changes in Prx5-deletion mice were accompanied with lipid metabolic disorders, such as excessive lipid accumulation in the liver, severe hepatic steatosis, and high levels of triglyceride in the serum. These results demonstrated that Prx5 deletion increased the susceptibility to HFD-induced obesity and several of its associated metabolic disorders. In conclusion, we suggest that Prx5 inhibits adipogenesis by modulating ROS generation and adipogenic gene expression, implying that Prx5 may serve as a potential strategy to prevent and treat obesity.

Relationships of Serum Iron Parameters and Hemoglobin with Forced Expiratory Volume in 1 Second in Patients with Chronic Obstructive Pulmonary Disease.

BACKGROUND: Although chronic obstructive pulmonary disease is a known cause of secondary polycythemia with elevated erythropoietic demands in response to hypoxemia, anemia is relatively common in patients with chronic obstructive pulmonary disease and is related to increased mortality. However, little is currently known about the relationship between various iron parameters and disease severity in chronic obstructive pulmonary disease patients. METHODS: Data from the fifth Korean National Health and Nutrition Examination Survey, a population-based epidemiologic survey conducted in 2010-2012, were used. A total of 1,129 patients with chronic obstructive pulmonary disease were examined to reveal the associations between the forced expiratory volume in 1 second (FEV1) and hemoglobin and iron parameters, including serum iron, ferritin, total iron binding capacity, and transferrin saturation, using Spearman correlations and multiple linear regression analyses. RESULTS: The FEV1 was positively correlated with serum hemoglobin (γ=0.37, P<0.001), iron (γ=0.20, P<0.001), transferrin saturation (γ=0.19, P<0.001), and ferritin (γ=0.22, P<0.001), and negatively correlated with age (γ=-0.40, P<0.001) and lower in female patients (γ=-0.56, P<0.001) in the Spearman correlation. The FEV1 was independently associated with serum iron (ß=0.049, P=0.035) and transferrin saturation (ß=0.049, P=0.035) after adjusting for age, sex, and body mass index in the multiple linear regression analyses. CONCLUSION: The serum iron and transferrin saturation levels were independently associated with FEV1 as a marker of chronic obstructive pulmonary disease severity.