A novel pyrazole derivative protects from ovariectomy-induced osteoporosis through the inhibition of NADPH oxidase

Joo, Jae Hong; Huh, Jeong Eun; Lee, Jee Hyun; Park, Doo Ri; Lee, Yoonji; Lee, Seul Gee; Choi, Sun; Lee, Hwa Jeong; Song, Seunghyun; Jeong, Yongmi; Goo, Ja Il; Choi, Yongseok; Baek, Hye Kyung; Yi, Sun Shin; Park, Soo‐Jin; Lee, Ji Eun; Ku, Sae Kwang; Lee, Won Jae; Lee, Kee In; Lee, Soo Young

doi:10.1038/srep22389

Cited by 43 publications

(55 citation statements)

References 48 publications

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“…Continued structural insights based on new crystallographic data (Magnani et al ., ) may help guide such efforts. Several other NOX inhibitors with some selectivity have been identified from high‐throughput screens of molecular libraries on cell models in which different NOX enzymes were ectopically expressed (Gianni et al ., ; Altenhofer et al ., ;Hirano et al ., ; Joo et al ., ), and two recently developed NOX2‐selective inhibitors were found to act by competitive inhibition of NADPH binding based on detailed mechanistic studies and molecular docking studies (Hirano et al ., ; Joo et al ., ). However, inhibitory actions of putative NOX inhibitors may also involve indirect mechanisms rather than selective targeting of the NOX protein, and technical issues with the assay methodology to assess NOX activity have in some cases led to false positives (Maghzal et al ., ; Seredenina et al ., ).…”

Section: The Search For Nox‐selective Inhibitorsmentioning

confidence: 99%

Dual oxidase: a novel therapeutic target in allergic disease

Vliet

Danyal

Heppner

2018

British J Pharmacology

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NADPH oxidases (NOXs) represent a family of enzymes that mediate regulated cellular production of reactive oxygen species (ROS) and play various functional roles in physiology. Among the NOX family, the dual oxidases DUOX1 and DUOX2 are prominently expressed in epithelial cell types at mucosal surfaces and have therefore been considered to have important roles in innate host defence pathways. Recent studies have revealed important insights into the host defence mechanisms of DUOX enzymes, which control innate immune response pathways in response to either microbial or allergic triggers. In this review, we discuss the current level of understanding with respect to the biological role(s) of DUOX enzymes and the unique role of DUOX1 in mediating innate immune responses to epithelial injury and allergens and in the development of allergic disease. These novel findings highlight DUOX1 as an attractive therapeutic target, and opportunities for the development of selective inhibitor strategies will be discussed. AbbreviationsCPZ, chlorpromazine; DPI, diphenylene iodonium; DUOX, dual oxidase; DUOXA, dual oxidase maturation factor; EGFR, EGF receptor; ER, endoplasmic reticulum; HDM, house dust mite; ILC2, type 2 innate lymphoid cell; LPO, lactoperoxidase; MPO, myeloperoxidase; NOX, NADPH oxidase; NOXA, NOX activator; PDB, protein database; PHD, peroxidase homology domain; ROS, reactive oxygen species; TK, tyrosine kinase; TLR, toll-like receptor; TPO, thyroperoxidase; TRX, thioredoxin IntroductionThe concept of oxidative stress has been widely embraced as a major factor in disease pathology and has fuelled a billion dollar industry based on antioxidant dietary supplements. However, clinical studies using antioxidant supplementation strategies have generally been unsuccessful in attenuating disease risk or progression, and antioxidant supplementation was in some cases found to even worsen pathological outcomes (Ghezzi et al., 2017). This lack of success likely relates to the flawed concept of oxidative stress as a pharmacological target. First, oxidative stress can be brought about by a range of ROS (the commonly used acronym to define this group of reactive metabolites), which can originate from external sources (e.g. environmental pollution and metabolism of xenobiotics) or be generated endogenously by various enzymatic systems, in some cases in a regulated and deliberate fashion to serve important biological functions [e.g. by activation of NADPH oxidases (NOXs)]. Therefore, generic non-selective approaches that indiscriminately suppress ROS may not have the desired outcome. A second flaw with such generic antioxidant approaches is the fact that ROS represent a diverse group of reactive metabolites that each have unique (bio)chemical properties, and it is often unclear to what extent antioxidant supplements counter the action of individual ROS species. To clarify this, it is helpful to distinguish primary from secondary ROS, with primary ROS representing the initial products of (enzymatic) O 2 reduction [i.e. superoxi...

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Section: The Search For Nox‐selective Inhibitorsmentioning

confidence: 99%

Dual oxidase: a novel therapeutic target in allergic disease

Vliet

Danyal

Heppner

2018

British J Pharmacology

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“…BMD, regarded as a valuable index of bone quality changes in clinical settings, is significantly decreased in osteoporotic animals, regardless of the cause (Diez, ; Joo et al, ; Jung et al, ; Kang et al, ; Syed & Khan, ). BMD has provided good predictive information about the efficacy of antiosteoporotic agents (Syed & Khan, ).…”

Section: Resultsmentioning

confidence: 99%

“…Bone strength also markedly decreased in osteoporosis, regardless of the cause (Diez, ; Joo et al, ; Jung et al, ; Kang et al, ; Syed & Khan, ). The strength (FL) of the right dry femur and tibia mid‐shaft regions in OVX control rats were significantly ( p < .01) decreased compared with those of the sham control rats.…”

Section: Resultsmentioning

confidence: 99%

“…Bone mineral content is generally significantly decreased as osteoporosis progresses (Joo et al, ; Kang et al, ). Among the different bone minerals, Ca and IP are the most dramatically decreased, though their ratio (Ca/IP) is not significantly altered due to the simultaneous decrease of both these minerals (Joo et al, ; Jung et al, ; Kang et al, ). Significantly ( p < .01) reduced femur, tibia, and L4 Ca and IP contents were detected in OVX controls compared with sham controls.…”

Section: Resultsmentioning

confidence: 99%

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Antiosteoporotic effects of 3:1 (g/g) mixed formulation of exopolymers purified fromAureobasidium pullulansSM-2001 andDendropanax morbiferaleaf extracts in ovariectomized rats

Cho¹,

Jeong²,

Kim³

et al. 2018

J Food Biochem

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The dose‐dependent antiosteoporotic potentials of the exopolymers from Aureobasidium pullulans (EAP): Dendropanax morbifera (DM) 3:1 (g/g) were observed in bilateral ovariectomized (OVX) rats. Twenty‐eight days after bilateral OVX surgery, 200 mg/kg EAP or DM, and 400, 200, and 100 mg/kg EAP : DM (3:1) were orally administered, once a day for 56 days. We measured changes in body weight and weight gain, bone weight, length, thickness, strength, and bone mineral density and contents. Additionally, histological profiles and histomorphometric analyses of serum biochemistry and urine biochemistry were conducted at sacrifice. Femur, tibia, and the 4th or 5th lumbar vertebrae were sampled, and histomorphometry of bone mass, structure, and resorption were also performed. In this study, the findings suggest that EAP : DM (3:1) synergistically increased the distinct antiosteoporotic potentials of the single formulations of EAP and DM in OVX rats, suggesting a promising new potent protective agent for relieving osteoporosis in menopausal women. Practical applications Osteoporosis is a metabolic bone disease characterized by decreased bone strength, leading to increased risk of fractures. EAP have antiosteoporotic activity and DM has various health beneficial effects including immunological enhancement. We hypothesized that appropriated mixtures consisting of EAP and DM leaf extracts (EAP : DM) will show more favorable synergistic antiosteoporotic effects due to increases in the diversity of bioactive ingredients. In the present study, rats treated with 200 mg/kg of EAP : DM 3:1 (g/g) showed significantly more favorable inhibitory activity against estrogen‐deficient osteoporosis symptoms induced by OVX compared with those treated with 200 mg/kg of EAP or DM. Therefore, EAP : DM 3:1 (g/g) may be a promising new potent protective agent for relieving osteoporosis in menopausal women.

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“…The dose of losartan was selected based on our previous pharmacological study in diabetic mice [18] and pharmacokinetic difference between rats and mice [20]. The chemical synthesis and characteristics of APX-115 are as previously described [21]. Control rats were injected with an equivalent volume of 0.5% methylcellulose.…”

Section: Animal Experimentsmentioning

confidence: 99%

A pan-NADPH Oxidase Inhibitor Ameliorates Kidney Injury in Type 1 Diabetic Rats

et al. 2018

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Background: NADPH oxidases (Nox) is a major enzyme system contributing to oxidative stress, which plays an important role in the pathogenesis of diabetic kidney disease (DKD). We have shown an elevation of renal Nox1, Nox2, and Nox4 in diabetic mice. APX-115, a pan-Nox inhibitor, attenuated the progression of DKD in mice. As the standard diabetic mice cannot fully mimic human DKD, the present study was aimed to show the dose-dependent effect and to provide a confirmatory evidence of APX-115 in attenuating DKD in diabetic rats. Method: Type 1 diabetes was induced by a single 60 mg/kg intraperitoneal injection of streptozotocin in Sprague-Dawley rats. 0.5, 5, or 30 mg APX-115/kg/day or losartan 1 mg/kg/day were administered orally to diabetic rats for 8 weeks. Results: APX-115 treatment showed an improvement in kidney function and tubular and podocyte injury, as well as attenuation of inflammation, fibrosis, and oxidative stress as much as losartan, a comparative drug and mainstay treatment in DKD. Therapeutic effect of APX-115 was exhibited in a dose-dependent manner; a dose of 30 mg/kg displayed a superior efficacy. Conclusion: This finding verified the pre-clinical data of APX-115 in protecting against DKD, which is important to bring APX-115 toward the next stage of drug development.

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A novel pyrazole derivative protects from ovariectomy-induced osteoporosis through the inhibition of NADPH oxidase

Cited by 43 publications

References 48 publications

Dual oxidase: a novel therapeutic target in allergic disease

Dual oxidase: a novel therapeutic target in allergic disease

Antiosteoporotic effects of 3:1 (g/g) mixed formulation of exopolymers purified fromAureobasidium pullulansSM-2001 andDendropanax morbiferaleaf extracts in ovariectomized rats

A pan-NADPH Oxidase Inhibitor Ameliorates Kidney Injury in Type 1 Diabetic Rats

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