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LOX inhibitor HOEC interfered arachidonic acid metabolic flux in collagen-induced arthritis rats.

ABSTRACT: Arachidonic acid (AA) metabolic network generates a variety of products that mediate or modulate inflammatory reactions. (+)-2-(1-hydroxyl-4-oxocyclohexyl) ethyl caffeate (HOEC), isolated from Incarvillea mairei var. granditlora (Wehrhahn) Grierson, was found as an inhibitor of 5-LOX and 15-LOX in vitro. When evaluated in collagen-induced arthritis (CIA) rats, however, lowdose of HOEC (1 mg/kg) showed better efficacy than that of high dose (10 mg/kg). To study how HOEC interfered the AA metabolic pathway, in this study, we dynamically observed the changes of plasma AA metabolites (LTB4, LTC4, 15-HETE, PGE2, TXB2 and PGD2) in the CIA rats treated with different doses of HOEC by using enzyme-linked immunosorbent assay (ELISA). The results showed that eicosanoids were elevated synchronously at three time points in different treated rats. The incidence of arthritis had a higher correlation with LOX pathway while the COX pathway might be more important in the severity of arthritis. HOEC in all doses could inhibit LOX pathway in the beginning of arthritis while highdose of HOEC could induce the increase of COX metabolites in the later stage of disease. These dynamic changes of eicosanoids, depending on the regulation of metabolic flux, can be interfered by HOEC and thus affect the output of efficacy.

SUBMITTER: Yang W

PROVIDER: S-EPMC6129533 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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LOX inhibitor HOEC interfered arachidonic acid metabolic flux in collagen-induced arthritis rats.

Yang Wen W Wang Xia X Xu Liuxin L Li Honglin H Wang Rui R

American journal of translational research 20180815 8

Arachidonic acid (AA) metabolic network generates a variety of products that mediate or modulate inflammatory reactions. (+)-2-(1-hydroxyl-4-oxocyclohexyl) ethyl caffeate (HOEC), isolated from <i>Incarvillea mairei var. granditlora</i> (Wehrhahn) Grierson, was found as an inhibitor of 5-LOX and 15-LOX in vitro. When evaluated in collagen-induced arthritis (CIA) rats, however, lowdose of HOEC (1 mg/kg) showed better efficacy than that of high dose (10 mg/kg). To study how HOEC interfered the AA m ...[more]

PMID: 30210691

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Project description:ObjectivesCathepsin K is expressed by osteoclasts and synovial fibroblasts and degrades key components of bone and cartilage. Inhibition of cathepsin K protease activity may be beneficial for the prevention of bone erosion and cartilage degradation in rheumatoid arthritis (RA). The collagen-induced arthritis (CIA) rat model is well established for studying the pathology and treatment of RA. We investigated the effect of ONO-KK1-300-01, a cathepsin K inhibitor (CKI), on arthritis and bone mineral density (BMD) in rats with CIA.MethodsSeven-month-old female Sprague Dawley rats were divided into 5 groups: rats without CIA (CNT); CIA rats that underwent ovariectomy (OVX) and were treated with CKI; CIA rats that underwent OVX and were treated with vehicle (Veh); CIA rats that underwent sham surgery and were treated with CKI; and CIA rats that underwent sham surgery and were treated with Veh. CKI was orally administered at a dose of 15 mg/kg, thus initiating collagen sensitization, until death at 4 weeks. We evaluated hind paw thickness and the arthritis score every week until death. Radiographs of the resected left foot were obtained with a soft X-ray apparatus. Destruction of bone and cartilage was classified and scored as previously described by Engelhardt et al. BMD was measured by bone densitometry at the halfway point between the distal metaphysis and the diaphysis of the resected right femur. We also performed histomorphometry of the proximal left tibia, histological evaluation of arthritis, and a bone strength test.ResultsCKI administration significantly reduced hind paw thickness and the arthritis score, and prevented a decrease in BMD. The radiographic score was significantly lower in the CKI group than in the Veh group. In the histomorphometric analysis, bone-resorption parameters were significantly lower in the CKI groups than in the Veh groups. CKI significantly inhibited synovial proliferation in the CIA rats. In the bone strength test, the ultimate stress was significantly higher in the CKI groups than in the Veh groups.ConclusionOur findings indicate that cathepsin K inhibitors may inhibit systemic and local bone loss, ameliorate arthritis, and attenuate the decrease of bone strength in an animal model of arthritis.

Project description:PurposeJintiange capsule (JTG), an approved drug developed as a substitute for tiger bone (TB), has been clinically applied for osteoporosis therapy since 2003. The drug is composed of bionic TB powder, in which peptides and proteins are primarily enriched from other bone extracts. However, as a precious material of traditional Chinese medicine (TCM), TB has been mainly understood and used in TCM to relieve osteoporosis, rheumatoid arthritis and bone injury. Inspired by those, the purpose of this study was to investigate whether JTG also had an effect on relieving rheumatoid arthritis in collagen-induced arthritic (CIA) rats and explore potential mechanism from the perspective of serum metabolic profile changes.MethodsJTG was analyzed using Nano LC-MS/MS and orally administered in CIA rats for 6 weeks. After administration, intervention effects of JTG on synovial inflammation, bone micro-architecture and bone metabolism were studied, and the impact of JTG on serum metabolic profiles in CIA rats was investigated by metabolomics.ResultsNine bioactive peptides were identified in JTG. In animal treatments, JTG alleviated paw swelling (P < 0.01), arthritic severity (P < 0.01) and synovial tissue proliferation, as well as inflammatory cell infiltration of ankle joint, decreased bone loss, improved microstructure of bone in CIA rats by regulating bone absorption and formation, specifically increasing bone mineral density (BMD) (P < 0.05), bone volume fraction (BVF) (P < 0.05), trabecular number (Tb.N) (P < 0.05) and decreasing trabecular separation (Tb.Sp) (P < 0.05). Besides, serum IL-6 was down-regulated remarkably in CIA rats (P < 0.05). Furthermore, metabolomics analysis revealed that 32 metabolites were regulated significantly (P < 0.05) by comparison between CIA model and JTG in 360 mg/kg dose. The pathway analysis implied that JTG was involved in regulation of biosynthesis of phenylalanine.ConclusionJTG alleviates rheumatoid arthritis and reverses changes in serum metabolic profile in CIA rats.

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LOX inhibitor HOEC interfered arachidonic acid metabolic flux in collagen-induced arthritis rats.

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LOX inhibitor HOEC interfered arachidonic acid metabolic flux in collagen-induced arthritis rats.

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