Arthritis Cure

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JMIR Res Protoc. 2017 Jul; 6(7): e132.
Published online 2017 Jul 11. doi: 10.2196/resprot.7636
PMCID: for 1 last update 2020/07/06 PMC5527251PMC5527251
PMID: 28698171
Monitoring Editor: Gunther Eysenbach
Reviewed by Mei Liu and Patricia Kurizky
Shiqiang Deng, BMed, PhD,#1 Jianwen Cheng, BMed, PhD,#1,2,3 Jinmin Zhao, BMed, PhD,1,2,3 Felix Yao, MBBS, PhD,1 and Jiake Xu, MBBS, PhD1,2,3
1 Molecular Laboratory, School of Biomedical Sciences, The University of Western Australia, Perth, Australia
2 Research Centre for Regenerative Medicine and Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning, China
3 Department of Orthopaedic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
Jiake Xu, Molecular Laboratory, School of Biomedical Sciences, The University of Western Australia, Room 1.4H, M Block, QEII Medical Centre, Nedlands, 35 Stirling Highway, Perth, WA 6009, Australia, Phone: 61 (08) 6457 2739, Fax: 61 (08) 6457 2891, Email: [email protected].

Arthritis Curehow to Arthritis Cure for Shiqiang Deng

1 Molecular Laboratory, School of Biomedical Sciences, The University of Western Australia, Perth, Australia

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Jianwen Cheng

1 Molecular Laboratory, School of Biomedical Sciences, The University of Western Australia, Perth, Australia

2 Research Centre for Regenerative Medicine and Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning, China

3 Department of Orthopaedic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China

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Jinmin Zhao

1 Molecular Laboratory, School of Biomedical Sciences, The University of Western Australia, Perth, Australia

2 Research Centre for Regenerative Medicine and Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning, China

3 Department of Orthopaedic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China

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Felix Yao

1 Molecular Laboratory, School of Biomedical Sciences, The University of Western Australia, Perth, Australia

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Jiake Xu

Arthritis Curehow to Arthritis Cure for 1 Molecular Laboratory, School of Biomedical Sciences, The University of Western Australia, Perth, Australia

2 Research Centre for Regenerative Medicine and Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning, China

Arthritis Curehow to Arthritis Cure for 3 Department of Orthopaedic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China

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Corresponding author.
#Contributed equally.
Corresponding Author: Jiake Xu [email protected]
Received 2017 Mar 3; Revisions requested 2017 Apr 19; Revised 2017 Apr 30; Accepted 2017 Apr 30.
Copyright ©Shiqiang Deng, Jianwen Cheng, Jinmin Zhao, Felix Yao, Jiake Xu. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 11.07.2017.
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Abstract

Background

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis affecting approximately 2% to 3% of the population globally, and is characterized by both peripheral articular manifestations the 1 last update 2020/07/06 and axial skeletal involvement. Conventional therapies for PsA have not been fully satisfactory, though natural products (NPs) have been shown to be highly effective and represent important treatment options for psoriasis. PsA is a multigenic autoimmune disease with both environmental and genetic factors contributing to its pathogenesis. Accordingly, it is likely that the use of natural compounds with a multi-targeted approach will enable us to develop better therapies for PsA and related disorders.Psoriatic arthritis (PsA) is a chronic inflammatory arthritis affecting approximately 2% to 3% of the population globally, and is characterized by both peripheral articular manifestations and axial skeletal involvement. Conventional therapies for PsA have not been fully satisfactory, though natural products (NPs) have been shown to be highly effective and represent important treatment options for psoriasis. PsA is a multigenic autoimmune disease with both environmental and genetic factors contributing to its pathogenesis. Accordingly, it is likely that the use of natural compounds with a multi-targeted approach will enable us to develop better therapies for PsA and related disorders.

Arthritis Curehow to Arthritis Cure for Objective

PsA, either on joint damage or on bone erosion, has been shown to respond to anti-psoriatic pharmacotherapy (APP), APP-like NPs, and their natural compounds. This study aims to uncover specific natural compounds for improved PsA remedies. Specifically, by targeting bone erosion caused by increased osteoclastic bone resorption, we aim to predict the key signaling pathways affected by natural compounds. Further, the study will explore their anti-arthritis effects using an in silico, in vitro, and in vivo approach. Following the signaling pathway prediction, a preclinical efficacy study on animal models will be undertaken. Collectively, this work will discover lead compounds with improved therapeutic effects on PsA.

Methods

We hypothesize that 9 potential APP-like NPs will have therapeutic effects on arthritis via the modulation of osteoclast bone resorption and signaling pathways. For in silico identification, the Latin name of each NP will be identified using the Encyclopedia of Traditional Chinese Medicine (Encyclopedia of TCM). The biological targets of NPs will be predicted or screened using the Herbal Ingredients'' Targets database (HIT, China), DrugBank (Canada), and Protein ANnotation THrough Evolutionary Relationship (PANTHER, USA) will be applied in the in silico identification procedure (Figure 2). All are available in English [13].

Target-directed in silico identification.

The Encyclopedia of TCM can successively locate the relevant Latin names and the contained chemical compounds with the individual and unique plant code of each promising NP species. Subsequently, HIT can access the relevant biological targets with their individual name identification (ID) and types in an Excel spreadsheet. With a dedicated search term(s) (eg, psoriatic arthritis), DrugBank can induce the reference targets (together with the previous cellular biomarkers) to be further filtered by the above biological targets.

For each identified natural compound, their known protein targets will be entered into the keyword search using the “homo sapiens” setting. For each target, the identified Gene ID will be saved a Notepad (txt) file. One Notepad file is created for each species. This file contains all the Gene IDs for all the known therapeutic targets of all the compounds that are known to be active in the species. Each file will be sequentially uploaded into the Gene List Analysis field in PANTHER. This will report the following 5 aspects in Excel for the particular species: (1) molecular function(s), (2) biological processes, (3) cellular component(s), (4) protein class, and (5) pathway(s). The Excel files will be sorted to identify the most commonly identified pathway for each species. For each of the most commonly identified pathways, all the identified proteins, excluding upstream and downstream proteins, will be entered into Excel. Since the nomenclatures used by PANTHER and by HIT differ, cross-referencing will be undertaken regarding the short and long names used for the proteins in both databases.

In Vitro Sample Preparation Using the Identified Compound Sources for Drug Development

This stage includes the extraction, fractionation, isolation, purification, and the formation of a series of bioassays for the identified compounds. The extraction method is specific to the nature of the source material and target compound. It typically involves a process of drying, grinding, homogenization, or maceration of the plant. For a pure single compound, the crude extract initially needs to be fractionated into various discrete fractions containing compounds in similar polarities or molecular sizes. NP isolation is also subject to the nature of the target compound(s) presented in the crude extract or fraction. Part sample compounds may be purchased from the market or supported by the relevant group. Qualitative chemical tests, preliminary thin-layer chromatography (TLC), and/or high performance liquid chromatography-photodiode array hyphenated technique (HPLC-PDA) can be used to obtain spectral profiles from molecular mixtures or chromatographically separated samples [23]. For isolation and purification, an efficient on-line purity monitoring strategy based on on-line coupling of high-speed counter-current chromatography (HSCCC) with high performance liquid chromatography-diode array detection (HPLC-DAD) will be performed. In summary, this part of project consists of the preparation of a crude extract, preparation of a 2-phase solvent system, HSCCC separation, and HPLC-DAD purity analysis of counter-current chromatography (CCC) peak fractions [24].

In Vitro Investigation of Drug Candidates

Arthritis Curehow to Arthritis Cure for We will perform in vitro studies on compounds prepared in stage 2 to investigate their effects on osteoclastogenesis and bone resorption (Figure 3). For osteoclast formation, 1×104 bone marrow macrophage (BMM) cells per well will be isolated from the femur and tibiae of 6-week-old C57BL/6 mice and will be cultured in media containing macrophage-colony stimulating factor (M-CSF) (30 ng/mL) and RANKL (100 ng/mL). After a cell viability evaluation, further investigations will be carried out using resorption pit assays, quantitative reverse transcription polymerase chain reactions (RT-PCR), western blot analysis, luciferase reporter gene activity assays, and osteoclastogenesis assays. For statistical analysis, the student Newmane-Keuls test will be applied with mean (SD) for data expression and P less than .05 for statistical significance [25].

Natural compound inhibitors of the RANKL pathway.

Preclinical Efficacy Evaluation Using Animal Models

The collagen-induced arthritis (CIA) model is regarded as the best-studied animal model for PsA [26] and will be used in this study to determine the anti-arthritic effects of NPs (as utilized in previously published work by this laboratory) [19,21].

A total of 30, 9-week old female Dark Agouti (DA) rats will be used with 10 assigned to the non-arthritic control group (C). The remaining 20 rate will be induced following the CIA protocol and will be randomly assigned to either the treatment group (A) or the placebo group (B) when PsA symptoms first appear. Groups A and B will be subject to a subcutaneous injection of the purified natural compound (1 mg/kg in 0.9% saline) or 0.9% saline control every second day from the 1 last update 2020/07/06 onset of symptoms (clinical score 2 or greater), until tissue collection at day 14. Natural compounds differ in their bioavailability and solubility in water. As such, the proposed dosage and/or administration of may be further adjusted if required. All rats will be raised with water, 0.9% sodium chloride (NaCl) and standard rodent food ad libitum in a 22℃ and 12h illuminated daily environment. Main outcome measures include a daily macroscopic scoring system and digital calipers to measure dorsal to plantar thickness (3 times per week) of each paw. Groups will be compared with (1) serological tests including serum albumin, alanine transaminase (ALT), aspartate transaminase (AST), and bilirubin using a clinical biochemical analyzer; (2) micro-computed tomography (micro-CT) image analysis of hind paws and femora and contact radiographs for both hind feet; and (3) histopathological assessment using tartrate-resistant acid phosphatase (TRAP) staining [27] of serial 5 μm sagittal sections through the digits. The latter requires at least 2 digits randomly taken from each rat. Each digit will have distal interphalangeal (DIP), proximal interphalangeal (PIP), and metatarsophalangeal (MTP) joints intact for scoring by 2 independent observers. Analysis of variance (ANOVA) and Fishers'' Targets databaseHPLChigh-performance liquid chromatographyHSCCChigh-speed counter-current chromatographyIDidentificationILinterleukinNPMnatural product medicationRANKLreceptor activator of nuclear factor-κB ligandTRAPtartrate-resistant acid phosphataseA total of 30, 9-week old female Dark Agouti (DA) rats will be used with 10 assigned to the non-arthritic control group (C). The remaining 20 rate will be induced following the CIA protocol and will be randomly assigned to either the treatment group (A) or the placebo group (B) when PsA symptoms first appear. Groups A and B will be subject to a subcutaneous injection of the purified natural compound (1 mg/kg in 0.9% saline) or 0.9% saline control every second day from onset of symptoms (clinical score 2 or greater), until tissue collection at day 14. Natural compounds differ in their bioavailability and solubility in water. As such, the proposed dosage and/or administration of may be further adjusted if required. All rats will be raised with water, 0.9% sodium chloride (NaCl) and standard rodent food ad libitum in a 22℃ and 12h illuminated daily environment. Main outcome measures include a daily macroscopic scoring system and digital calipers to measure dorsal to plantar thickness (3 times per week) of each paw. Groups will be compared with (1) serological tests including serum albumin, alanine transaminase (ALT), aspartate transaminase (AST), and bilirubin using a clinical biochemical analyzer; (2) micro-computed tomography (micro-CT) image analysis of hind paws and femora and contact radiographs for both hind feet; and (3) histopathological assessment using tartrate-resistant acid phosphatase (TRAP) staining [27] of serial 5 μm sagittal sections through the digits. The latter requires at least 2 digits randomly taken from each rat. Each digit will have distal interphalangeal (DIP), proximal interphalangeal (PIP), and metatarsophalangeal (MTP) joints intact for scoring by 2 independent observers. Analysis of variance (ANOVA) and Fishers'' Targets databaseHPLChigh-performance liquid chromatographyHSCCChigh-speed counter-current chromatographyIDidentificationILinterleukinNPMnatural product medicationRANKLreceptor activator of nuclear factor-κB ligandTRAPtartrate-resistant acid phosphatase

Footnotes

Contributed by

Authors' Contributions: All authors contributed to the design of the study and have read, commented on, revised, and approved the manuscript. Shiqiang Deng and Jianwen Cheng contributed equally to this study.

Conflicts of Interest: None declared.

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