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Anti-arthritic and cartilage damage prevention via regulation of Nrf2/HO-1 signaling by glabridin on osteoarthritis
⁎Corresponding authors. qinjian@njmu.edu.cn (Jian Qin)
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Received: ,
Accepted: ,
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.
Abstract
Osteoarthritis is a common degenerative disease linked with inflammatory disorders and oxidative stress. Glabridin is an isoflavonoid and major active constituent of licorice. This study aims to investigate the anti-arthritic effects of glabridin on nuclear factor erythroid 2 – related factor 2 (Nrf2) signaling pathway, inflammatory responses, and cartilage degeneration in in-vitro and in-vivo models. Studies on IL-1β-induced chondrocyte model was performed to evaluate matrix metalloproteinase (MMP), Nrf2 signaling pathway. Glabridin was orally administered in monosodium-iodoacetate (MIA)-induced osteoarthritic (OA) rats for in-vivo evaluation. Pain and swelling of limbs were observed, oxidative stress markers and inflammatory cytokines were measured. Histomorphological changes in the joint cartilage were analyzed. Glabridin significantly reduced the arthritic score and paw swelling along with improved body weight, and organ index of rats. Histopathological score showed significant prevention of joint cartilage degeneration by glabridin. Expressions of TNF-α, IL-6, IL-10, and IL-1β were attenuated by glabridin (p < 0.05) in MIA-induced rats. Protein expressions of iNOS, COX-2, ADAMTS5, MMP-3, and MMP-13 were suppressed (p < 0.05) whereas the Nrf2/HO-1 signaling was activated by glabridin (p < 0.05) in osteoarthritic chondrocytes. Therefore, anti-arthritic and chondroprotective activity of glabridin is suggested by the inhibition of MMP expression and regulation of Nrf2/HO-1 signaling.
Keywords
Glabridin
MMP
Inflammatory cytokines
Nrf2/HO-1
Monosodium-iodoacetate
1 Introduction
Osteoarthritis is often described with progressive loss of articular cartilage, deterioration of subchondral bone, resulting in chronic pain and the most susceptible form of arthritis among elders (Blasioli and Kaplan, 2014). Although this degenerative disease was once acknowledged for “wear and tear” concept of the bone cartilages, current investigations lead to a new understanding on inflammatory disorders linked with reactive oxygen species (ROS) causing cartilage degeneration (Wojdasiewicz et al., 2014; Huang et al., 2018). Pro-inflammatory cytokines, chemokines, and ROS that are produced in the subchondral bone, synovium, and cartilage during oxidative stress eventually initiates degeneration of the joint tissues, releasing matrix metalloproteinases (MMPs) thus causing degeneration of cartilage (Park et al., 2016). The transcription factor, nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and its downstream protein hemeoxygenase-1 (HO-1) are specifically studied for the role against the development of osteoarthritis and several other oxidative stress related diseases in different organs. The antioxidant response elements (ARE) are regulated by gene expression of Nrf2 and is primarily responsible to exert antioxidant defense. The regulation of these proteins have been proven to exert protection against osteoarthritis in numerous animal models (Cai et al., 2019a). Current treatment methods for osteoarthritis include non-steroidal anti-inflammatory drugs and temporary pain relief drugs. These drugs have drawbacks in the treatment of osteoarthritis due to side-effects causing gastritis, peptic ulcers, and other gastrointestinal complications in patients (Wu et al., 2018; Poulet and Staines, 2016). Considering the severity of functional disability caused by osteoarthritis, therapeutic drugs with significance to the prevention of pathogenesis of osteoarthritis are required to overcome the problem. Antioxidants especially flavonoids are widely reported with anti-inflammatory and ROS scavenging functions in a range of diseases (Jeong et al., 2015; Jain et al., 2015).
Licorice originates from the dried roots of Glycyrrhiza species in the form of crude extracts, known to treat various ailments in Chinese traditional medical practice. Glabridin (Fig. 1) is an isoflavonoid found as the main active constituent of licorice (Yokota et al., 1998; Simmler et al., 2013). It is noteworthy that glabridin possesses many pharmacological properties including anti-inflammatory (Parlar et al., 2020), anti-proliferative effect on breast cancer cells (Tamir et al., 2000), alters cardiotoxicity (Huang et al., 2019), hepatoprotective (Komolkriengkrai et al., 2019; Ma et al., 2021), anti-melanogenesis (Yokota et al., 1998; Chen et al., 2016), and anti-obesity (Ahn et al., 2013). Licorice extracts are reported with anti-arthritic and anti-inflammatory effects in collagen-induced rheumatoid arthritis in mice (Kim et al., 2010). According to a review by Huang et al. (2016), the active constituents of licorice, mainly glycyrrhizin and glycyrrhetinic acid, have the potential to treat rheumatoid arthritis as well reduce the adverse effects caused by NSAIDs by suppressing COX-2/TxA2 pathway. This is mainly due to the anti-inflammatory potential of the active constituents. Being the active constituent of licorice, the anti-arthritic effect of glabridin has not been reported till date, hence this report is the first to describe the anti-arthritic mechanism of glabridin in IL-1β-induced chondrocytes and monosodium-iodoacetate (MIA) induced osteoarthritis in rat models. Considering the role of inflammatory reaction and oxidative stress in the progression of osteoarthritis, the antioxidant and anti-inflammatory properties of glabridin is likely to prevent the degenerative disease in rat model.
2 Materials and methods
2.1 Chondrocyte cell culture
Primary rat chondrocytes were isolated based on the methods described by Zhang et al. (2018). Briefly, primary chondrocytes were excised from knee articular cartilage of Sprague-Dawley male rats under deep ether anesthesia, subsequently the animals were euthanized with excess anesthesia. The excised cartilage was sliced, washed in phosphate buffered saline (PBS), digested for 20 min with trypsin-EDTA (0.25%) and collagenase type II (0.02%) (Sigma, St. Louis, USA) for 3 h at 37 °C. The digested primary chondrocytes were cultured in DMEM supplemented with 10% fetal bovine serum, 1% penicillin/streptomycin at 37 °C in a 5% CO2 incubator.
2.2 Chondrocyte treatment with glabridin and cell viability
Chondrocytes were seeded in a 96-well microtiter plate (2 × 105 cells/mL) and allowed for adhesion for 24 h following the method of Huang et al. (2018), using cell counting kit-8 (CCK-8) (Beyotime, Nanjing, China). Various concentrations (0, 10, 20, 40, 80, 100 µM) of glabridin (Sigma, St. Louis, USA) were applied on the chondrocytes and incubated for 72 h for determination of cytotoxicity. On a separate microtiter plate, glabridin (10, 30, 50 µM) was incubated with chondrocytes (2 × 105 cells/mL), with and without IL-1β (10 ng/mL) for 24 h for experimental verification and glabridin dose selection. Cell viability was observed using CCK-8 assay as described by manufacturer.
2.3 Western blot for protein expressions in chondrocytes
Protein expressions in the experimental chondrocytes were performed as described previously (Cai et al., 2019a). Primary chondrocytes were incubated with glabridin at 10 and 30 µM and induced with or without IL-1β (10 ng/mL) for 24 h. Proteins from cell lysate were blotted with anti-MMP3 (cat no. BS90872; 1:2000), anti-MMP13 (cat no. BS90868; 1:2000), anti-ADAMTS5 (cat no. BS74041; 1:2000), anti-Caspase 3 (cat no. BS61583; 1:1000), anti-Caspase 9 (cat no. BS6444; 1:1000), anti-iNOS (cat no. BS90715; 1:1000), anti-COX-2 (cat no. BS1076; 1:1000), anti-Bcl-2 (cat no. BS70205; 1:1000), anti-Nrf2 (cat no. BS1258; 1:2000), anti-HO-1 (cat no. BS6626; 1:2000) (Bioworld Technologies, Nanjing, China), and anti-GAPDH (cat no. BS60630; 1:1000) (Cell Signaling Technologies, Beverly, USA) antibodies to detect the changes caused by glabridin in apoptosis, inflammatory, and antioxidant defense signaling pathways. The immunoblots were developed using enhanced chemiluminescence (ECL) kit (Millipore, Bedford, USA) following the manufacturer’s description. Bio-Rad Image Lab System version 6.0 (Bio-Rad Lab, CA, USA) was used to quantify and analyze the relative expressions of protein bands.
2.4 Monosodium-iodoacetate (MIA)-induced osteoarthritis in rats
Male Sprague-Dawley rats (8 weeks old) weighing 180–210 g were caged (4 rats in a cage; 2 cages per group) in standard plastic cages under 12:12 day/dark cycle, at controlled temperature (24 ± 2 °C), and access to food and water ad libitum. The animal protocols and ethics were monitored and approved by the ethical board of Sir Run Run Hospital, Nanjing Medical University (2020-SR-S012). The rats were acclimatized for a week prior to experiment that was performed for 25 days. Animals were divided into 4 groups with 8 rats in each group; Group I as the normal control; Group II as the osteoarthritis (OA) model; Group III experimental orally administered once a day with glabridin (30 mg/kg in 0.5% Tween 80 aqueous solution) using gavage; Group IV as positive control orally treated once a day with indomethacin (3 mg/kg) using gavage. The dosage of glabridin was selected based on our preliminary test results, referring to the in-vivo study on cardioprotective effect of glabridin (Huang et al., 2019). Animals in all four groups were anesthetized with isoflurane (2.5%). Animals in Group II, III, and IV received injection of monosodium-iodoacetate (MIA) (Sigma, St. Louis, USA) in 50 µL saline through the patellar ligament into the intra-articular space of right knee, using a 26.5-G needle, whereas Group I received equal volume of saline injection. Animals were carefully inspected every day by personnel blinded of the experimental groups, to measure the paw volume, and inspect other physical and behavioral changes. Pain behavioral changes were monitored as described previously (Cai et al., 2019b), where observations or signs of physical and behavioral changes were considered. All rats were sacrificed through cervical dislocation under excess anesthesia (ether inhalation) on the next day after final dose administration, the articular cartilage from knee joints were excised. Thymus and spleen of the rats were also excised to measure the organ index based on the percentage calculation of wet organ weight (g) over final body weight (g) ration.
2.5 Serum hematology and oxidative stress
Hematological parameters; white blood cell (WBC), red blood cell (RBC), hemoglobin (Hb) count, and serum levels of alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were determined using automated hematology analyzer (HB7501 Hematology analyzer, Guangzhou, China) and serum liver marker colorimetric assay kits (Sigma, St. Louis, USA) following standard methods provided by manufacturer to determine the effect of glabridin on changes in liver, spleen and thymus organs. Serum reduced glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) levels were measured using colorimetric diagnostic kits (Nanjing Jiancheng Bioengineering Institute, Jiangsu, China) to determine the effect of glabridin on activities of antioxidant enzymes.
2.6 Enzyme-linked immunosorbent assay (ELISA) for inflammatory cytokine detection
Serum levels of inflammatory cytokines IL-1β, IL-6, IL-10, and TNF-α were performed using commercial ELISA assay diagnostic kits (Biological Technology Company Ltd., Shanghai, China) following the manufacturer’s protocols, to determine the effect of glabridin on the changes in cytokine levels. The measurements were standardized for each sample in all groups.
2.7 Histopathology and scoring
Articular cartilage of rats fixed in 10% buffered formalin were sliced and decalcified in 10% formic acid. The processed tissues were fixed in paraffin and trimmed (5 µm) for hematoxylin and eosin (H & E) staining. The stained sections were studied under light microscope at 100× magnification for histological alterations. The histopathological injuries were scored using Mankin’s scoring system with some modifications as explained by Jeong et al. (2015). The scores ranged from 0 to 6 for articular injuries with 0 (no visible injury or normal) to 6 (heavily disorganized structure, clusters, calcified cartilage layer), whereas 0–3 for cellular irregularities with 0 (normal) to 3 (hypocellularity). Scoring was given for the articular injuries and cellular irregularities upon histopathological observations by a blinded observer unaware of the experimental groups.
2.8 Statistical analysis
All results were given as mean ± S.D. The statistical significance for each experiment was performed using one-way ANOVA and Tukey’s post-hoc analysis, (SPSS Inc., US). Values of p < 0.05 were regarded significant.
3 Results
3.1 Effects of glabridin on cell viability of rat primary chondrocytes
Glabridin was treated at different concentrations (10, 20, 40, 80, 100 µM) on rat primary chondrocytes for 72 h to determine its cytotoxicity. Glabridin did not exert cytotoxicity to the cells at 10 up to 100 µM, compared to the untreated control chondrocytes. Cell viability of chondrocytes induced with IL-1β were reduced (p < 0.01) as compared to untreated control. The IL-1β-induced chondrocytes were treated at lower doses of glabridin (10, 30, 50 µM) showed dose-dependent increase (p < 0.01) in cell viability compared to IL-1β-induced model group. Cell viability results are shown in Fig. 2. The concentrations of 10 and 30 µM glabridin were selected for further analysis.
3.2 Effects of glabridin on ADAMTS5, MMP-3, MMP-13, iNOS, COX-2 protein expressions
The protein expressions of extracellular proteolytic enzymes MMP-3, MMP-13, a disintegrin-like and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) were identified to be elevated in IL-1β-treated model chondrocytes. Glabridin dose-dependently inhibited the protein expressions of ADAMTS5, MMP-3, MMP-13 (p < 0.01) compared to the model group. The effects of glabridin on inflammatory response signaling pathway of iNOS/COX-2 were evaluated and found that protein expressions of iNOS and COX-2 were decreased in glabridin treated chondrocytes in a dose-dependent effect (p < 0.01) as compared to the IL-1β-induced model chondrocytes. The protein expression results are given in Fig. 3.
3.3 Glabridin suppressed apoptosis markers in IL-1β-induced chondrocytes
The effect of glabridin on cellular apoptosis inducing markers caspase-3, caspase-9, and B-cell lymphoma-2 (Bcl-2) in chondrocytes were evaluated and found that protein expressions of Cas-3 and 9 were significantly (p < 0.01) reduced in glabridin treated groups. Moreover, the expression of Bcl-2 protein was increased (p < 0.01) in glabridin treated chondrocytes compared to IL-1β triggered model chondrocytes (Fig. 4).
3.4 Glabridin elevated Nrf2 and HO-1 protein expressions in chondrocytes
The effect of glabridin on Nrf2/HO-1 signaling pathway was evaluated in IL-1β-triggered chondrocytes. Western blot results showed elevated protein expressions of Nrf2 and HO-1 (p < 0.01) in glabridin treated chondrocytes compared to the IL-1β alone treated chondrocytes (Fig. 5). The protein expressions of Nrf2 and HO-1 were suppressed (p < 0.01) in IL-1β alone treated chondrocytes.
3.5 Glabridin attenuated body weight of rats, paw volume, organ index and arthritic scores
Final body weight of rats in glabridin treated group was increased (p < 0.05) as compared to the osteoarthritic model group II similar to the indomethacin treated positive control group (Fig. 6). Spleen and thymus index of osteoarthritic model group rats were increased in comparison with the normal control rats (Fig. 6). Glabridin treated rats significantly prevented the elevation of spleen and thymus index (p < 0.05) (Fig. 6). The paw volume measured using a Plethysmometer 37140 (UgoBasile, Italy), showed significant increase in size for all experimental rats induced with MIA for the first 10 days except for normal rats, followed by gradual decrease in glabridin and indomethacin treated groups for the remaining 15 days (Fig. 6). Arthritic scores were given based on observations of swelling and redness around the knee joints. Osteoarthritic model rats showed increased scores throughout the experimental period of 25 days whereas the glabridin and indomethacin treated rats showed increasing arthritic scores for the initial 15 days, followed by gradual decrease for the last 10 days (Fig. 6).
3.6 Glabridin mitigated hematological changes and liver marker enzymes in MIA-induced rats
Liver marker enzymes (AST, ALT, and ALP) were significantly elevated (p < 0.05) in MIA-induced osteoarthritic group as compared to the normal group (Fig. 7). The indicators of liver damage (AST, ALT, ALP) were remarkably reduced in glabridin treated group (p < 0.05) compared to model group. Indomethacin treated group also showed reduced levels (p < 0.05) of the enzymes in comparison with the model group. Hematological changes in levels of red blood cells, white blood cells and hemoglobin due to MIA-induced osteoarthritis were reversed by glabridin and indomethacin treatment (p < 0.05) in their respective groups (Fig. 7).
3.7 Glabridin prevented oxidative stress in MIA-induced rats
Oxidative stress markers (GSH, SOD, CAT, and MDA) were measured in the normal and MIA-induced rats. Levels of GSH and activities of antioxidant enzymes SOD and CAT were increased in glabridin treated rats (p < 0.05) compared to the MIA-induced model rats (Fig. 8). The expression of lipid peroxidation (MDA level) was significantly reduced (p < 0.05) in glabridin treated rats in contrast to the model group rats. Indomethacin treated rats also exhibited similar findings.
3.8 Glabridin protected articular cartilage from damage caused by MIA
Histological changes in knee articular cartilage of MIA-induced rats were clearly observed in the model group with erosion in articular cartilage, fibrillation, and features of inflammation as compared to the histology of normal control rats (Fig. 9). The effects of MIA of cartilage erosion and inflammation were reduced in glabridin and indomethacin treated rats. Total Mankin scores were given overall for the histological alterations and irregularities in all groups (Fig. 9). Model group II received the highest score, whereas glabridin and indomethacin treated groups received relatively lower scores.
3.9 Glabridin inhibited inflammatory reaction in MIA-induced rats
Inflammatory cytokines (IL-1β, IL-6, TNF-α, and IL-10) were measured using ELISA test to determine MIA-induced inflammation in rats. The levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) were significantly suppressed (p < 0.05) by glabridin and indomethacin compared to the MIA-triggered model group (Fig. 10). The level of anti-inflammatory cytokine IL-10 was reduced (p < 0.05) in MIA model rats compared to normal control rats. Glabridin treatment significantly elevated (p < 0.05) the level of IL-10 in rats, similar to indomethacin treated rats.
4 Discussion
Degradation of articular cartilage is an important event in the progression of osteoarthritis. Oxidative stress is one of the significant factors that causes joint cartilage damage. Under oxidative stress conditions, levels of antioxidants and activities of antioxidant enzymes drop drastically whereas lipid peroxidation occurs within the cells leading to degeneration of cellular membrane (Jeong et al., 2015). This process eventually triggers multiple cellular signaling events including inflammatory reactions and apoptosis. Glabridin treatment inhibited oxidative stress induced by MIA through prevention of lipid peroxidation, preservation of the antioxidant GSH and regulation of antioxidant enzymes SOD and CAT. Parlar et al. (2020) reported the anti-inflammatory properties of glabridin in carrageenan induced rats by inhibiting PGE2, suppressing TNF-α, reduced paw edema, and there were no signs of severe behavioral changes due to pain. Moreover, they also reported that the acute toxicity test results for glabridin at 400 mg/kg showed no signs of toxicity or mortality in the animals. Anti-inflammatory effects of antioxidant compounds on chemically-induced cartilage damage are supported by down-regulation of oxidative stress (Moon et al., 2012; Liu and Li, 2017). In this study, glabridin exhibited similar anti-inflammatory effects through prevention of pro-inflammatory cytokines IL-6, TNF-α, and IL-1β, elevation of the anti-inflammatory cytokine IL-10, and reduced paw volume. Pain behavioral changes were not shown by the animals treated with glabridin and indomethacin similar to the results obtained by Moon et al. (2014) and Wang et al. (2016). Arthritic patients have been reported with anemia conditions due to the denaturation of RBC and loss of hemoglobin due to diminished erythropoietin levels caused by bone marrow degradation (Qiao et al., 2018). The amount of WBC increases drastically during inflammatory conditions specifically due to elevation of pro-inflammatory cytokine IL-1β (Lima-Garcia et al., 2011) These observations were exhibited in MIA-induced model group rats, but glabridin treated rats exhibited the opposite where RBC, Hb, and WBC levels were preserved to almost normal. Spleen and thymus organs are involved in immune cell regulation and filtration of damaged or dead cells (Chen et al., 2018). Increase in the organ index of MIA treated model group rats can be explained by excessive functioning of the organs to regulate the immune cells during inflammation and the amount of dead or damaged cells that has to be filtered by the organs. The use of NSAIDs for treatment of osteoarthritis is mainly focused on reducing inflammation and related pain. Prolonged use of these drugs leads to unwanted effects like gastrointestinal toxicity (Lee et al., 2018). Serum AST, ALT and ALP levels are indicators of hepatic damage. MIA caused elevation in the levels of these markers in the model group rats but glabridin reversed the effects of MIA by reducing the levels of AST, ALT and ALP. Indomethacin did reduce the serum levels of the hepatic damage markers compared to the model group rats but was marginally higher that glabridin treated rats.
Catabolism of cartilage during an inflammation causes apoptosis in chondrocytes and further leads to pathogenesis of osteoarthritis (Lee et al., 2018). Apoptosis of chondrocytes during inflammation is large caused by pro-inflammatory cytokines (Zhu et al., 2018). Chondrocytes induced by IL-1β in the in-vitro evaluation showed increasing apoptosis effects through protein expressions of Bcl-2, caspase 3 and 9. Apparently, glabridin prevented apoptosis of IL-1β treated chondrocytes by inhibiting downregulation of Bcl-2 and upregulation of caspase 3 and 9. Prevention of cartilage degradation and inflammation is necessary to prevent apoptosis in chondrocytes. In fact, histological changes in the articular cartilage of MIA-induced rats showed signs of cartilage degeneration, whereas oral administration of glabridin reversed the effect of MIA by preserving the articular cartilage structure, similarly reported by Lee et al. (2013).
MMPs, particularly MMP-3 and 13 are excessively produced during progression of osteoarthritis as triggered by cartilage degeneration. These MMPs functions to degrade extracellular matrix components to create an environment for progression of osteoarthritis by increasing the inflammatory reactions (Lee et al., 2018). Protein expressions of MMP-3 and 9 were suppressed by glabridin in IL-1β treated chondrocytes, thus can be related to the inhibition of pro-inflammatory cytokines in the in-vivo model. ADAMTS4 and ADAMTS5 are extracellular proteolytic enzymes, aggrecanases, that have direct relation in pathogenesis of joint diseases. ADAMTS5 is specifically intense in the erosion of aggrecans during osteoarthritis (Ding et al., 2018). Glabridin significantly regulated the protein expression of ADAMTS5 in IL-1β triggered chondrocytes, exhibiting chondroprotective effects against osteoarthritis. COX-2 and iNOS are important regulators of inflammatory response. Inhibition of COX-2 is the common conduct of commercial anti-inflammatory drugs for osteoarthritis such as celecoxib (Nagy et al., 2017). The iNOS/COX-2 pathway triggered by IL-1β in chondrocytes was presumably inhibited by glabridin as demonstrated by the protein expressions in western blot results. From our previous reports, upregulation of Nrf2 and its downstream HO-1 is important in prevention of osteoarthritis (Cai et al, 2019a, 2019b). Similar studies were reported by other researchers that regulation of Nrf2/HO-1 pathway is crucial in the prevention of oxidative damage and inflammation during progression of osteoarthritis (Li et al., 2018; Chen et al., 2019). The western blot results of Nrf2 and HO-1 in IL-1β-induced rat primary chondrocytes in-vitro supported the findings of Li et al. (2018) and Chen et al. (2019), where glabridin significantly elevated the protein expressions of Nrf2/HO-1 in a dose-dependent effect. Glabridin significantly elevated the protein expression of Nrf2/HO-1 above the levels of protein expressed in normal chondrocytes, indicating the effectiveness of glabridin in triggering the antioxidant defense to prevent inflammation and oxidative stress against the development of osteoarthritis and cartilage damage. The regulation of Nrf2/HO-1 can be interrelated to the prevention of oxidative stress and anti-inflammatory effects of glabridin in IL-1β treated chondrocytes and MIA-induced osteoarthritis in rats.
5 Conclusion
In conclusion, glabridin possesses significant anti-arthritic effect against MIA-induced osteoarthritis and IL-1β-induced chondrocyte models. Inhibiting inflammatory reaction and oxidative stress could be the basis for the prevention of cartilage damage and protective mechanism by glabridin. Moreover, regulation of MMPs and activation of Nrf2/HO-1 signaling pathway in chondrocytes suggests that glabridin exerted anti-arthritic effect in the in-vivo model through similar pathway. Further studies are necessary to develop glabridin as therapeutic agent for osteoarthritis in humans.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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