EGCG and arthritis -
a Institute of Bioengineering and Bioimaging, 31 Biopolis Way, The Nanos, Singapore , Singapore E-mail: mkurisawa ibn. Fibroblast-like synoviocytes are a key effector cell type involved in the pathogenesis of rheumatoid arthritis.
The major green tea catechin, epigallocatechin O -gallate EGCG , has attracted significant interest for rheumatoid arthritis therapy because of its ability to suppress the proliferation and interleukin-6 secretion of synoviocytes.
However, therapeutic efficacy of EGCG has been limited by a lack of target cell specificity. Herein we report hyaluronic acid—EGCG HA—EGCG conjugates as an anti-arthritic agent that is capable of targeting fibroblast-like synoviocytes via HA—CD44 interactions. These conjugates exhibited superior anti-proliferative and anti-inflammatory activities compared with EGCG under simulated physiological conditions.
Near-infrared fluorescence imaging revealed preferential accumulation of the conjugates at inflamed joints in a collagen-induced arthritis rat model, and their anti-arthritic efficacy was investigated by measuring a change in the edema and histopathological scores.
Our findings suggest the potential of HA—EGCG conjugates as an anti-arthritic agent for the treatment of rheumatoid arthritis. Lee, K. Bae, S. Ng, A. Yamashita and M.
Kurisawa, RSC Adv. This article is licensed under a Creative Commons Attribution 3. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.
Read more about how to correctly acknowledge RSC content. Real-time PCR was performed in duplicate for each sample to determine relative gene expression, using glyceraldehyde 3-phosphate dehydrogenase as a housekeeping control, with the comparative cycle threshold method.
To evaluate the efficacy of EGCG on DMM-induced OA initiation and progression, the structural integrity of the articular cartilage was examined by microscopy after Safranin O staining and OARSI evaluation. Four weeks after DMM, the articular cartilage in the DMM limb in the vehicle-treated mice exhibited mild OA pathological changes characterized by proteoglycan loss, cartilage fibrillation and an average OARSI score of 2.
In contrast, the cartilage in the DMM limb of EGCG-treated mice exhibited less proteoglycan loss and cartilage fibrillation, and the mean OARSI score 1. Sham-operated mice that received either vehicle or EGCG treatment did not exhibit pathologic changes in the articular cartilage and had OARSI scores of 0.
Epigallocatechin 3-gallate administration slows progression in early and midstage osteoarthritis in mice that underwent surgical destabilization of the medial meniscus. Mice underwent sham surgery or surgical destabilization of the medial meniscus DMM , and cartilage specimens were treated with vehicle or epigallocatechin 3-gallate EGCG.
Arrowheads indicate the areas of cartilage fibrillation or erosion, and arrows indicate loss of Safranin O staining. The vehicle-treated DMM mice exhibited more severe OA at 8 weeks than at 4 weeks, characterized by more pronounced proteoglycan loss and cartilage erosion, with an average OARSI score of 6.
In DMM mice treated with EGCG, OA severity was significantly lower OARSI score, 2. Sham-operated animals treated with vehicle control or EGCG exhibited no significant cartilage degradation, with average OARSI scores of 0.
On the basis of the immunostaining intensities of six randomly selected areas of the articular cartilage at 4 weeks following DMM, we found that type II collagen cleavage in vehicle-treated controls increased to 1.
At 8 weeks, the immunostaining intensities of the type II collagen cleavage epitope were 2. Sham-operated animals treated with vehicle or EGCG had no significant immunostaining for type II collagen degradation at 4 or 8 weeks Figures 2 A to 2 D. Epigallocatechin 3-gallate administration reduced the degradation of type II collagen in the articular cartilage matrix.
E Representative staining of tissue sections with isotype control mouse immunoglobulin G IgG. Immunohistochemical staining similarly showed that EGCG treatment reduced the levels of cleaved aggrecan NITEGE in DMM mice compared to vehicle-treated DMM mice at 8 weeks Figure 3.
At 8 weeks after DMM, the immunostaining intensity of cleaved aggrecan in EGCG-treated DMM mice was reduced to 1. Sham-operated animals treated with vehicle or EGCG did not exhibit significant immunostaining for cleaved aggrecan at 4 or 8 weeks Figures 3 A to 3 D.
Epigallocatechin 3-gallate administration reduced the degradation of aggrecan in the articular cartilage matrix. E Representative staining of tissue sections with isotype control rabbit immunoglobulin G IgG. Cartilage matrix degradation is mediated mainly by two major families of proteolytic enzymes: MMPs and ADAMTS [ 24 ].
In particular, MMP is the most potent enzyme in cleaving type II collagen, the principal form in articular cartilage, whereas ADAMTS5 has been shown in mice to cleave aggrecan, the major cartilage proteoglycan [ 2 ]. Therefore, using immunohistochemistry, we examined whether reduction of MMP and ADAMTS5 could underlie the chondroprotective effect of EGCG.
MMPpositive chondrocytes in the vehicle-treated DMM mice were distributed in all three zones of the articular cartilage of the femoral and tibial condyles. In contrast, the MMPpositive chondrocytes in EGCG-treated mice were localized mainly in the middle and deep zones Figures 4 A and 4 B.
Epigallocatechin 3-gallate administration reduced matrix metalloproteinase 13 levels in articular cartilage. EGCG did not significantly alter the percentage of ADAMTS5-positive cells in sham-operated mice Figures 5 C and 5 D.
These data suggest that EGCG treatment improves the integrity of the articular cartilage by preserving both collagen and aggrecan components in posttraumatic OA mice and that the chondroprotective effects exerted by EGCG are mediated, at least in part, by reducing MMP and ADAMTS5 levels.
Epigallocatechin 3-gallate administration reduced ADAMTS5 levels in the articular cartilage. To further understand the mechanism underlying the effects of EGCG on cartilage integrity, we examined the expression of genes encoding proteins with functions closely related to cartilage homeostasis, in addition to MMP and ADAMTS5, including proteolytic enzymes MMP-1, MMP-2, MMP-3 and MMP-8; the MMP-repressing transcriptional regulator CITED2; and proinflammatory cytokines, IL-1β and TNF-α.
The data demonstrate that EGCG exerts a broad spectrum of anti-inflammatory and anticatabolic effects, involving cytokines, inflammatory mediators, proteolytic enzymes and transcriptional regulators.
Epigallocatechin 3-gallate treatment results in a chondroprotective gene expression profile. Adamts5 , A disintegrin and metalloproteinase with thrombospondin motifs 5; Il1b , interleukin 1 beta; Tnfa , Tumor necrosis factor alpha.
The progression of OA is accompanied by secondary clinical symptoms, most prominently pain [ 25 ],[ 26 ]. There was no significant difference observed in rearing Figure 7 B or tactile sensitivity of the paw Figure 7 C in EGCG-treated mice.
Epigallocatechin 3-gallate reduces osteoarthritis-related pain symptoms. Behavior assessments of mice that underwent sham operations or surgical destabilization of the medial meniscus DMM that were treated with vehicle or epigallocatechin 3-gallate EGCG at 8 weeks after DMM surgery. A Distance traveled.
B Number of times mice reared in an open cage within 6 minutes. C von Frey testing mechanical allodynia. The chemokine monocyte chemoattractant protein MCP -1 and its receptor, chemokine receptor 2 CCR2 in the DRG, are central to the development of pain associated with OA.
Increased mRNA levels of Mcp1 and Ccr2 in the ipsilateral DRG at 8 weeks after DMM are causally related to pain-related behaviors [ 26 ]. There is currently no therapeutic agent with a clearly demonstrated ability to modify the course of OA [ 27 ].
In this study, we provide direct in vivo evidence that administration of EGCG slows the progression of posttraumatic OA in the DMM mouse model. EGCG-treated mice exhibited less cartilage erosion and proteoglycan loss, improved preservation of type II collagen and aggrecan and reduced levels of MMP and ADAMTS5, two crucial proteolytic enzymes involved in the degradation of those matrix components [ 24 ].
Although the efficacy of EGCG in human OA has not yet been tested in controlled trials, our findings provide fundamental evidence and a sound rationale for advancing EGCG-based treatments toward clinical application.
The chondroprotective effects of EGCG on attenuating inflammation and catabolic activity have been established in vitro in studies using human chondrocytes [ 8 ]-[ 10 ],[ 28 ]-[ 32 ], synovial fibroblasts [ 33 ]-[ 36 ] and human and bovine cartilage explants [ 12 ], as well as in rheumatoid arthritis animal models [ 37 ]-[ 41 ].
Consistent with these studies, our present study demonstrates that EGCG exerts broad chondroprotective effects in a posttraumatic OA mouse model in vivo by suppressing the expression of genes encoding inflammatory cytokines IL-1β and TNF-α and multiple cartilage-degrading enzymes, including MMPs 1, 3, 8 and 13 and ADAMTS5, as well as by inducing gene expression of the MMP-repressing transcriptional regulator Cited2.
In our previous study, we demonstrated that, in response to moderate mechanical loading, CITED2 represses MMP-1 and MMP gene transcription in vitro [ 14 ] and in vivo [ 15 ]. Of note, EGCG elevated Cited2 expression in OA DMM as well as non-OA sham articular cartilage, suggesting that it may play cartilage-protective roles under both physiological and OA pathological conditions.
The in vivo evidence provided in this study, together with a well-established chondroprotective effect demonstrated in previous studies, supports the concept that EGCG may be an effective chondroprotective agent for OA treatment.
In this study, we also provide evidence for an OA-related pain-relieving effect of EGCG in a posttraumatic OA mouse model. OA pain can be triggered by joint movement and typically results in diminished use and reduced joint mobility [ 25 ]. Patients with OA also have lower mechanical stimuli pain-sensing thresholds, suggesting that central sensitization also contributes to OA-related pain [ 42 ].
In our study, EGCG-treated DMM mice exhibited increased locomotor behavior that is, distance traveled compared to vehicle-treated mice, suggesting an improvement in OA-related pain. Of note, there was no significant difference in rearing or tactile sensitivity of the paw in EGCG-treated mice compared to vehicle controls.
Because rearing standing on the hind limbs and tactile sensitivity are both measurements related to mechanical sensitivity of the limbs due to OA [ 26 ], this suggests that the improvement of pain by EGCG may not rely simply on the mechanical sensitivity of the diseased limb; however, it merits further study.
Interactions between neuropathic pathways and OA tissues influence the development of pain behaviors and alterations in gene transcription and protein expression in the sensory neurons of the DRG [ 43 ]-[ 46 ]. A previous study suggested that MCP-1 and CCR2 mediate pain development in OA mice, and the investigators reported a transient upregulation of MCP-1 and CCR2 at 8 weeks following DMM surgery [ 26 ].
To understand the mechanisms underlying the analgesic effects of EGCG, we examined expression of genes encoding the chemokine MCP-1 and its receptor CCR2, as well as the chronic pain-related proinflammatory cytokines IL-1β and TNF-α, in the DRG. Interestingly, in EGCG-treated DMM mice, gene expression of Ccr2 is significantly lower than in vehicle controls.
This fact, together with reduced mRNA levels of Il1b and Tnfa , provides supporting evidence that EGCG exerts effects on pain-related disease modification by targeting the pain-associated mediators and cytokines in the pain sensitization pathway, in addition to structure-modifying effects through reducing OA severity.
Consistent with our findings, a previous study demonstrated that intravenous infusion of EGCG improved pain symptoms in chronically injured spinal cord of adult rats [ 47 ].
EGCG has shown promise in clinical trials for the treatment of various cancers and cardiovascular and neurodegenerative disorders [ 48 ]-[ 52 ]. Furthermore, the chondroprotection of EGCG has been well established in vitro and in vivo , including in rheumatoid arthritis animal models [ 8 ]-[ 10 ],[ 28 ]-[ 41 ],[ 53 ], providing a solid foundation for further exploration of its therapeutic potential in preclinical and clinical studies.
One advantage of using nutraceutical-based treatments such as EGCG is that they exhibit favorable safety profiles. Early studies demonstrated that EGCG was nontoxic to human chondrocytes [ 8 ].
In humans, daily doses of mg of EGCG for 4 weeks are safe and well tolerated [ 54 ]. EGCG is mostly absorbed by the small intestine and may undergo gastrointestinal inactivation [ 54 ]. Therefore, oral administration of EGCG may reduce its bioavailability.
Accordingly, in our study, we chose to administer EGCG systemically via intraperitoneal injection, which leads to higher bioavailability compared to oral consumption [ 54 ].
In future trials, researchers should consider optimizing EGCG bioavailability when given orally. Destabilization of the medial meniscus is a commonly used surgically induced OA mouse model.
In this model, OA results primarily from altered joint biomechanics and pathologic changes, including cartilage destruction, subchondral bone thickening and osteophyte formation, similar to those observed in human OA [ 16 ]. In the present study, we focused on the effects of EGCG on moderate to severe OA and therefore chose the 8-week experimental period because, based on previous studies [ 16 ] and also confirmed in this study, moderate to severe OA develops reproducibly at this time point following DMM surgery in mice.
A study with a longer injury and treatment period is needed to evaluate the efficacy of EGCG on OA progression in severe and late-stage posttraumatic OA in mice. One limitation of this acute mouse trauma model is that it may not represent the more slowly progressive human OA such as that seen during aging.
Further studies undertaken to investigate the efficacy of EGCG on other relevant OA models, such as spontaneous or aging-related OA, are of interest. In this study, we show evidence for the beneficial effects of EGCG on disease modification and symptom modification in mice with posttraumatic arthritis.
Further studies addressing whether EGCG would have a clinical impact on OA are clearly needed to advance EGCG-based treatments toward applicability in humans.
Accumulating evidence indicates that EGCG exerts a variety of biological effects such as anti-inflammatory, antioxidative and anticatabolic effects on chondrocytes [ 8 ]-[ 10 ],[ 28 ]-[ 32 ],[ 55 ], suggesting that the mechanism which couples these different responses to EGCG may involve a common receptor.
Tachibana et al. identified a 67 kDa nonintegrin cell surface laminin receptor that confers EGCG responsiveness to cancer cells at physiologically relevant concentrations [ 56 ]. Researchers in a subsequent study identified the motif to which EGCG binds to this receptor [ 57 ].
It will be interesting to uncover whether such a receptor or similar mechanism may exist in chondrocytes and, if it does, whether it plays a required role in mediating the effects of EGCG on chondrocytes.
Our study demonstrates significant efficacy of EGCG in disease and symptom modification of posttraumatic OA, and combining EGCG with other potential therapeutic agents may further enhance its efficacy.
Furthermore, a combination therapy of methotrexate and EGCG, compared to each treatment used individually, exerted a more profound reduction of the gene expression of proinflammatory cartilage cytokines TNF-α and IL-6 and potentiated the antiarthritic decrease in hind paw volume and antioxidant effects [ 39 ].
Together, these studies suggest that the chondroprotective effect of EGCG may be amplified when used with other antiarthritic agents in the management of OA. Taken together, the results of this study provide the first evidence in an OA animal model that EGCG provides significant efficacy in arresting OA disease progression and exerts a substantial effect in OA pain relief.
Our study suggests that the effect of EGCG on OA disease modification may be due to the action of modulating a broad spectrum of molecules that are critical for cartilage homeostasis.
The effect of EGCG on symptom modulation in relieving OA-related pain involves suppression of the pain marker CCR2 and chronic pain-related proinflammatory cytokines in the DRG, in addition to reduced disease progression. Lawrence RC, Felson DT, Helmick CG, Arnold LM, Choi H, Deyo RA, Gabriel S, Hirsch R, Hochberg MC, Hunder GG, Jordan JM, Katz JN, Kremers HM, Wolfe F: National Arthritis Data Workgroup: Estimates of the prevalence of arthritis and other rheumatic conditions in the United States: part II.
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Sci Rep. By Carol Eustice Carol Eustice is a writer covering arthritis and chronic illness, who herself has been diagnosed with both rheumatoid arthritis and osteoarthritis.
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Table of Contents View All. Table of Contents. Catechins and RA. Dietary Use. Dosage and Intake. Buying Supplements. New Tea Research Boasts Heart, Brain, and Immune Benefits.
TEA VARIETIES COLOR Jasmine Green Matcha Green Oolong Between green and black Assam Black Ceylon Black Chai Black blended with spices Pu-erh Black, naturally fermented.
Benefits of Green Tea Supplements.
A compound found in green Green tea heart health could be an effective treatment adthritis rheumatoid arthritis, according Artgritis the results of a new study. In the journal Arthritis and Arthritixresearchers from Washington Green tea heart health University WSU Goji Berry Mental Clarity Spokane reveal how the compound — called epigallocatechingallate EGCG — reduced ankle swelling in a mouse model of the disease. Rheumatoid arthritis RA is a disease that affects the joints of the body, most commonly the joints of the hands, feet, wrists, elbows knees and ankles. In RA, the immune system mistakingly attacks the synovial tissues surrounding the joints, causing inflammationswelling and pain. This can cause damage to the cartilage and bone.EGCG and arthritis -
late was not able to ameliorate destruction and inflammation of PIA. In summary the histological analysis nicely reflect scoring values observed in the single experimental groups. The displayed pictures are representative examples for tissue sections obtained from healthy animals A , from the saline-treated control group B and from EGCG treated groups C: EGCG p.
early and D: EGCG i. For experimental details regarding arthritis-induction and treatment see Fig 1. In all cases the metacarpus section of the forepaw was stained with Nuclear Fast Red, Aniline blue and Orange G.
A : In the healthy control group no signs for joint swelling and destruction were observed. Different tissue types bone cartilage: blue, muscle: red, skin: red-orange were clearly distinguishable. B : In contrast, in the positive control a massive joint swelling was observable.
Moreover, especially the bone and cartilage tissue was considerably destructed dark blue regions. C : Only mild cartilage destruction was apparent in the metacarpi of rats early and orally treated with EGCG whereas rats from the EGCG i.
late treatment group D mostly showed patho-histological signs of arthritis very similar to the saline-treated positive control B. The scale bars correspond to 1 mm overviews and μm inserts. As a marker for the inflammatory state we repeatedly determined the myeloperoxidase activity in the neutrophils of the rats.
For this analysis blood was collected from the animals under short-time anaesthesia via punctuation of the retrobulbar venous plexus. The blood samples were heparinised and neutrophils were isolated within 24 h by using a standardised protocol.
By applying the HOCl-specific dye APF only the chlorinating activity of the enzyme was addressed during the subsequent flow cytometry analysis. Thereby by analysing the data obtained on d0 before pristane injection we observed strongly differing basal MPO activities within the several groups which, however, also emerges from the different sizes of the experimental groups.
The averaged fluorescence value obtained by considering all animals By considering the relative mean value and the relative standard deviation observed in the single experimental groups this value never exceeded For each animal the geometric mean of the APF-dependent fluorescence intensity distribution was determined as a sign for the HOCl-producing MPO activity of the blood neutrophils.
In the other EGCG treatment groups the HOCl production recurrently exceeded the range of normal MPO activity determined on d0 dashed lines. Yet the differences were never statistically significant. The data obtained during the repeated analysis of blood samples from the single experimental groups until d Fig 5A were individually normalised to d0.
Moreover, in the graph the relative deviation of the MPO activity observed in the groups on d0 is shown dashed lines. In the healthy control group white columns with black outline the chlorinating MPO activity was always quite comparable to d0 with the lowest value observed on d14 This illustrates well that no notable inflammatory reaction was induced in the animals in the absence of pristane and corresponds with the fact that no arthritis symptoms were observed in this experimental group throughout the whole experiment.
In striking contrast to the healthy control animals in the positive control black columns, pristane injection, saline treatment starting on d14 considerably elevated values were found for the chlorinating MPO activity This reflects well the scoring data see 3.
Thus the chlorinating MPO activity seems to be a good marker for the onset of inflammatory reactions. The value determined for d28 Even the abatement of the acute phase till d50 was reflected by the MPO activity data: On d42 a value of only During the chronic phase of the disease the values determined for the HOCl-production by MPO rose again.
Thereby, while the scoring of arthritic symptoms revealed an onset of the chronic arthritic phase at about d57, the MPO activity already reached a maximum on d54 Moreover while the joint swelling and redness was relatively stable during the chronic phase see 3.
Yet, on d99 Maybe these fluctuations reflect the recurring flare-up and subsiding of inflammatory reactions during the chronic phase of the PIA. In summary, regarding the positive control the determination of the chlorinating MPO activity is well in line with the scoring data: The onset, maximum and abatement of the acute arthritic phase as well as the onset of the chronic arthritis can be followed.
Moreover during the latter phase the MPO data seem to indicate a wavelike course of the underlying inflammatory reaction.
Yet during the statistical comparison between the healthy and the positive control see S1 Table we never found significant differences, most likely due to the small number of animals in the former experimental group.
The usability of the chlorinating MPO activity as a marker for the inflammatory events taking place during PIA is also illustrated by the blood analysis data obtained from the experimental groups treated with MTX Fig 5A : If the drug was injected from d1 after disease induction early treatment, white columns with light grey outline the obtained MPO activity data were quite comparable to those observed in the negative control.
This holds for the onset of the acute phase d14 and its maximum d28 as well as for its decline d42 and the onset of the chronic arthritic phase d In fact, the relative MPO activity values never exceeded These results are in perfect line with the clinical score where animals of this group developed much weaker acute and chronic arthritic symptoms as compared to the positive control saline treatment.
Again these results are nicely reflected by the data obtained from the MPO activity analysis in the blood of the animals: On d14 onset of the acute phase as well as during its abatement d42 the values obtained from the MTX i. late group were higher as compared to the MTX i.
early group. Yet the values in the former group were still within the range of the MPO activity observed in healthy animals dashed lines and on d28 maximum of the acute phase were quite comparable to the values in the latter group early MTX treatment.
Thus in this case the MPO activity data misleadingly suggest a therapeutic effect of the late MTX treatment while no change in the arthritic symptoms joint swelling and redness was observed in this group. During the chronic phase the MPO activity data in the MTX i. late group are always higher than in the corresponding early treatment group.
Yet they only exceed the range of physiological enzyme activity dashed lines on d54 Still as they follow the wavelike pattern also observed in the saline-treated positive control see 3.
The latter is well in line with the scoring data which did not differ between the MTX i. late group and the saline-treated positive control group.
In summary, the MPO activity data obtained from the animals treated with methotrexate nicely reflect the therapeutic effect of the drug upon early injection while the lack of this effect upon later treatment with MTX is only partially reflected by the MPO activity measurements.
In Fig 5B the MPO activity data obtained from the experimental groups treated with epigallocatechin gallate are summarised. Among these groups only the animals treated orally with the flavonoid via the drinking water starting on d1 early application showed significantly reduced joint swelling scores as a sign for an anti-rheumatic effect of EGCG.
In line with these scoring data the determined MPO activity data were nearly always except d28 the lowest in this experimental group white dashed columns with grey outline.
Only on d28 maximum of the acute phase and on d54 onset of the chronic phase the values slightly exceeded the range of normal MPO activity in healthy animals dashed lines with values of In contrast to the EGCG p.
early treatment the late oral application of the flavonoid grey dashed columns with grey outline or the early white columns with grey outline or late grey columns with grey outline injections of the compound did not attenuate the acute and chronic arthritic symptoms, as determined by clinical assessment of arthritic symptoms scoring of swelling and redness, see 3.
These results are again reflected by the MPO activity measurements. Especially on d14 onset of the acute phase , on d54 onset of the chronic arthritis and during the latter phase d82, d99, d the MPO activity data obtained from these groups did not only exceed those of the EGCG p.
early group but also the range of MPO activity in healthy animals dashed lines. The highest values were observed on d54 with top values in the EGCG i. early group Yet while in the latter group the MPO activity was also high on d28, in the three therapeutic inefficient EGCG treatment groups surprisingly low MPO activities were found.
In summary, regarding the treatment of PIA in the rats with EGCG the considerably milder course of the arthritic disease after the early oral application of EGCG is nicely reflected by the MPO activity measurements.
The absence of a therapeutic effect upon later oral application or injection of the flavonoid is also, at least partially, reflected by the MPO activity measurements as higher enzyme activities were found in these experimental groups. Yet it has to be stated that during the comparison of the MTX and EGCG treatment groups among each other or to the controls see S1 Table we sometimes observed statistically significant differences which, however, did not follow a clear pattern.
This can again be attributed to the small animal numbers in some experimental groups e. in the healthy control.
For — -epicatechin EC it has been shown that this flavonoid efficiently reacts with both Compound I and Compound II of MPO following the peroxidase cycle of MPO [ 39 ]. The chlorination cycle of MPO, i. the production of HOCl, includes ferric MPO and Compound I.
However Compound I is easily converted to Compound II by one-electron donors and H 2 O 2 and thus the latter enzymatic redox intermediate is typically the dominating redox intermediate in biological fluids, especially under inflammatory conditions [ 40 ].
Compound II cannot oxidize chloride but can be efficiently be reduced by EC to ferric MPO thereby regenerating the HOCl production by MPO [ 41 ]. Because of the structural similarity between EC and EGCG we assume that the latter flavonoid may also be easily one-electronically oxidized by MPO Compound I and II.
Therefore independently from the animal experiments we also performed stopped-flow kinetic experiments studying the direct reaction of Compounds I and II of MPO with epigallocatechin EGC , the likely intracellular form of EGCG.
As shown in Fig 6A , the spectral changes observed after the addition of buffer to 2 μM MPO, pre-incubated with 25 μM H 2 O 2 for 50 ms, show a monophasic transition from Compound I to Compound II. While the first spectrum recorded after about 2 ms bold black is characteristic for Compound I Soret maximum at nm after 50 ms bold grey a slight shoulder formation at about nm takes place, indicating the formation of Compound II.
The last spectrum recorded after 5 s bold light grey shows a complete transition to Compound II with typical absorbance maxima at nm and nm and a broad shoulder at about nm [ 42 , 43 ]. Especially the latter spectral detail allows a clear discrimination from other MPO redox states like e.
low-spin complexes [ 44 ]. The isosbestic point at about nm proves a direct reaction from Compound I to Compound II [ 42 ].
This slow H 2 O 2 -derived transition second-order rate constant: 4. However, after the addition of 20 μM EGC Fig 6B this transition was considerably faster: The first spectrum bold black recorded after 33 ms already shows a considerable formation of Compound II as indicated by the formation of absorbance maxima at nm and nm and a shoulder at nm.
After about 2 s bold grey this first reaction is completed. Within the next 18 s, a second spectral transition takes place which shows the re-formation of native MPO. Accordingly the absorbance maxima at nm and nm and the shoulder around nm decreased while new maxima at nm and nm rose, accompanied by isosbestic points at nm and nm [ 43 ].
The last spectrum recorded after 20 s indicates a complete regeneration of native MPO. In the absence of EGC only MPO and H 2 O 2 Compound II reduction was never observed, even at longer measuring times not shown.
All measurements were performed at 22°C in mM phosphate buffer, pH 7. Final concentrations of MPO and H 2 O 2 were 2 μM and 25 μM, respectively. Representative spectra from at least three independent experiments are shown. The indicated time points were selected from 50 to recorded spectra.
Compound I was pre-formed by incubating the enzyme with a A : In the absence of EGC a slow H 2 O 2 -derived transition to compound II was observed within the 5 s. B : However, in the presence of 20 μM EGC final concentration this Compound II formation was considerably faster and followed by a second transition where native MPO is regenerated from Compound II.
In order to determine apparent second-order rate constants kinetic measurements at nm and different flavonoid concentrations were performed. As illustrated in Fig 7A for 20 μM EGC typical time traces are biphasic with an initial absorbance increase at nm reflecting Compound II formation followed by subsequent decrease during the regeneration of native MPO.
Upon fitting the two transitions to single exponential functions k obs values were obtained and plotted versus the flavonoid concentration Fig 7B and 7C.
From the slopes of the linear curves, apparent bimolecular rate constants were calculated to be 5. Experimental conditions are given in Fig 6. A : As illustrated for 20 μM EGC time traces recorded at nm are suitable to follow both transitions.
By using fitting functions k obs values were determined and re-plotted against the flavonoid concentration. B : For the formation of Compound II a second-order rate constant of 5.
The time traces A used for the determination of k obs values represent averaged curves from three to four independent measurements. The linear dependence between the k obs values and the EGC concentration is illustrated by the R 2 values obtained during the application of linear fitting functions B and C.
The pristane-induced arthritis PIA in female Dark Agouti rats was used as an animal model for chronic rheumatoid arthritis RA in man [ 45 ]. In fact, as shown by the standardised assessment of clinical symptoms joint swelling and redness evaluation , about two weeks after pristane injection in almost all animals the injection of pristane led to the development of an acute arthritic phase.
Moreover, after a temporary decline of the symptoms, also a chronically recurring inflammation of the joints occurred. Both the high incidence of the disease as well the temporary abatement of the arthritic symptoms [ 46 ] after the acute phase and their chronic recurrence at later time points are well in line with studies of others on PIA in female Dark Agouti rats [ 7 , 8 , 45 ] and show that this animal model nicely reflects the recurrent joint inflammation observed at RA in man [ 1 , 2 ].
In line with the literature, in all animals which developed arthritic symptoms at later stages also ankylosis joint stiffness and joint malfunction occurred [ 47 ]. This was observable from changes in the behaviour of the animals especially within the second half of the experiment.
Also the underlying pathological mechanism, i. the development of a permanent pro-inflammatory systemic immune status as reflected by increased α1AGP levels in the blood leading to relapsing phases of joint swelling and their subsequent destruction as evaluated by histology , is well reflected by the model.
The comparability of PIA in rats to RA in man is also shown by the fact that an early application of methotrexate MTX , a classical disease-modifying anti-rheumatic drug DMARD [ 1 , 2 , 26 ], delayed the onset of the disease and considerably attenuated the symptoms.
In contrast, upon late MTX treatment both in the acute and in the chronic phase no clear reduction of the arthritic symptoms was observed. These results are in line with the assumption that MTX most likely acts via suppression of the innate immune response during the onset of RA [ 16 , 21 ]. The flavonoid epigallocatechin gallate EGCG was already applied in different animal studies on chronic inflammatory diseases including RA [ 23 , 28 , 29 ].
Thereby often an attenuation of the symptoms was observed which was attributed to anti-inflammatory e. inhibition of IL-6 synthesis [ 23 , 26 ] and radical-scavenging properties [ 48 ] of this polyphenol.
Also indirect anti-inflammatory effects like the induction of the inducible nitric oxide synthase iNOS were discussed as reasons for the observed therapeutic effects [ 29 ]. Yet to date EGCG was never tested for its long-term effects on RA as the used animal models, unlike PIA in rats, only lead to an acute inflammatory response in the animals [ 22 ].
Moreover, no systematic study was undertaken to evaluate the role of the time and manner of EGCG application on its anti-rheumatic effects. In our study we were able to show that upon early and continuous oral application of the polyphenol therapeutic effects were achieved which are similar to those of the early injection of MTX: Both in the acute and in the chronic phase of the disease strongly reduced scoring data as well as a markedly decreased degree of chronification were observed.
Even a tendency for the later onset of the arthritic symptoms was found. The orally applied EGCG concentration 0. These results are remarkable as MTX is still used as a gold standard both in human RA therapy and in animal arthritis models [ 21 , 27 ].
Moreover, as both MTX and biologicals used for RA therapy are not only sometimes ineffective but also show manifold adverse effects [ 25 ], the reported results may provide a basis for alternative therapeutic strategies.
Throughout the experiment we observed a daily uptake of about 19 ml drinking water per rat which means 19 mg flavonoid in the EGCG p. This means to a daily dose of about — mg EGCG per kg. As revealed by studies on the oral administration of radioactively labelled EGCG to rats the flavonoid shows a peak blood concentration about 24 h after administration [ 49 ] which confirms the suitability of the daily application chosen in our study.
Thereby the bioavailability of EGCG in the blood is reported to be in the range of 0. In contrast to the results stated above upon late oral application no beneficial effect on the course of the disease was observed. These results were also reflected by marked differences in the degree of joint destruction observed upon histological analysis see Fig 4 C and 4 D and indicate an effect of EGCG on the immunological events during disease onset, suggesting that the polyphenol mainly acts via the suppression of the innate immune response.
When applied after establishment of the disease the polyphenol was unable to combat the mutual interaction between the innate and the adaptive immune system which leads to chronically recurrent arthritic joint inflammations.
In fact, in several animal models for chronic inflammatory diseases the early application of EGCG was shown to especially dampen the acute response of the innate immune system [ 28 , 29 ], preventing, thus, a prolonged pro-inflammatory state, autoimmune reactions of the adaptive immune system and a subsequent disease chronification.
In line with our results other studies with EGCG and animal models for chronic inflammatory diseases e. atherosclerosis often but not always [ 26 ] also only showed beneficial effects of the flavonoid after oral application but not upon injection [ 23 , 28 , 29 ].
in the liver and enters the blood circulation [ 49 ]. Yet it remains unclear whether these degradation products contribute to the observed therapeutic effects of EGCG upon oral application.
The assumption that EGCG, upon early oral application, mainly acts via inhibition of the acute immune response induced by pristane injection is also in line with the determination of α1AGP blood levels determined at d21 of the experiment.
As already reported by others both in RA patients and in corresponding animal models the hepatic mRNA expression levels as well as plasma levels of this acute phase protein are known to be markedly elevated [ 50 — 52 ], making this acute-phase protein a suitable marker for the course of the disease.
Accordingly, in our study the injection of pristane led to about 4. Thus a permanent pro-inflammatory immune status can be assumed to be induced by pristane injection.
While the exact physiological function of α1AGP is still unknown [ 50 , 51 ], the observation that antibodies against this glycoprotein react with granulocytes and monocytes suggests some immune-regulatory effects of α1AGP on the innate immune system [ 50 ].
Thus the decrease of the α1AGP blood level observed upon early and continuous oral application of EGCG provides another hint that it mainly acts via inhibition of the acute response of the innate immune system.
Although we also obtained plasma samples from the other experimental groups, only for the three indicated groups we were able to properly determine α1AGP levels. So we can only guess that the level of this acute phase protein was also significantly lower in the MTX i.
The obtained results suggest, in line with recent studies, that the innate immune system and neutrophils play an important role especially during the onset of RA [ 11 ]. In order to address the systemic activation status of these cells we determined the chlorinating activity i.
the formation of hypochlorous acid, HOCl of one of the most abundant neutrophil enzymes, namely myeloperoxidase MPO. By using a standardised method the erythrocyte amount in the samples was diminished and the chlorinating MPO activity was measured by using the dye aminophenyl fluorescein APF [ 37 , 55 ].
To our knowledge such a repeated evaluation of the MPO activity whereby especially its HOCl-producing activity is addressed was not performed in an animal model before.
As illustrated by the analysis of blood samples from d0, the basal MPO activity showed strong individual differences. Still it was possible to define a range for the range of its physiological activity. In fact, by repeated analysis of blood samples from the healthy control group no pristane injection this range was never exceeded throughout the experiment.
In striking contrast to this in the positive control pristane injection, NaCl treatment the MPO activity values clearly followed the course of the disease including onset and abatement of the acute phase and beginning of the chronic phase.
Within the latter stadium the MPO activity levels seemed to follow a periodic pattern. Thus the HOCl-producing MPO activity nicely reflects the arthritic symptoms observed during the course of the experiment.
In fact, expression and plasma levels of the proteins are elevated both in RA patients and in animal models for the disease [ 12 , 20 , 56 ]. It is assumed that these increased protein levels correlate with a higher HOCl-producing enzyme activity, while often only the general enzymatic activity [ 20 ] or the formation of HOCl-derived protein modifications e.
chlorotyrosine [ 56 ] is measured. Moreover as illustrated by the fluctuating values observed during the chronic phase the assessment of the chlorinating activity may provide additional information about the actual systemic inflammatory status, which are not directly visible from the symptom assessment.
In man RA is known to be characterized by recurring flare-ups of the immune system intermitted by phases of low immune activity [ 1 , 2 , 4 ]. The suitability of the chlorinating MPO activity as a marker for the systemic inflammatory status during RA is also reflected by the data obtained from the MTX early treatment group: In line with the observed therapeutic effect the HOCl production rates were always within the physiological range.
Surprisingly, while the late MTX injection did not significantly influence the occurrence of arthritic symptoms also in this experimental group the corresponding MPO activity data were significantly lower as compared to the positive control.
Maybe after establishment of the disease a reduction of the systemic inflammatory status by the drug as reflected by the MPO activity measurements is not sufficient to compete with the mutual interaction between the innate and the acquired immune system.
Thus again the detection of the chlorinating MPO activity provides more insights into the inflammatory status than the clinical assessment of the symptoms and, thus, may represent a new biomarker to follow the course of chronic inflammatory disease [ 4 ].
In line with the therapeutic effect observed upon early and continuous oral application of EGCG in this group the determination of the chlorinating MPO activity almost always yielded values which were in the range of the physiological enzyme activity determined on d0. Only on d28 acute phase and on d54 onset of the chronic phase the values slightly exceeded this physiological range.
Still even in these experimental groups where EGCG showed no therapeutic effect the HOCl production rates were lower as compared to the positive control pristane injection, NaCl treatment suggesting a certain anti-inflammatory effect of the flavonoid.
Still it has to be clearly stated that while the analysis of the chlorinating MPO activity turned out as a good marker to distinguish between healthy animals and untreated animals with PIA saline-treated positive control as well as to detect efficient anti-rheumatic treatments MTX i.
early and EGCG p. early , the HOCl production by MPO turned out to only partially reflect the clinical scoring data observed in less effective treatment groups. Thus, MPO contributes to local tissue damage during RA but may also have a protective systemic role during disease chronification [ 20 ].
In fact, as has been recently shown, the chlorinating activity of the enzyme may contribute to the inhibition of pro-inflammatory neutrophil and macrophage signalling and, thus, limit long-lasting systemic pro-inflammatory conditions [ 40 , 57 , 58 ].
The observation that MPO is inactive in the synovial fluid of RA patients provides a further hint for the role of its enzymatic activity to counteract chronic pro-inflammatory conditions [ 56 ]. Recent findings suggest a negative correlation between oxidative burst capacity and arthritic symptoms: In DA rats the polymorphism of neutrophil cytosolic factor 1 Ncf1 , a gene essential for NADPH oxidase complex formation and ROS production in neutrophils, increased the susceptibility to PIA [ 59 ].
In fact, upon induction of the ROS production a lower T cell activation was observed in the Ncf1 DA rats [ 59 ]. An interesting aspect regarding the immunological role of the HOCl production by MPO comes from the fact that several well-known anti-inflammatory compounds e.
the plant-derived polyphenol — -epicatechin [ 41 , 60 ] as well as drugs like ascorbic acid [ 61 ] and acetaminophen [ 62 ] are well known for their ability to regenerate to chlorinating MPO activity which is often impaired at inflammation: Several conditions at inflammatory loci including excess hydrogen peroxide, high nitric oxide levels [ 40 , 63 ] are known to inhibit the HOCl production by driving MPO to Compound II, an enzymatic redox intermediate which is not able to catalyse the two-electron oxidation of chloride [ 64 ].
The above stated substrates regenerate the HOCl production by reduction of Compound II to the ferric MPO state [ 40 ]. We thus hypothesize that the well-known anti-inflammatory effects of — -epicatechin [ 41 , 60 ] and the named drugs may, at least in part, be linked to their activity-promoting effect on the HOCl production by MPO [ 40 ].
The effect of one-electron donors on the chlorinating MPO activity depends on two main factors: I The currently prevailing redox state of the enzyme which strongly depends on the actual patho- physiological conditions and II the reaction rates of potential substrates with Compound I k 2 and Compound II k 3 of the enzyme.
For tryptophan, a ratio of While this ratio is not as low as observed for — -epicatechin it can still be guessed that under conditions of Compound II accumulation the polyphenol contributes to the regeneration of the chlorinating MPO activity.
Most interestingly, salicylates e. acetylsalicylic acid , one of the earliest known NSAIDs against RA, are also well-known substrates for MPO which bring back Compound II to the native enzymatic form [ 6 , 62 ]. Yet it has to be stated that other NSAIDs used in RA treatment are also known to promote Compound II accumulation of MPO [ 66 , 67 ], showing the ambivalent immunological role of MPO and its HOCl-producing activity in RA.
While the studies on isolated MPO were performed with EGC the obtained results are still transferable to the application of EGCG in the rat experiments as the latter is metabolised to EGC by intestinal bacteria [ 49 ].
As for any animal model the differences in the organisation of the immune system between rodents and humans also limit the comparability between PIA in rats and RA in humans [ 68 ]. For instance, blood levels of the acute phase protein α1-AGP used as a systemic inflammatory marker in this animal study are about ten times lower in humans [ 51 ].
The phenotypes and the immunological activity of neutrophils are also different between man and rodents which was shown to play an important role by assessing the suitability of animal models for RA [ 9 ]. Still the observation that the higher intake of pristane by fishermen results in a higher prevalence for RA suggests a link between the pathology of PIA in rats and RA in man [ 69 ].
Furthermore it has to be stated that the described method is not suitable to determine changes in the amount of neutrophils in the blood as the applied erythrocyte depletion method for neutrophil enrichment obscures e.
elevated neutrophil levels which are likely to occur during inflammation [ 11 ]. In fact, a relative amount of Moreover also e. a possible activation of the cells during RA [ 17 ] is not perfectly reflected by the MPO activity data as the gate defined during the flow cytometry analysis includes resting as well as activated neutrophils.
Here the application of additional markers would provide more insights and may help to figure out why the chlorinating MPO activity investigated in this study did not always reflect the inflammatory status of the animals as determined e.
by α1AGP plasma levels or the scoring of clinical symptoms. In fact, in previous studies where we applied the same leukocyte enrichment method we observed that neutrophils from mice and rats, unlike human cells, do not show considerably increased FSC- or SSC-values during flow cytometry analysis [ 37 ].
In our animal study the early and continuous oral application of EGCG had a strong therapeutic effect. Yet these results are not directly transferable to humans as the applied polyphenol concentration 0. Yet such high concentrations can be reached by intake of the flavonoid as a food supplemental as e.
illustrated by clinical studies on the pharmacological effect of EGCG [ 70 ]. However, there are also reports about adverse effects resulting from the continuous intake of such high concentrations of this green tea polyphenol [ 71 ].
In this study on PIA in rats the repeated determination of the chlorinating MPO activity turned out as a suitable marker to follow the underlying systemic inflammatory reaction. Therapeutic effects of MTX and EGCG were also reflected by the MPO activity values.
Since neutrophils are much less abundant in mice and rats than in man [ 68 , 72 ] we expect that the determination of the HOCl-producing MPO activity could provide a suitable new marker for clinical studies on RA in man. This fact, the small amount of blood necessary for this analysis [ 37 ] and the assumption that the innate immune system, neutrophils and MPO may play a bigger role in RA as classically assumed [ 6 , 9 , 56 ] provide further arguments for considering the activity of this enzyme in future studies on rheumatoid arthritis.
As already stated neutrophils do not only participate in the onset and solidification of RA [ 6 , 9 ] as well as in the tissue destruction observed at later stages of the disease [ 10 , 11 ] but there are also indications for a physiological role of these cells in limiting systemic inflammatory reactions occurring at RA [ 20 , 40 ].
As proven by new studies thereby the secretion of serine proteases by the cells most likely play a role which lead to the degradation of pro-inflammatory cytokines and chemokines [ 73 , 74 ].
Thereby the formation of nuclear extracellular traps NETs appears to be essential as a failed NETosis leads to chronic inflammatory conditions [ 73 ].
This protease-dependent anti-inflammatory role of neutrophils was shown to be independent of the oxidative burst capacity of the cells [ 74 ]. Still as the NET formation is known to be ROS-dependent [ 73 ] these results may suggest another explanation for the anti-inflammatory role of MPO activity at chronic inflammatory diseases like RA.
PIA was induced on d0 in all female DA rats except the healthy control group. The onset of the disease was assumed at a score of one and individually determined for each animal.
From these data the average day of disease onset was calculated. In the positive control saline treatment as well as in both early EGCG groups p. and i. the mean value for the PIA onset was d12 while in the MTX i. early group a disease onset on d14 was determined. This work was made possible by funding from the German Federal Ministry of Education and Research BMBF, as well as by the Sächsische Aufbaubank SAB project from a funding of the European Regional Development Fund ERDF.
Conceived and designed the experiments: AL IB JF. Performed the experiments: AL IB PF JF. Analyzed the data: AL IB PF JF. Wrote the paper: FL JF. Browse Subject Areas? Click through the PLOS taxonomy to find articles in your field. Article Authors Metrics Comments Media Coverage Reader Comments Figures.
Abstract Rheumatoid arthritis RA —a widespread chronic inflammatory disease in industrialized countries—is characterized by a persistent and progressive joint destruction. Highlights Epigallocatechin gallate EGCG , upon early and continuous oral application, considerably attenuates the symptoms in Dark Agouti rats with pristane-induced arthritis PIA Arthritic symptoms are not only dampened in the acute but also in the chronic phase of the disease, which means a lower risk for the development of chronic recurring joint inflammation The therapeutic effect is comparable to the early injection of methotrexate MTX and is not observed upon late oral application or injection of EGCG Stopped-flow kinetic measurements show that epigallocatechin EGC derived from EGCG exhibits a considerable activity with Compounds I and II of myeloperoxidase MPO It can be guessed that the reactivation of the chlorinating MPO activity by EGCG may contribute to the anti-inflammatory effect of the polyphenol.
Introduction 1. Material and Methods 2. Results 3. Download: PPT. Fig 3. Plasma concentrations of α1AGP on d21 after pristane injection. Fig 4. Histological analysis of metacarpal sections on d after pristane injection.
Fig 5. Chlorinating MPO activity in the time course of pristane-induced arthritis. Fig 7. EGC-derived formation of Compound II and regeneration of native MPO.
Discussion 4. Supporting Information. S1 Fig. Onset of the PIA in DA rats. s TIF. S1 Table. s DOCX. Acknowledgments This work was made possible by funding from the German Federal Ministry of Education and Research BMBF, as well as by the Sächsische Aufbaubank SAB project from a funding of the European Regional Development Fund ERDF.
Author Contributions Conceived and designed the experiments: AL IB JF. References 1. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO III, et al.
Arthritis Rheum Sep;62 9 — Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet Sep 25; — Kannan K, Ortmann RA, Kimpel D. Animal models of rheumatoid arthritis and their relevance to human disease.
Pathophysiology Oct;12 3 — McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med Dec 8; 23 — Holmdahl R, Carlsén S, Mikulowska A, Vestberg M, Brunsberg U, Hansson A-S, et al. Genetic analysis of mouse models for rheumatoid arthritis. In: Adolpho KW, editor. Human genome methods.
New York: CRC Press; Pillinger MH, Abramson SB. The neutrophil in rheumatoid arthritis. Rheum Dis Clin North Am Aug;21 3 — Olofsson P, Holmdahl R. Pristane-induced arthritis in the rat. Methods Mol Med ;— Vingsbo C, Sahlstrand P, Brun JG, Jonsson R, Saxne T, Holmdahl R. Pristane-induced arthritis in rats: a new model for rheumatoid arthritis with a chronic disease course influenced by both major histocompatibility complex and non-major histocompatibility complex genes.
Am J Pathol Nov; 5 — Wright HL, Moots RJ, Edwards SW. The multifactorial role of neutrophils in rheumatoid arthritis. Nat Rev Rheumatol Oct;10 10 — Ji H, Ohmura K, Mahmood U, Lee DM, Hofhuis FM, Boackle SA, et al. Arthritis critically dependent on innate immune system players. Immunity Feb;16 2 — Wright HL, Moots RJ, Bucknall RC, Edwards SW.
Neutrophil function in inflammation and inflammatory diseases. Rheumatology ;— Fernandes RM, da Silva NP, Sato EI. Increased myeloperoxidase plasma levels in rheumatoid arthritis. Rheumatol Int Jun;32 6 —9. Lefkowitz DL, Lefkowitz SS. Macrophage-neutrophil interaction: a paradigm for chronic inflammation revisited.
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Different therapeutic and bystander effects by intranasal administration of homologous type II and type IX collagens on the collagen-induced arthritis and pristane-induced arthritis in rats.
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Studies have shown it also helps preserve cartilage and bone, although there are no widespread controlled trials of it in people with arthritis.
Coffee Research shows coffee also has antioxidant polyphenols. That means coffee can help fight free radicals in the body, which cause cell damage.
Other research suggests coffee may have a protective effect against gout as well. The link between coffee and increased risk of rheumatoid arthritis RA and osteoporosis is debatable.
Some studies say coffee increases the risk, while others do not. Tips: In general, the best rule of thumb is to drink coffee in moderation — no more than one or two cups of coffee a day.
Watch your caffeine intake and be mindful of coffee and espresso drinks that are full of whipped cream and syrups that cause calories and sugar levels to skyrocket.
Milk Some claim that dairy-free is the way to go for arthritis, but the jury is still out when it comes to linking dairy consumption and inflammation.
Like coffee, some studies show dairy can be inflammatory, while other studies show it helps reduce inflammation. For the most part, the benefits of avoiding dairy are highly individual, and there is not enough research to suggest that people with arthritis should ditch milk.
Tips: Drinking milk, which is a good source of calcium, vitamin D and protein, may help prevent gout and fight the progression of osteoarthritis OA.
Make sure you opt for low-fat milk to avoid consuming extra calories and saturated fat. Juices Orange, tomato, pineapple and carrot juices are all high in the antioxidant, vitamin C, which can neutralize free radicals that lead to inflammation.
Tart cherry juice has been shown to protect against gout flares and reduce OA symptoms. Smoothies Many dietitians prefer smoothies over juices because they require using the whole fruit or vegetable— giving you the added bonus of fiber, which helps clean out arteries and fight constipation.
Colorful fruits and vegetables are also high in antioxidants. Adding berries or leafy greens like spinach or kale can give you big doses of vitamins and nutrients. Tips: Smoothies containing yogurt are full of good bacteria probiotics as well as vitamins.
Also, adding a fermented beverage like kefir can boost probiotic content, which can decrease inflammation in your body. Alcohol Red wine has a compound in it called resveratrol, which has well-established anti-inflammatory effects. Some studies show wine consumption is associated with a reduced risk of knee OA, and moderate drinking is also associated with a reduced risk of RA.
Other research shows that alcohol has detrimental effects on arthritis. But if you do enjoy an occasional adult beverage, drink it in moderation, says Beth McDonald, a nutritionist at the Department of Integrative Medicine at Mount Sinai Beth Israel Hospital in New York City. The general recommendation is one drink a day of alcohol for women, two for men.
Antioxidants may reduce the severity of RA symptoms. Green tea heart health tea may arthriyis prevent EGCG and arthritis treat rheumatoid arthritis RA. These antioxidants are called catechins. Polyphenols are a type of catechin. These substances stabilize molecules— free radicals —that have become unstable for a variety of reasons.Agthritis of Inflammation volume 12Article number: EGGCG Cite this article. Metrics details. Recent arthriitis suggest that EGCG can modulate both andd innate and adaptive arms of the immune system.
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All experimental procedures were examined and arthrotis by the Institutional Care and Use Committee at the University of Texas Southwestern Medical Center at Dallas. Bovine type II collagen CII was dissolved in 0. Starting 18 days after the primary immunization, three independent observers examined the severity of arthritis three times a week for up to 6 weeks.
The final score was an average value of three independent joint evaluations. Blood was collected from the orbital sinus of EGCG-treated and control mice at the peak of clinical disease. Louis, MO and then incubated with sera at a dilution ofBound total or CII-specific IgG1 or IgG2a were detected by incubation with horseradish peroxidase HRP -conjugated goat anti-mouse IgG1 or IgG2a-specific antibodies cat AP and AP from Bethyl Laboratories, Inc.
The reaction was terminated with 4. The optical density OD values were measured at nm using an Automatic Microplate Reader BLx, BIO-TEK, Winooski, Vermont. Red blood cells were depleted from splenocytes and lymph node cells using lysis buffer which contained 10 mM potassium bicarbonate KHCO 30.
For analysis of lymphocytes the following rat anti-mouse antibodies were used: CD4-PerCP-Cy5. Tregs were identified using anti-mouse FoxP3-FITC clone FJKa; eBioscience and CDAPC clone 3C7; Biolegend.
GolgiStop BD Biosciences was added and the cells were harvested after 5 h of culture. Cells were first stained extracellularly with anti-CD4 PerCP-Cy5.
Directly conjugated isotype-matched rat anti-mouse antibodies were used as controls for nonspecific staining. During the last 16—18 h of the three-day assay, cells were pulsed with 1 uCi of [ 3 H]-thymidine Perkin Elmer, Waltham, MA per well.
The incorporation of [ 3 H]-thymidine was determined using a Betaplate scintillation counter Perkin-Elmer, Waltham, MA.
Hind paws and knees were removed from the sacrificed mice, frozen in liquid nitrogen and lysed using a buffer containing 20 mM Tris—HCl pH 7. The crude extract was then sonicated for 30 s.
The homogenate was centrifuged at 20, X g for 15 min, and the resulting supernatant was collected. The total protein content of samples was quantified using the Bradford assay Sigma. abrabbit antibody to phosphorylated Nrf-2, anti-p-Nrf2 ab and a mouse IgG1 monoclonal antibody that recognizes mouse heme oxygenase-1, anti-HO-1 ab, clone HO ; all from Abcam and all have been previously shown to react with murine proteins.
The loading control was an anti-GAPDH clone 6C5; Advanced ImmunoChemical which reacts to mouse and other species. Appropriate HRP-conjugated secondary antibodies which included goat anti-rabbit or goat anti-mouse Jackson ImmunoResearch were used at and detected with the SuperSignalWest Femto Chemiluminescent Substrate Kit Thermo Scientific.
Protein expression levels were visualized and quantitated using the gel documentation system, G:BOX Syngene, Frederick, MD. The supernatants were then harvested and assayed for kynurenine. Then, 40 ul of supernatant was added to an equal volume of Ehrlich reagent 5 ml of glacial acetic acid with mg P -dimethylamino-benzaldehyde.
The OD was measured at nm using a NanoDrop LMS. Purified L -kynurenine 0— uM; Sigma-Aldrich was used as the standard. Spleens from mice were collected, embedded in Tissue-Tek Optimal Cutting Temperature O.
compound and snap-frozen in liquid nitrogen. Fluorescence images were acquired using an LSN confocal microscope Carl Zeiss, Oberkochen, Germany. Mice were sacrificed seven weeks after immunization.
The spleens obtained from the mice were treated with RPMI Invitrogen containing dithiothreitol DTT and EDTA for 90 min at 37 °C to remove the epithelial cells and then washed with HBSS and digested with DNase.
Before the stimulation with CII, the cells were pretreated with the IDO-specific inhibitor 1-methyl dL tryptophan 1-MTobtained from Sigma-Aldrich, for two hours.
Tissue sections 6 μm were prepared and stained with hematoxylin, eosin and safranin O. Inflammation and joint damage were assessed by scoring five parameters. Disease was scored on a scale of 0 to 3 for inflammation ranging from no inflammation to severe inflammation, loss of proteoglycans ranging from fully stained to destained cartilage, cartilage destruction ranging from appearance of dead chondrocytes to complete loss of the articular cartilage, and was scored on a 0 to 5 scale for loss of bone ranging from no damage to complete loss of bone structure.
For histology of both knee and paw, a composite score was calculated by summing the individual parameters. Phenotypes were examined using repeated measures one-way analysis of variance ANOVAwith treatment and time as fixed factors and mouse number as the random factor.
Data from in vitro and ex vivo experiments were analyzed for statistical significance using the Mann-Whitney U test GraphPad Prism 6, GraphPad Software, Inc. We determined whether EGCG modulated disease activity in a murine collagen-induced arthritis CIA model.
Mice treated with PBS vehicle control developed the typical signs of CIA both in terms of clinical score and paw swelling seven weeks after the initial immunization Fig. In contrast, EGCG-treated mice displayed a significant decrease in severity of arthritis and paw thickness compared to animals treated with vehicle alone Fig.
As expected, vehicle-fed CIA mice developed severe symptoms of arthritis including marked swelling, redness, and erythema of the hind paws and the forepaws. In contrast, EGCG-fed mice exhibited markedly reduced clinical manifestations of fully developed CIA Fig.
a Effects of EGCG on arthritis score of CIA mice. A booster injection of ug of CII was given on day 14 to induce CIA in mice. PBS was given to the CIA control group over the same time period. Data shown is representative of three independent experiments.
b Effects of EGCG on paw swelling of CIA mice. Mice were untreated DBA-1 or immunized with CII as described above and treated with PBS vehicle or EGCG. c Representative photographs depicting vehicle-fed upper and EGCG-fed CIA mice lower on day 49 after 1 st immunization.
d Histopathology of paw and knee joints from representative CIA mice treated with vehicle left or EGCG right. Five mice were examined per group.
Serum samples were obtained on day 49 post first CII immunization. The histological images of the paws shown in Fig. Joint tissue samples from arthritic vehicle-fed mice revealed the expected histopathological changes, including marked synovial hyperplasia, erosion, and loss of articular cartilage and bone.
In this group, there was extensive cartilage and bone erosions with massive infiltration of polymorphonuclear and mononuclear leukocytes as indicated by the elevated histopathological score Fig.
The joint swelling and pannus formation appeared to be dependent on disease severity. A similar analysis of arthritic joints from the EGCG-fed group showed a marked reduction in the number of infiltrating leukocytes, with less visible cartilage or bone erosion when compared with the vehicle-fed CIA mice Fig.
Thus, these results indicate that EGCG reduced infiltration of inflammatory cells and diminished the severity of arthritis as assessed by clinical and histological scores. Consistent with previous reports, our results demonstrate that the oral administration of EGCG successfully ameliorates disease activity in an inflammatory arthritis model.
Previous studies have shown that humoral immunity plays an essential role in the pathogenesis of CIA [ 2526 ]. IFN-γ induces activation of macrophages that produce proinflammatory cytokines, such as TNF-α and IL-1β which are abundant in arthritic joints in animal models and RA [ 252829 ].
We therefore measured pro-inflammatory cytokines in the serum and knee homogenates of the experimental mice Fig. At day 49 after induction of CIA, EGCG significantly reduced serum levels of IL-6, TNF-α, and IFN-γ compared to vehicle-fed control CIA mice.
However, there was no statistical difference in the production of IL-1β while IL levels were elevated in the serum of EGCG-fed mice Fig. Similar results were obtained when pro-inflammatory cytokines were measured in knee homogenates Fig.
The levels of IL-1β, IL-6, TNF-α and IFN-γ were significantly lower and IL was higher in EGCG-fed mice when compared with vehicle-fed CIA mice.
We also quantitated the frequency of cells producing Th1 cytokines including IFN-γ and TNF-α in the draining lymph nodes of EGCG-fed mice and vehicle-fed control mice Fig.
: EGCG and arthritis| Green Tea May Combat Rheumatoid Arthritis | The major green tea catechin, epigallocatechin O -gallate EGCG , has attracted significant interest for rheumatoid arthritis therapy because of its ability to suppress the proliferation and interleukin-6 secretion of synoviocytes. However, therapeutic efficacy of EGCG has been limited by a lack of target cell specificity. Herein we report hyaluronic acid—EGCG HA—EGCG conjugates as an anti-arthritic agent that is capable of targeting fibroblast-like synoviocytes via HA—CD44 interactions. These conjugates exhibited superior anti-proliferative and anti-inflammatory activities compared with EGCG under simulated physiological conditions. Near-infrared fluorescence imaging revealed preferential accumulation of the conjugates at inflamed joints in a collagen-induced arthritis rat model, and their anti-arthritic efficacy was investigated by measuring a change in the edema and histopathological scores. Our findings suggest the potential of HA—EGCG conjugates as an anti-arthritic agent for the treatment of rheumatoid arthritis. Lee, K. Bae, S. Ng, A. Yamashita and M. Kurisawa, RSC Adv. This article is licensed under a Creative Commons Attribution 3. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given. Read more about how to correctly acknowledge RSC content. Fetching data from CrossRef. This may take some time to load. Loading related content. Jump to main content. Jump to site search. You do not have JavaScript enabled. Please enable JavaScript to access the full features of the site or access our non-JavaScript page. Issue 24, , Issue in Progress. From the journal: RSC Advances. This article is Open Access. A more recent study, however, claimed drinking too much green tea may do more harm than good. Published in the Journal of Functional Foods , the research found excessive amounts of the beverage impaired the reproductive function of fruit flies and the development of their offspring. Minocycline is an antibiotic that can reduce inflammation and help symptoms of rheumatoid arthritis RA , but newer treatments are more common. Low-dose naltrexone LDN is a medication that may help to treat autoimmune conditions, including rheumatoid arthritis. Learn more here. A Chinese herbal remedy - Triptergium wilfordii Hook F - is just as effective for treating symptoms of rheumatoid arthritis than commonly used drug…. The methotrexate dosage for rheumatoid arthritis can start from 7. Rheumatoid arthritis in the feet results from an autoimmune condition. Read on to learn about symptoms, treatment, and more. My podcast changed me Can 'biological race' explain disparities in health? Why Parkinson's research is zooming in on the gut Tools General Health Drugs A-Z Health Hubs Health Tools Find a Doctor BMI Calculators and Charts Blood Pressure Chart: Ranges and Guide Breast Cancer: Self-Examination Guide Sleep Calculator Quizzes RA Myths vs Facts Type 2 Diabetes: Managing Blood Sugar Ankylosing Spondylitis Pain: Fact or Fiction Connect About Medical News Today Who We Are Our Editorial Process Content Integrity Conscious Language Newsletters Sign Up Follow Us. Medical News Today. Health Conditions Health Products Discover Tools Connect. Green tea compound shows promise for treating rheumatoid arthritis. By Honor Whiteman on February 17, Share on Pinterest EGCG — a compound found in green tea — could help treat rheumatoid arthritis, new research suggests. EGCG targets key signaling protein to reduce RA inflammation. How we reviewed this article: Sources. Medical News Today has strict sourcing guidelines and draws only from peer-reviewed studies, academic research institutions, and medical journals and associations. We avoid using tertiary references. We link primary sources — including studies, scientific references, and statistics — within each article and also list them in the resources section at the bottom of our articles. You can learn more about how we ensure our content is accurate and current by reading our editorial policy. Share this article. Latest news Ovarian tissue freezing may help delay, and even prevent menopause. RSV vaccine errors in babies, pregnant people: Should you be worried? Scientists discover biological mechanism of hearing loss caused by loud noise — and find a way to prevent it. How gastric bypass surgery can help with type 2 diabetes remission. Atlantic diet may help prevent metabolic syndrome. Related Coverage. |
| Compound in green tea found to block rheumatoid arthritis | Green tea EGCG, T arthritus, and T ane autoimmune diseases. This slow H 2 O 2 -derived transition Green tea heart health rate Knee cramp causes 4. Artthritis DL, Mills K, Lefkowitz SS, Bollen A, Moguilevsky N. Article PubMed Google Scholar Nguyen DH, Zhou T, Shu J, Mao JH: Quantifying chromogen intensity in immunohistochemistry via reciprocal intensity. Chlorinating MPO activity in the time course of pristane-induced arthritis. Check with your healthcare provider before using green tea medicinally. The reaction was terminated with 4. |
| Best Drinks for Arthritis | Arthritis Foundation | There they contribute to the creation of pro-inflammatory conditions, the activation of arthritiss leukocytes from EGCG and arthritis innate and acquired immune system as well arthrigis to cartilage and srthritis destruction Herbal weight loss later stages of Enhance cognitive decision-making skills [ 69 ]. CIA mice were arthrotis with EGCG or PBS vehicle for 7 weeks after CIA induction and ab dLN sections were stained for CD11b and IDO, respectively magnification: X Green, white, and black teas all come from the Camellia sinensis plant. Mellor AL, Munn DH. CAS Google Scholar. Green tea is generally viewed as the most beneficial of all because its active ingredient is a polyphenol known as epigallocatechin 3-gallate EGCG. In contrast, upon late MTX treatment both in the acute and in the chronic phase no clear reduction of the arthritic symptoms was observed. |
Aller ist über ein und so unendlich
Meiner Meinung nach wurde es schon besprochen
sehr neugierig:)