Ревматоидный артрит Rheumatoid Arthritis

8. Curcumin

The first preliminary study on the anti-rheumatic activity of curcumin was published in 1980. Unfortunately, this study was fundamentally flawed because of the lack of appropriate controls [139]. Studies in a rat model of joint inflammation showed that oral administration of capsaicin and curcumin lowered the levels of paw inflammation [140]. In early 2000 work on synovial fibroblasts derived from RA patients showed that curcumin inhibits the macrophage migration inhibitory factor (MIF) induced up-regulation of matrix metalloproteinases MMP-1 (interstitial collagenase) and MMP-3 (stromelysin) [141]. Curcumin strongly inhibits collagenase and stromelysin expression at micromolar concentrations [142]. Curcumin is actually a potent inhibitor of MIF [143]. Curcumin is a potent inhibitor of the production of inflammatory and catabolic mediators by chondrocytes, suggesting that this natural compound could be efficient in the treatment of OA [144]. Curcumin can induce apoptosis and inhibit prostaglandin E(2) (PGE2) production in synovial fibroblasts of patients with RA, suggesting that curcumin might be used to control hyperplasia of the synovial fibroblasts in RA [145].

8. 
   Куркумин
   Curcuma longa или куркума-это тропическое растение родом из Южной и юго-Восточной тропической части Азии. Он является членом семейства имбирных (Zingiberaceae) и является одним из наиболее важных индийских специй. Куркумин (diferuloyl метан является основным curcuminoid и наиболее активный компонент куркумы. Она может составлять 2-5% от общей spice в куркума. Коммерческие куркумин состоит из трех основных компонентов: diferuloylmethane (82%), demethoxycurcumin (15%) и bisdemethoxycurcumin (3%), а вместе именуемые " curcuminoids [133], все из которых обладают противовоспалительной активностью. Куркума используется в аюрведической Медицине (традиционная индийская медицина) в течение тысяч лет для лечения различных распространенных заболеваний, в том числе желудочно-кишечные заболевания (т.е., язва желудка), желтуха, артрит, РАН и кожных и глазных инфекций [134-136]. Доклинические и клинические исследования показали, что куркумин обладает потенциальной терапевтической ценности против большинства хронических заболеваний, в том числе опухолевых заболеваниях, неврологических, сердечно-сосудистых, легочных, артрита, метаболизма и заболеваний. Несколько недавних исследований показали, что куркумин обладает потенциалом для дополнительного лечения артрита [137,138].
   

Work from our laboratories has demonstrated some of the protective and anti-inflammatory effects of curcumin using biochemical and morphological techniques. To test the hypothesis that curcumin protects chondrocytes from morphological alterations induced by IL-1β, we investigated its in vitro effects on apoptotic signaling proteins and key cartilage-specific matrix components in IL-1β-stimulated chondrocytes. Transmission electron microscopy was employed to demonstrate that curcumin inhibits the early degenerative changes induced by IL-1β [148]. Additionally, curcumin antagonized the suppression of collagen type II and β1-integrin synthesis and caspase-3 activation induced by IL-1β was inhibited by curcumin [148]. This study clearly demonstrated that curcumin exerts anti-apoptotic and anti-catabolic effects on IL-1β-stimulated articular chondrocytes and may have novel therapeutic potential for treating OA and related osteoarticular diseases [148]. We used an explant model of cartilage inflammation to demonstrate that IL-1β-induced ECM degradation and glycosaminoglycan release can be inhibited by curcumin [13].

Curcumin appears to exert its anti-inflammatory effects in a “concentration-dependent” or “dose-dependent” manner. Studies on RA-derived synovial fibroblasts have shown that curcumin dose-dependently abrogates the effect of IL-18 on VEGF production [149]. Interestingly, a study on biological activities of turmeric extract has shown that the three major curcuminoids in turmeric are responsible for its anti-arthritic effects while the remaining compounds in crude turmeric extracts may actually inhibit its anti-inflammatory and protective effects [150]. Studies on other curcuma plants have shown that there is a possible curcuminoid-independent pathway mediated by curcuma phaeocaulis extract [151]. Further studies are required to corroborate these findings.

Treatment of chondrocytes with curcumin suppresses IL-1β-induced NF-κB activation via inhibition of IκBα phosphorylation, IκBα degradation, p65 phosphorylation and p65 nuclear translocation [152]. Curcumin also inhibits the IL-1β-induced stimulation of up-stream protein kinase B Akt, molecular events that correlate with down-regulation of NF-κB targets including COX-2 and MMP-9 [152].

Curcumin is also able to antagonize the IL-1β and TNF-α-dependent up-regulation of MMPs and COX-2. Curcumin has been shown to inhibit the inflammatory and apoptotic effects of IL-1β on chondrocytes and this correlates with down-regulation of NF-κB-specific gene products that are known to mediate inflammation, degradation and apoptosis of chondrocytes in OA. Additionally, both curcumin suppressed IL-1β-induced down regulation of the cartilage specific ECM component collagen type II and of the cartilage specific master transcription factor Sox-9. Furthermore, inhibition of NF-κB activation by curcumin occurs mainly through the IKK inhibition [135,138,141,152].

Работа от нашей лаборатории продемонстрировал некоторые из защитный и противовоспалительный эффекты куркумин, используя биохимические и морфологические методы. Для проверки гипотезы о том, что куркумин защищает хондроцитов от морфологических изменений, индуцированное ИЛ-1B, мы изучили in vitro эффекты на сигнальных белков апоптоза и ключ хряща-специфические компоненты матрицы в IL-1B, стимулированного хондроцитов. Просвечивающей электронной микроскопии был использован, чтобы продемонстрировать, что куркумин тормозит начале дегенеративных изменений, вызванных IL-1B [148]. Кроме того, куркумин отталкивала борьбе коллагена типа II и β1-интегрина синтез и каспазы-3 активации, индуцированное ИЛ-1B был тормозится куркумин [148]. Это исследование наглядно продемонстрировал, что куркумин оказывает антиапоптозных и анти-катаболическим эффектами на ИЛ-1B, стимулированного суставных хондроцитов и, возможно, новых терапевтических потенциалом для лечения ОА и сопутствующих заболеваний костно - [148]. Мы использовали эксплантов модель воспаление хряща, чтобы продемонстрировать, что IL-1B-индуцированной ECM деградации и гликозаминогликанов релиз может быть вызвана куркумин [13].

When considering the biological effects of curcumin in cartilage and synovial cells and joint tissues, the overriding question is whether curcumin is safe. The research conducted to date with curcumin suggests that it has a good safety record. However, this is not supported by clinical evidence and data from clinical trials. Another important and largely neglected issue is the bioavailability of curcumin and curcuminoids, which is poor generally. Enhancing the bioavailability of curcumin is an important and goal and is likely to bring this promising natural product to the forefront of therapeutic agents for treatment of human diseases [153]. Curcumin is also a powerful inhibitor of inflammatory pathways and mediators. The schematic shown in Figure 4 summarizes the available information in PubMed on the effects of curcumin on the TNF-α receptor and its downstream signaling pathway.

Its anti-catabolic effects, namely reducing degradative enzyme expression and activity, and its positive influence on anabolic gene expression suggests that it may be a suitable adjunct to conventional pharmaceutical (i.e., NSAID) therapy. The available information suggests that curcumin could be an alternative to NSAIDs. In contrast to NSAIDs, curcumin has no gastrointestinal side effects, and can even protect the gastric mucosa. Therefore, curcumin could be beneficial in the management of chronic inflammatory-related joint disease, including OA. However, despite this optimistic view, it must be recognized that there is still a paucity of data regarding possible adverse effects of curcumin at concentrations that are biologically effective in vitro. Indeed, the absence of systemic adverse effects after oral administration of curcumin is probably the result of its poor bioavailability and chemical modification by the gut and liver. Whilst some evidence exists for toxicity, at super-physiological concentrations, these are unlikely to be experienced or achieved in vivo. Nevertheless, we cannot exclude the possibility that increasing curcumin absorption, by chemical or natural process, could have unsuspected deleterious effects. It is now documented that curcumin at concentrations in excess of 50 mM shows cytotoxicity in a chondrocyte cell line [154]. The relevance of this toxicity in in vitro models is highly questionable. Nevertheless, the long-term effects of curcumin have not been studied and there is no published information about the possible side effects of the metabolites of curcumin. Further work is therefore required to address the issues of bioavailability and tissue accumulation in order to calculate appropriate dose formulations to assess whether curcumin can be convincingly considered as an aid to treating OA. Curcumin regulates inflammatory cytokines such as IL-1β, IL-6, IL-12, TNF-α and IFN-γ and associated JAK-STAT, AP-1, and NF-κB signaling pathways in immune and connective tissue cells [155].

При рассмотрении биологических эффектов куркумин в хряща, синовиальной клетках и тканях сустава, основной вопрос заключается в том, что куркумин безопасно. Исследования, проведенные до настоящего времени с куркумой предположить, что он имеет хорошие показатели безопасности. Однако это не подтверждается клинические данные и данные клинических испытаний. Еще одним важным и во многом игнорировался вопрос биодоступность куркумин и curcuminoids, что малообеспеченные слои населения в целом. Повышение биодоступности куркумин является важным и цели и, вероятно, принесет это перспективное натуральный продукт forefront терапевтических средств для лечения болезней человека [153]. Куркумин также мощный ингибитор воспалительных путей и посредников. Схемы, показанной на Рис. 4 приведены имеющейся информации в PubMed по действию куркумин на TNF-a рецептора и его сигнальный путь вниз по течению.

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