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Efficacy and mechanism of action of turmeric supplements in the treatment of experimental arthritis

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Abstract

Scientific evidence is lacking for the antiarthritic efficacy of turmeric dietary supplements that are being promoted for arthritis treatment. Therefore, we undertook studies to determine the antiarthritic efficacy and mechanism of action of a well-characterized turmeric extract using an animal model of rheumatoid arthritis (RA). The composition of commercial turmeric dietary supplements was determined by high-performance liquid chromatography. A curcuminoid-containing turmeric extract similar in composition to these supplements was isolated and administered intraperitoneally to female Lewis rats prior to or after the onset of streptococcal cell wall-induced arthritis. Efficacy in preventing joint swelling and destruction was determined clinically, histologically, and by measurement of bone mineral density. Mechanism of action was elucidated by analysis of turmeric's effect on articular transcription factor activation, microarray analysis of articular gene expression, and verification of the physiologic effects of alterations in gene expression. A turmeric fraction depleted of essential oils profoundly inhibited joint inflammation and periarticular joint destruction in a dose-dependent manner. In vivo treatment prevented local activation of NF-kappaB and the subsequent expression of NF-kappaB-regulated genes mediating joint inflammation and destruction, including chemokines, cyclooxygenase 2, and RANKL. Consistent with these findings, inflammatory cell influx, joint levels of prostaglandin E(2), and periarticular osteoclast formation were inhibited by turmeric extract treatment. These translational studies demonstrate in vivo efficacy and identify a mechanism of action for a well-characterized turmeric extract that supports further clinical evaluation of turmeric dietary supplements in the treatment of RA.

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... In addition, increased levels of proinflammatory cytokines, CRP and ESR, have been shownwith a streptococcal cell wall (SCW)-induced arthritis rat model of RA (Choy & Panayi, 2001). Curcumin (23 mg/kg/day) was found to decrease the expression of pro-inflammatory cytokines (such as IL-1β), chemokine (such as MCP-1), and growth-related oncogene/keratinocyte chemoattractant (GRO/KC) (Funk et al., 2006). The anti-inflammatory effects of curcumin were found to be associated with the prevention of both synovitis and granulomatous inflammation. ...
... The anti-inflammatory effects of curcumin were found to be associated with the prevention of both synovitis and granulomatous inflammation. Curcumin also significantly inhibits granuloma formation in the liver and spleen (Funk et al., 2006). In RA, endothelial cells in the synovium activate and express adhesion molecules that increase the recruitment of inflammatory cells into the joint (Funk et al., 2006). ...
... Curcumin also significantly inhibits granuloma formation in the liver and spleen (Funk et al., 2006). In RA, endothelial cells in the synovium activate and express adhesion molecules that increase the recruitment of inflammatory cells into the joint (Funk et al., 2006). Curcumin can decrease the gene expression of adhesion molecules, β3 and β7 integrins, and thereby decease joint inflammation in RA (Funk et al., 2006). ...
Article
Curcumin is a dietary polyphenol from turmeric with numerous pharmacological activities. Novel animal and human studies indicate that curcumin can affect different immune cells, such as various T lymphocyte subsets, macrophages, dendritic cells, B lymphocytes and natural killer cells, which results in decreasing severity of various diseases with immunological etiology. The present review provides a comprehensive overview of the effects of curcumin on different immune cells and immune system-related diseases. This article is protected by copyright. All rights reserved.
... In these cases, mechanistic pre-clinical studies in the same or mechanistically similar conditions can sometimes provide direction. For example, in the course of conducting pre-clinical turmeric studies documenting remarkable in vivo anti-arthritic efficacy, our laboratory identified direct and indirect inhibitory effects of turmeric on the formation of bone resorbing osteoclasts (14), key mediators of bone loss across all disease states (14)(15)(16). Subsequent pre-clinical studies by our laboratory verified anti-resorptive effects of turmeric in a model of menopausal bone loss, a clinically silent disorder, that were subsequently confirmed clinically (16,17). ...
... In these cases, mechanistic pre-clinical studies in the same or mechanistically similar conditions can sometimes provide direction. For example, in the course of conducting pre-clinical turmeric studies documenting remarkable in vivo anti-arthritic efficacy, our laboratory identified direct and indirect inhibitory effects of turmeric on the formation of bone resorbing osteoclasts (14), key mediators of bone loss across all disease states (14)(15)(16). Subsequent pre-clinical studies by our laboratory verified anti-resorptive effects of turmeric in a model of menopausal bone loss, a clinically silent disorder, that were subsequently confirmed clinically (16,17). For other biological processes, such as menopause, symptomatology can be culturally dependent (18), and pharmacogenetic differences between populations can also impact botanical responses (19), a caveat that should be kept in mind when designing-and perhaps most importantly-when interpreting clinical trial results. ...
... Similarly, in vivo and in vitro pre-clinical studies from our own laboratories have demonstrated in vivo inhibition of NF-κB activation by curcumin (14), an effect likely attributable to adduct formation between oxidative curcumin metabolites and IκB kinase β (IKKß), the activating kinase upstream of NF-κB (14,(27)(28)(29). Furthermore, our laboratories have demonstrated that in vivo inhibition of NF-κB activation in a pre-clinical arthritis model is associated with decreased NF-κB-induced cytokines or NF-κB-mediated tissue destructive processes (i.e., formation of bone-resorbing osteoclasts) known to be closely linked with adverse clinical outcome (Figure 1) (14)(15)(16). ...
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Plant-derived compounds, without doubt, can have significant medicinal effects since many notable drugs in use today, such as morphine or taxol, were first isolated from botanical sources. When an isolated and purified phytochemical is developed as a pharmaceutical, the uniformity and appropriate use of the product are well defined. Less clear are the benefits and best use of plant-based dietary supplements or other formulations since these products, unlike traditional drugs, are chemically complex and variable in composition, even if derived from a single plant source. This perspective will summarize key points–including the premise of ethnobotanical and preclinical evidence, pharmacokinetics, metabolism, and safety–inherent and unique to the study of botanical dietary supplements to be considered when planning or evaluating botanical clinical trials. Market forces and regulatory frameworks also affect clinical trial design since in the United States, for example, botanical dietary supplements cannot be marketed for disease treatment and submission of information on safety or efficacy is not required. Specific challenges are thus readily apparent both for consumers comparing available products for purchase, as well as for commercially sponsored vs. independent researchers planning clinical trials to evaluate medicinal effects of botanicals. Turmeric dietary supplements, a top selling botanical in the United States and focus of over 400 clinical trials to date, will be used throughout to illustrate both the promise and pitfalls associated with the clinical evaluation of botanicals.
... [3] Because of the structural similarity of the most abundant curcuminoids (curcumin [CURC], demethoxycurcumin [DMC] and bisdemethoxycurcumin [BDMC]), polyphenol-enriched extracts prepared from turmeric root contain a mixture of these naturally occurring curcuminoids. [4][5][6][7] Interest in the health benefits of turmeric have largely focused on curcuminoids, whose anti-inflammatory properties have been attributed to their impact on various molecular targets including NF-κB, TNF-α, IL-1, IL-6 and COX-2, [5,8,9] rather than turmerone-enriched volatile essential oils, which also have demonstrable anti-inflammatory effects. [10][11][12] Despite their therapeutic potential, turmeric DS in the US are categorized and regulated as dietary supplements, as defined by the Dietary Supplement Health and Education Act of 1994 (DSHEA), with oversight of content and quality assurance left largely to the manufacturer, and federal regulation primarily limited to product removal from the marketplace if adverse effects occur and are reported. ...
... [3] Because of the structural similarity of the most abundant curcuminoids (curcumin [CURC], demethoxycurcumin [DMC] and bisdemethoxycurcumin [BDMC]), polyphenol-enriched extracts prepared from turmeric root contain a mixture of these naturally occurring curcuminoids. [4][5][6][7] Interest in the health benefits of turmeric have largely focused on curcuminoids, whose anti-inflammatory properties have been attributed to their impact on various molecular targets including NF-κB, TNF-α, IL-1, IL-6 and COX-2, [5,8,9] rather than turmerone-enriched volatile essential oils, which also have demonstrable anti-inflammatory effects. [10][11][12] Despite their therapeutic potential, turmeric DS in the US are categorized and regulated as dietary supplements, as defined by the Dietary Supplement Health and Education Act of 1994 (DSHEA), with oversight of content and quality assurance left largely to the manufacturer, and federal regulation primarily limited to product removal from the marketplace if adverse effects occur and are reported. ...
... Capsular curcuminoid content was calculated based on labeled information, manufacturer's websites and/or previously published information on the curcuminoid content of proprietary formulations [20,21,24,27,28,[36][37][38] or dried turmeric rhizomes. [3][4][5] In a minority of products ( This article is protected by copyright. All rights reserved. ...
Article
Scope Turmeric is a top selling dietary supplement (DS) in the United States with rapidly expanding usage. Therefore, turmeric DS formulations available for sale in an urban US retail marketplace were analyzed, and point of sale information was related to measures of quality relevant to safety. Methods and Results Eighty‐seven unique turmeric DS were identified; a majority (94%) contained turmeric‐derived curcuminoid extracts (TD‐CE), which were combined with other bioactives in 47% of products, including piperine (24%), an additive that could alter the metabolism of concurrent medications. While curcuminoid content was within 80% of anticipated for a majority of products analyzed (n = 35), curcuminoid composition (% curcumin) did not meet USP criteria for TD‐CE in 59% and was suggestive of possible unlabeled use of synthetic curcumin in some. Lead content was associated with inclusion of turmeric root and exceeded USP limits in one product. Residues of toxic class 1 or 2 solvents, which are not needed for TD‐CE isolation, were present in 71% of products, although quantified levels were within USP‐specified limits. Conclusion Assessment of turmeric DS quality at point of sale is difficult for consumers and may best be managed in partnership with knowledgeable health care professionals. This article is protected by copyright. All rights reserved
... Astaxanthin (Chen et al., 2014a) Apigenin Astragalin (Ma et al., 2015) Aucubin Baicalein Bavachin Berberine Zhao et al., 2014;Liu et al., 2015;Zhou et al., 2015) Betulin (Ra et al., 2017) Biochanin A Catechins (Leong et al., 2014) Celastrol (Ding et al., 2013) Crocin (Ding et al., 2010) Curcumin (Funk et al., 2006;Nonose et al., 2014). ...
... The compound showed ameliorative effects on inflammation of the joint in an animal model of arthritis (Nonose et al., 2014). A preparation of CL total extract exerted an inhibitory effect against periarticular tissue damage and joint inflammation in an in vivo arthritis model via inhibiting the NF-κB signaling pathway (Funk et al., 2006). ...
Article
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Osteoarthritis is a chronic degenerative articular disorder. Formation of bone spurs, synovial inflammation, loss of cartilage, and underlying bone restructuring have been reported to be the main pathologic characteristics of osteoarthritis symptoms. The onset and progression of osteoarthritis are attributed to various inflammatory cytokines in joint tissues and fluids that are produced by chondrocytes and/or interact with chondrocytes, as well as to low-grade inflammation in intra-articular tissues. Disruption of the equilibrium between the synthesis and degradation of the cartilage of the joint is the major cause of osteoarthritis. Hence, developing a promising pharmacological tool to restore the equilibrium between the synthesis and degradation of osteoarthritic joint cartilage can be a useful strategy for effectively managing osteoarthritis. In this review, we provide an overview of the research results pertaining to the search for a novel candidate agent for osteoarthritis management via restoration of the equilibrium between cartilage synthesis and degradation. We especially focused on investigations of medicinal plants and natural products derived from them to shed light on the potential pharmacotherapy of osteoarthritis.
... Pothitirat and Gritsanapan reported that the quantity of curcumin content in the dried rhizome extracts of C. longa of various species growing in ailand was in the higher range of 46.45% to 67.31% [33,34]. A series of other studies reported the curcumin content in crude extracts (21.4% and 25.7%) as well as in essential oils depleted (21.69% and 34.50%), which is very close to our findings [35,36]. ...
... In the present study, effects of oral curcumin in attenuating the damaging effect of induced arthritis may be attributed to the fact that certain inflammatory agents mimicking RA inflammatory metabolites released during adjuvant-induced arthritis models were counteracted by the oral curcumin in dosage of 250 mg/kg resulting which might have restored the gastrointestinal environment causing folic acid absorption and, hence, restoration of RBC count and the Hb concentration [35]. As compared to others in case of the iontophoretic transdermal delivery method, the improvements available were better because curcumin had better penetration. ...
Article
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Background: According to previous studies, oral administration of curcumin elucidates anti-inflammatory effect irrespective of its poor bioavailability. This study aims to measure the efficacy of lyophilized curcumin extracts with iontophoresis in arthritic rat models. Methods: Lyophilization and characterization of curcumin using the standard HPTLC method was carried out followed by induction of inflammatory arthritis in male albino rats. The animals were then treated with curcumin in three different forms, i.e., oral curcumin (OCU), oral curcumin with topical application (OCU + TOCU), and oral curcumin along with iontophoretically applied curcumin (OCU + IOCU). Various objective variables including body weight, paw edema, arthritic scores, and hematological and biochemical parameters, as well as histopathological examinations were conducted. Results: All the curcumin-treated groups showed significant alleviation of arthritic condition (p ∗ < 0.05) when compared with arthritic controls. Group V (OCU + IOCU) demonstrated maximum therapeutic effect by restoring the body weight, decreasing the paw edema, and normalizing the Erythrocyte sedimentation rate and leukocyte count, when compared with other experimental rat groups (p ∗∗ < 0.01). Conclusions: Iontophoretic administration of curcumin may ameliorate arthritic symptoms significantly, and the effect is assumed to be due to better penetration and enhanced bioavailability. Geriatrics patients are supposed to be benefited fairly by this technique.
... C. longa L. is having various constituents, such as curcuminoids, which are comprised of three groups; 5.5% bis-demethoxycurcumin, 17.6% demethoxycurcumin, and 76.9% curcumin. In addition, it comprises resins, proteins, sugars, and volatile oils (zingiberone, atlantone, and tumerone) [83][84][85]. The natural products from turmeric (C. ...
... Traditional medicine, mainly TCM, and Ayurvedic systems, have utilized different parts of the plant, including the fruits and seeds [94]. In Chinese traditional medicine, it is believed that pumpkin can benefit the lungs and invigorate the spleen [84], regulate blood circulation, clears heat and dampness, and promote urine [93]. C. pepo L. contains different categories of phytoconstituents, such as linoleic acids, oleic acid, alkaloids, flavonoids, and palmitic, which may be responsible for its medicinal properties [95]. ...
Article
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Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is the most frequent form of prostatitis, and has a serious impact on patients' quality of life, and causes severe symptoms. The pain in the pelvic, perineal and penile areas, lower abdominal pain, and pain during urination or ejaculation are the main complaints of CP/CPPS. The underlying complex and unknown pathophysiology of this syndrome have made the management of CP/CPPS and the availability of monotherapy challenging. To identify an effective monotherapy, a plethora of clinical trials failed due to its puzzling etiology. Antibiotics, anti-inflammatory, and a-blockers have been commonly used for the treatment of CP/CPPS, but the desired and complete effects have not been gotten yet. The patients and clinicians are attracted to alternative therapies because of their multi-targeted effects. Attention toward natural compounds effectiveness and safety, supporting the development of a new nutraceutical science. In the alternative remedies for the treatment of prostatic diseases, medicinal herbs, in the form of herb parts or extracts, are getting attention due to their positive effects on prostatic diseases. At present, there is no available detailed literature review about the efficacy of medicinal herbs in the treatment of CP/CPPS. This review aimed to explore the useful medicinal herbs in the treatment of CP/CPPS from different perspectives and their possible mechanism of action in managing CP/CPPS.
... It has been reported that not only these inhibitors but also components contained in plant extracts, such as turmeric supplements, Trachelospermi caulis, Moutan cortex radicis, or Saposhnikovia divaricata, can suppress the activation of the classical NF-κB pathway, which mediates excessive immune responses and inflammation followed by cartilage destruction in arthritis [58][59][60][61][62][63][64][65][66]. The dietary ω-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), originating from fish oils, also reduce pain and inflammation in RA by suppressing IL-1 or TNF-α production via NF-κB activation. ...
... It is currently used as one of the therapeutic agents for RA and has been reported to be effective [56]. Thus, targeting NF-κB is effective at maintaining bone mass during inflammation [13][14][15][34][35][36][37][49][50][51][52][53][54][55][56][58][59][60][61][62][63][64][65][66][67][68][69]85,[91][92][93][94], and there is a possibility for "killing two birds with one stone". However, embryonic lethality has been reported in mice where molecules involved in the NF-κB signaling have been knocked out [26][27][28][29][30][31], and it is necessary to consider the possibility of causing serious side effects simply by inhibiting NF-κB. ...
Article
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Nuclear factor-κB (NF-κB) is a transcription factor that regulates the expression of various genes involved in inflammation and the immune response. The activation of NF-κB occurs via two pathways: inflammatory cytokines, such as TNF-α and IL-1β, activate the “classical pathway”, and cytokines involved in lymph node formation, such as CD40L, activate the “alternative pathway”. NF-κB1 (p50) and NF-κB2 (p52) double-knockout mice exhibited severe osteopetrosis due to the total lack of osteoclasts, suggesting that NF-κB activation is required for osteoclast differentiation. These results indicate that NF-κB may be a therapeutic target for inflammatory bone diseases, such as rheumatoid arthritis and periodontal disease. On the other hand, mice that express the dominant negative form of IκB kinase (IKK)-β specifically in osteoblasts exhibited increased bone mass, but there was no change in osteoclast numbers. Therefore, inhibition of NF-κB is thought to promote bone formation. Taken together, the inhibition of NF-κB leads to “killing two birds with one stone”: it suppresses bone resorption and promotes bone formation. This review describes the role of NF-κB in physiological bone metabolism, pathologic bone destruction, and bone regeneration.
... Currently, other properties have been recognized for this herb including anticancer (Garg, Ingle, & Maru, 2008;W. Zhu & Fung, 2000), hepatoprotective (Miyakoshi et al., 2004;Rahmani et al., 2016), hypoglycemic (Honda et al., 2006), antiarthritic (Funk et al., 2006), and cardioprotective properties (Mohanty, Arya, & Gupta, 2006). Numerous studies have also reported anti-inflammatory, antioxidant (Razavi & Hosseinzadeh, 2020), antidotal (Hosseini & Hosseinzadeh, 2018), and antimicrobial properties (Mahady, Pendland, Yun, & Lu, 2002;Reddy, Vatsala, Keshamouni, Padmanaban, & Rangarajan, 2005) of turmeric. ...
... C. longa and curcumin are potential alternative medicines for arthritis by their anti-inflammatory and antinociceptive properties (Daily, Yang, & Park, 2016;Funk et al., 2006). ...
Article
Turmeric (Curcuma longa) and its constituent, curcumin, have been used for their therapeutic properties for a long time. Most of the medicinal impacts of turmeric and curcumin might be attributed to their anti‐inflammatory, antinociceptive, and antioxidant effects. In the present review, the preventive and therapeutic potentials of turmeric and its active constituent, curcumin, on inflammatory disorders and pain as well as patents related to their analgesic and anti‐inflammatory effects, have been summarized to highlight their value on human health. A literature review was accomplished in Google Scholar, PubMed, Scopus, Google Patent, Patentscope, and US Patent. Several documents and patents disclosed the significance of turmeric and curcumin to apply in several therapeutic, medicinal, and pharmaceutical fields. These phytocompounds could be applied as a supplementary therapy in phytotherapy, inflammatory disorders such as arthritis, inflammatory bowel diseases, osteoarthritis, psoriasis, dermatitis, and different types of pain including neuropathic pain. However, because of inadequate clinical trials, further high‐quality studies are needed to firmly establish the clinical efficacy of the plant. Consistent with the human tendency to the usage of phytocompounds rather than synthetic drugs, particular consideration must be dedicated to bond the worth of turmeric and curcumin from basic sciences to clinical applications.
... Of these, curcumin is proved to be a potential candidate of inhibiting bone resorption. Recently published studies have demonstrated the antiarthritic effects of curcumin in an animal model of rheumatoid arthritis, including its ability to decrease bone resorption and osteoclast number, and inhibit the expression of RANKL in arthritic joints ( Funk et al., 2006). Similar findings were reported by Kim et al., (2011);Yang et al., (2011) andZhou et al., (2013) in ovariectomized, APP/PS1 transgenic mice and experimental periodontitic rats, respectively. ...
Article
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The main target of this study is to investigate the possible protective effect of both rosemary and turmeric as powder spices on glucocorticoid-induced bone loss in female rats. The alleviating roles of these spices on some other side effects of glucocorticoid therapy were also studied. Forty female albino rats (Sprague Dawley strain) weighing 110±10 g were used and randomly divided into eight equal groups. The first group was fed on basal diet as a negative control, while other groups were fed on basal diets containing 100 mg of prednisone as a glucocorticoid/ kg diet (GCD) to induce severe bone loss. Of them, the positive control group was kept feeding on GCD alone, while others were fed on GCD containing 1 and 2% of rosemary leaves powder, 1 and 2% of turmeric powder or mixtures of the two spices, as the low mixture consisted of 0.5% of each spice, while the high mixture consisted of 1% of each spice. The experiment lasted for 4 weeks. Feed intake, body weight gain and feed efficiency ratio were finally calculated. Bone mineral concentration (BMC), bone mineral density (BMD) as well as the concentrations of calcium and phosphorus in both serum and left femur bones were determined. In addition, the activities of serum transaminases, as the most specific markers of liver injury, were also determined. Moreover, right femur bones were histopathologically examined. Results indicated that feeding GCD resulted in a significant decline in BMC, BMD and the concentrations of calcium and phosphorus in both serum and left femur bones 2 which was supported by histopathological findings. Feed intake, body weight gain and hence feed efficiency ratio were also significantly reduced. Conversely, the activities of serum transaminases were significantly increased revealing a marked liver injury. Supplementation of GCD with the studied spices alleviated the marked lesion noticed in bone tissue and increased its mineralization and density. Feed intake and liver functions were improved in spices-fed groups, while body weight was decreased. Finally, dietary supplementation with either rosemary leaves powder or turmeric powder is recommended in order to prevent glucocorticoid-induced bone loss and some other side effects. The co-supplementation was more potent in elevating bone mineral density.
... Nevertheless, these medications have a wide variety of harmful side effects that resemble stomach upset, nephrotoxicity, protein loss, toxicity, lack of target specificity, immunosuppressive effects that ultimately lead to poor patient consistency [3,4]. As a result, the importance of various anti-inflammatory drugs has decreased and plant -based agents associated with the least side effects are in the process of treating rheumatoid arthritis [5]. ...
Article
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Current research reports the development, optimization and evaluation of Quercetin (QCT) loaded nanoemulsion (NE)-based gel for the effective rheumatoid arthritis (RA) management. The formulation of QCT- NE was developed using spontaneous emulsification techniques using the Box- Behnken experimental design. The cytotoxicity study and effect on TNF-α production were evaluated respectively on HIG-82 and RAW 264.7 cells. The study showed that QCT- NE has no toxic effect on synoviocytes and a strong inhibitory effect on LPS-induced TNF-α production. QCT- NE gel has confirmed adequate rheological behavior with a good texture profile and improved drug permeation compared to free QCT gel. In addition, the gel was found to be non-irritating and showed the inhibition of paw edema in rats induced by CFA over 24 h contrary to free QCT gel. In conclusion, the formulation of QCT- NE gel is an efficient topical treatment strategy for rheumatoid arthritis.
... The anticancer properties of turmeric include inhibiting cell proliferation and inducing apoptosis of cancer cells. Yellow spice exhibits anticancer (Azuine and Bhide 1994;Deshpande, Ingle, and Maru 1997;Garg, Ingle, andMaru 2008), hepatic-protective (Miyakoshi et al. 2004), cardioprotective (Mohanty, Arya, andGupta, 2006), hypoglycemic (Kuroda et al., 2005;Honda et al., 2006), and antiarthritic properties (Funk et al., 2006). Phytochemical analysis of turmeric has revealed a large number of compounds, including curcumin, volatile oil, and curcuminoids, which have been found to have potent pharmacological properties. ...
... 31−33 Moreover, while our laboratory has recently demonstrated the ability of aglycone curcumin, but not curcumin-glucuronide, to inhibit osteoclast formation indirectly in osteolytic bone metastasis models, 20 direct effects of aglycone vs glucuronidated curcumin on osteoclast formation have, to our knowledge, not been previously reported. Therefore, experiments were undertaken to (1) determine whether inhibitory effects of curcumin on receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis, the master regulator of bone resorption, 6 are similarly attributable to aglycone, but not glucuronidated curcumin, (2) to examine for the first time the bone-specific pharmacokinetics of curcumin in mice, including an investigation of the capacity of bone marrow to hydrolyze curcumin-glucuronide delivered in vivo to the normal bone microenvironment, and (3) to examine the enzyme dependence of such a process. ...
Article
The biological basis for documented in vivo bone-protective effects of turmeric-derived curcumin is unclear since curcumin is barely detectable in serum, being rapidly conjugated to form what is thought to be an inactive glucuronide. Studies were therefore undertaken to test the postulate that antiresorptive effects of curcumin require deconjugation within bone to form the bioactive aglycone and that β-glucuronidase (GUSB), a deconjugating enzyme expressed by hematopoietic marrow cells, facilitates this site-specific transformation. Consistent with this postulate, aglycone, but not glucuronidated, curcumin inhibited RANKL-stimulated osteoclastogenesis, a key curcumin target in bone. Aglycone curcumin, expressed relative to total curcumin, was higher in bone marrow than in serum of curcumin-treated C57BL/6J mice, while remaining a minor component. Ex vivo, under conditions preventing further metabolism of the unstable aglycone, the majority of curcumin-glucuronide delivered to marrow in vivo was hydrolyzed to the aglycone, a process that was inhibited by treatment with saccharolactone, a GUSB inhibitor, or in mice having reduced (C3H/HeJ) or absent (mps/mps) GUSB activity. These findings suggest that curcumin, despite low systemic bioavailability, may be enzymatically activated (deconjugated) within GUSB-enriched bone to exert protective effects, a metabolic process that could also contribute to bone-protective effects of other highly glucuronidated dietary polyphenols.
... Curcumin is composed of several components, namely curcuminoids, which are comprised of three groups as shown in Fig. 3.43.1: 76.9% curcumin, 17.6% demethoxycurcumin, and 5.5% bis-demethoxycurcumin (Funk et al., 2006;Lawand and Gandhi, 2013). Additionally, it contains volatile oils (tumerone, atlantone, and zingiberone), sugars, proteins, and resins. ...
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Among the plants known for their medicinal values, the plants of the Curcuma genus, which encompass 70 known species, have been traditionally used as a spices, food preservatives, and coloring materials, and are highly significant for their therapeutic potential (Krup et al., 2013). Curcuma longa L., or turmeric, is an everlasting herb and member of the Zingiberaceae (ginger) family which is cultured widely in South East Asia, mostly in India and China (Labban, 2014; Mehrotra et al., 2013). The height of the C. longa tree is approximately 91.44 cm and their leaves appear like lance structures with yellow flower prickles that ripen in its fleshy rhizome or in its underground stem. The source of turmeric medicinal powder is the orange pulp enclosed inside the rhizome (Kocaadam and Şanlier, 2015; Ulbricht et al., 2011). Dried C. longa is the main source of turmeric. The vigorous component of turmeric and the one responsible for its yellow color is known by different names in different countries, for example, it is named curcumin (Fig. 3.43.1) in Arab countries, in India it is called saffron or Haridra (Sanskrit, Ayurvedic), it is known as Jianghuang (yellow ginger) in China, and Kyoo or Ukon in Japan (Goel et al., 2008).
... Thus, just as BCa cells are thought to induce the site-specific release of TGFβ within bone, which drives metastases progression, bone marrow cells may similarly facilitate a microenvironment-specific treatment, mediating the local production of bioactive curcumin. As bone-protective effects of curcumin have also been reported for other disease states, such as arthritis, deconjugation of this polyphenol within bone may be a prerequisite for its bioactivity in other bone diseases as well [52][53][54][55]. Furthermore, these findings suggest that a physiologic role for tissue-specific deconjugation may also extend to other highly glucuronidated naturally occurring polyphenols with bone-protective effects. ...
Article
Breast cancer (BCa) bone metastases (BMETs) drive osteolysis via a feed-forward loop involving tumoral secretion of osteolytic factors (e. g., PTHrP) induced by bone-matrix-derived growth factors (e. g., TGFβ). In prior experiments, turmeric-derived curcumin inhibited in vivo BMET progression and in vitro TGFβ/Smad-signaling in a TGFβ-stimulated PTHrP-dependent human xenograft BCa BMET model (MDA-SA cells). However, it is unclear whether curcumin or curcumin-glucuronide mediates in vivo protection since curcumin-glucuronide is the primary circulating metabolite in rodents and in humans. Thus, effects of curcumin vs. curcumin-glucuronide on Smad-dependent TGFβ signaling were compared in a series of BCa cell lines forming TGFβ-dependent BMET in murine models, and tissue-specific metabolism of curcumin in mice was examined by LC–MS. While curcumin inhibited TGFβ-receptor-mediated Smad2/3 phosphorylation in all BCa cells studied (human MDA-SA, MDA-1833, MDA-2287 and murine 4T1 cells), curcumin-glucuronide did not. Similarly, curcumin, but not curcumin-glucuronide, blocked TGFβ-stimulated secretion of PTHrP from MDA-SA and 4T1 cells. Because the predominant serum metabolite, curcumin-glucuronide, lacked bioactivity, we examined tissue-specific metabolism of curcumin in mice. Compared to serum and other organs, free curcumin (both absolute and percentage of total) was significantly increased in bone, which was also a rich source of enzymatic deglucuronidation activity. Thus, curcumin, and not curcumin-glucuronide, appears to inhibit bone-tropic BCa cell TGFβ-signaling and to undergo site-specific activation (deconjugation) within the bone microenvironment. These findings suggest that circulating curcumin-glucuronide may act as a prodrug that preferentially targets bone, a process that may contribute to the bone-protective effects of curcumin and other highly glucuronidated dietary polyphenols.
... Ex-vitro treatments showed the prevention of initiation and progression of NF-KB involving chemokine, cyclooxygenase 2, and RANKL-regulated inflammation and destruction of genes mediating joints. Consistent with these findings, turmeric extract treatment inhibits the influx of inflammatory cells, levels of prostaglandin E2 in the joints and particularly the synthesis of osteoclasts (Funk et al., 2006). Scientist treated female rates with turmeric essential oil TEO to induce changes in the arthritis that were induced with streptococcal cell wall (SCW). ...
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Plant based traditional health care is one of the ancient remedies used to prevent and treat different health related disorders. Due to increasing cost of medicine in the modern era, people are now moving towards the utilization of ancient ethno medicinal plants based remedies to prevent and treat diseases as well as to maintain their health. Curcuma longa, commonly known as turmeric has been used since ancient times as ethno medicinal plant due to its pharmacological and therapeutic potential. The rhizome of this plant is commonly used to prevent the lifestyle related disorders. Its biologically active components can also be extracted and utilized directly to enhance the efficacy. Purpose of this review is to highlight the importance of turmeric as it contains various biologically active components that are beneficial in prevention and treatment of various health related disorders. Turmeric has been demonstrated to exhibit anti-cancer, immunostimulant, skin protection, ulcer treating, anti-inflammatory, anti-malarial, anti-bacterial, anti-fungal, anti-viral, anti-parasitic, anti-hyperglycemic, anti-oxidant, anti-hyperlipidemic, hepatoprotective, renal protection and hematological parameters maintenance properties. There is no evidence of adverse effects of turmeric in literature. Only the people who are allergic to it can have side effects otherwise it is almost stomach friendly due to which it can be used for treatment of various health related disorders.
... Curcumin (Diferuloylmethane, 1, 7-bis (4-Hydroxy-3-methoxyphenyl)-1, 6-heptadiene-3, 5 -dione) [25] is the active polyphenolic compound extracted from the rhizomes of turmeric (Curcuma longa L., Zingiberaceae) a member of the ginger family, grown in tropical Southeast Asia [26]. Some studies demonstrated the efficacy of turmeric extracts in the prevention of bone loss in animal models of rheumatoid arthritis and postmenopausal osteoporosis [27][28][29]. In vitro investigations have identified that the anti-inflammatory effects of curcumin able to prevent osteoclast differentiation [30,31]. ...
... The natural substance curcumin (diferuloylmethane), isolated directly from the rhizome of the healing plant turmeric (Curcuma longa L. Zingiberaceae), is broadly applied in the field of traditional medicine [16,17]. In addition, it has been reported that curcumin has robust potency as an anti-inflammatory, anticytokine, anti-bacterial, anti-viral, anti-tumor, cardioprotective agent, and can also suppress cytokine production by specifically suppressing the NF-kB phosphorylation, which is why it is referred to as a natural NF-kB inhibitor [18][19][20][21]. Its modulatory effects on inflammatory processes and related diseases, including OA and RA, have also been studied. ...
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Inflammation has a fundamental impact on the pathophysiology of osteoarthritis (OA), a common form of degenerative arthritis. It has previously been established that curcumin, a component of turmeric (Curcuma longa), has anti-inflammatory properties. This research evaluates the potentials of curcumin on the pathophysiology of OA in vitro. To explore the anti-inflammatory efficacy of curcumin in an inflamed joint, an osteoarthritic environment (OA-EN) model consisting of fibroblasts, T-lymphocytes, 3D-chondrocytes is constructed and co-incubated with TNF-α, antisense oligonucleotides targeting NF-kB (ASO-NF-kB), or an IkB-kinase (IKK) inhibitor (BMS-345541). Our results show that OA-EN, similar to TNF-α, suppresses chondrocyte viability, which is accompanied by a significant decrease in cartilage-specific proteins (collagen II, CSPG, Sox9) and an increase in NF-kB-driven gene proteins participating in inflammation, apoptosis, and breakdown (NF-kB, MMP-9, Cox-2, Caspase-3). Conversely, similar to knockdown of NF-kB at the mRNA level or at the IKK level, curcumin suppresses NF-kB activation, NF-kB-promotes gene proteins derived from the OA-EN, and stimulates collagen II, CSPG, and Sox9 expression. Furthermore, co-immunoprecipita-tion assay shows that curcumin reduces OA-EN-mediated inflammation and chondrocyte apopto-sis, with concomitant chondroprotective effects, due to modulation of Sox-9/NF-kB signaling axis. Finally, curcumin selectively hinders the interaction of p-NF-kB-p65 directly with DNA-this association is disrupted through DTT. These results suggest that curcumin suppresses inflammation in OA-EN via modulating NF-kB-Sox9 coupling and is essential for maintaining homeostasis in OA by balancing chondrocyte survival and inflammatory responses. This may contribute to the alternative treatment of OA with respect to the efficacy of curcumin.
... Upon heat stress exposure, it can increase the expression of heat stress chaperones like HSP27, B crystallin, and HSP70. Its arthritis and joint erosion inhibitory potentialities have also been reported in a dose-dependent manner in the T cell mediated approach using an experimental model of streptococcal cell wallinduced arthritis [604]. A study conducted in broilers for assessing the impact of Tulsi (O. ...
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Background: Constant exposure to various stressors, such as immune pressure, rapidly increasing population, deleterious changes in the ecosystem, climate change, infection with emerging and re-emerging pathogens, and fast-paced lifestyle, is a critical factor in the globally increasing incidences of immunocompromising health conditions, as well as stress. Synthetic chemotherapeutic agents, which are widely available in the commercial market, may be highly efficacious, but most are immunosuppressive and exert many side effects. Methods: Herein, we comprehensively reviewed current literature from various scientific databases such as Bentham Science, PubMed, Scopus, Elsevier, Springer, etc. The inclusion/exclusion criteria based on literature with high importance was adopted to analyze and compile salient information from the authentic bibliographic sources. Results: Undoubtedly, the pivotal characteristics of immunostimulants and immunomodulators in the maintenance of the health and productivity of humans, as well as animals, cannot be overlooked. Numerous herbs used in ethnoveterinary medicine can be successfully employed as adjuvant rehabilitators to negate the deleterious effects of chemotherapeutics. The sources of these medicinal remedies are part of long traditions in different regions of the world, such as Indian Ayurveda and Traditional Chinese Medicine, which have been developed through empirical experience. Traditional medicine employs a holistic approach to the prevention of disease, and traditional herbal medicines are a source of many components with a high therapeutic value that are used in modern allopathic medicine. Globally, many studies have been conducted on these herbs and have revealed unique active constituents that activate the innate immune system through the stimulation of macrophages and lymphocytes, and modulation of the cytokine profile, which leads to a state of alertness with a subsequent reduction in the incidence of infection. Immunomodulatory constituents with herbal origins are termed as phytochemicals, including flavonoids, glycosides, polysaccharides, terpenoids, essential oils, various bitters, and alkaloids; all these compounds exert vital, multidimensional effects. Efforts have focused on screening plant preparations to identify adjuvant immune properties; furthermore, several potent phytol adjuvants have been experimentally proven to downregulate inflammatory reactions in addition to enhance specific adaptive responses to vaccines. Conclusions: In summary, this review summarizes the current status and future prospects regarding the immunomodulatory potential of various herbs and plants and their promising utility for designing and developing effective drugs and medicines in safeguarding the health of humans, animals, and poultry.
... In folk medicine, turmeric is used for respiratory diseases such as allergy, liver problems, sinusitis and anorexia [12]. Nowadays other effects have identified from this medicinal herb such as anticancer [13,14], cardioprotective [15], hepatoprotective [16,17], antiarthritic properties [18] and hypoglycemic [19]. Also it is applied in oral cancer, skin cancer [20], stomach cancer [21] and metabolic syndrome [22]. ...
Article
Curcuma longa is a rhizomatous perennial herb that belongs to the family Zingiberaceae, native to South Asia and is commonly known as turmeric. It is used as herbal remedy due to the prevalent belief that the plant has medical properties. C. longa possesses different effects such as antioxidant, anti-tumor, antimicrobial, anti-inflammatory, wound healing, and gastroprotective activities. The recent studies have shown that C. longa and curcumin, its important active ingredient, have protective effects against toxic agents. In this review article, we collected in vitro and animal studies which are related to protective effects of turmeric and its active ingredient against natural and chemical toxic agents.
... Extract of turmeric has been shown to inhibit joint inflammation and peri-articular joint destruction in arthritic mice model. A study showed a suppression of NFκB regulated joint inflammation and destruction by suppressing the expression of chemokines, COX-2, and RANKL [22] . Another study showed that turmeric can reduce inflammation and promote the repair parameters of healing process during gingival healing in beagle dogs [23] . ...
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Korean oriental medicine prescription is widely used for the treatment of gouty diseases. In the present study, we investigated anti-inflammatory effects of modified Korean herbal formulation, mixed extract of medicinal herbs (MEMH), and its modulatory effects on inflammatory mediators associated with gouty arthritis. Both in vitro and in vivo studies were carried out to assess the anti-inflammatory efficacy of MEMH on monosodium urate (MSU) crystals-induced gouty inflammation. MSU crystals stimulated human chondrosarcoma cell line, SW1353, and human primary chondrocytes were treated with MEMH in vitro. The expression levels of pro-inflammatory mediators and metalloproteases were analyzed. The effect of MEMH on NFκB signaling pathway in SW1353 cells was examined. Effect of MEMH on the mRNA expression level of pro-inflammatory mediators and chemotactic factor from human monocytic cell line, THP-1, was also analyzed. The probable role of MEMH in the differentiation process of osteoblast like cells, SaOS-2, after MSU treatment was also observed. To investigate the effects of MEMH in vivo, MSU crystals-induced ankle arthritic model was established. Histopathological changes in affected joints and plasma levels of pro-inflammatory mediators (IL-1β and TNFα) were recorded. MEMH inhibited NFκB signaling pathway and COX-2 protein expression in chondrocytes. MSU-induced mRNA expressions of pro-inflammatory mediators and chemotactic cytokines were suppressed by MEMH. In MSU crystals-induced ankle arthritic mouse model, administration of MEMH relieved inflammatory symptoms and decreased the plasma levels of IL-1β and TNFα. The results indicated that MEMH can effectively inhibit the expression of inflammatory mediators in gouty arthritis, demonstrating its potential for treating gouty arthritis.
... However, countries such as India where holistic medicine is practiced and curcumin (Figure 3a) has been traditionally consumed in meals almost every day for millennia, show the lowest incidence of any type of cancer in the world. Moreover, many investigations have shown the positive impact of curcumin, curcuminoids (Figure 3b), and derivatives on controlling and healing cancers and other diseases (26)(27)(28)(29)(30)(31)(32)(33). ...
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The burden of chronic diseases, such as cancer, diabetes, heart disease, and hypertension is so heavy that health care systems’ provisions are hampered in many countries. The high incidence of chronic diseases might be mainly explained through poor diets and detrimental conditions of lifestyle. A distinct insight on healing and preventing those diseases will be described in this short review, which includes our own work.
... Results were promising as at least 42 NF-jBregulated genes were targeted. Furthermore, the expression of genes controlled by NF-jB-regulated gene products were also affected by turmeric treatment in SCW-induced arthritis model (Funk et al. 2006). ...
Article
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune destructive arthropathy prevalent among people in the age group of 40-70 years. RA induces severe pain, swelling and stiffness of joints resulting in bone damage. RA leads to reduced life expectancy when left untreated. RA is characterized by synovial hyperplasia, infiltration of inflammatory cells resulting in formation of pannus. Synovial hyperplasia is mediated by proinflammatory cytokines, notably IL-1 and TNF-α. NF-κB is a predominant transcription factor in amplifying the inflammatory response. The translocation of activated NF-κB into the nucleus triggers the transcription of several genes that induce proinflammatory cytokine production. The inhibition of NF-κB translocation aids blocking the activation of proinflammatory cascades. The quest for more effective and side-effect free treatment for RA unveiled phytochemicals as efficacious and promising. Phytochemicals have been a source of therapeutic substances for many ailments from ancient times. Their therapeutic ability helps in developing potent and safe drugs targeting immune inflammatory diseases driven by NF-κB including RA. This review highlights the importance of NF-κB inflammatory cascade in RA so as to elucidate the crucial role of phytochemicals that inhibit the activity of NF-κB.
... Active constituents are curcumin (curcumin I), desmethoxycurcumin (curcumin II), bisdesmethoxycurcumin (curcumin III), and dihydrocurcumin 12 . Experimental antiarthritic activity shown by inhibition of the expression of cyclooxygenase (COX)-2, reduction of PGE 2 , preventing the activation on nuclear factor-kB (NF-kB) 13 . Studies carried out for antirheumatic activity showed absence of side effect, efficient, safe to use, suppress the fibroblast-like synoviocytes proliferation and DNA synthesis induced by plateletinduced growth factor [14][15][16][17] . ...
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Rheumatoid arthritis (RA) is chronic, debilitating disease that follows a progressive course characterized by persistent inflammation and erosive joints damage leading to functional disability. The cause of rheumatoid arthritis remains unknown. Several disadvantages like serious side effects, high cost and requirement of parenteral administration still invite more research in this area to provide a convenient, affordable therapy with lesser or no side effects. The medicinal properties of plants have been investigated in the light of recent scientific developments throughout the world, due to their potent pharmacological activities, low toxicity and economic viability. The present review focuses on pharmacology of rheumatoid arthritis and traditional herbs which are potential candidate for treatment of rheumatoid arthritis. Due to effectiveness, safety, economical reasons herbal treatments will open doors for advanced research in treatment of rheumatoid arthritis. © 2017, National Institute of Science Communication and Information Resources (NISCAIR). All rights reserved.
... Animal studies. In an animal arthritis model a preparation from CL lacking essential oil strongly suppressed joint inflammation and periarticular damage in correlation with decreased activation of NF-κB and of the ensuing cascade of events (involving mediators of inflammation and injury such as chemokines, cyclooxygenase 2, and receptor activator of nuclear factor kappa-B ligand (RANKL)) [49]. The ability to prevent the destructive changes in joints and periarticular bone seems to be comparable to that of betamethasone [50,51]. ...
Article
Chronic joint inflammatory disorders such as osteoarthritis and rheumatoid arthritis have in common an upsurge of inflammation, and oxidative stress, resulting in progressive histological alterations and disabling symptoms. Currently used conventional medication (ranging from pain-killers to biological agents) is potent, but frequently associated with serious, even life-threatening side effects. Used for millennia in traditional herbalism, medicinal plants are a promising alternative, with lower rate of adverse events and efficiency frequently comparable with that of conventional drugs. Nevertheless, their mechanism of action is in many cases elusive and/or uncertain. Even though many of them have been proven effective in studies done in vitro or on animal models, there is a scarcity of human clinical evidence. The purpose of this review is to summarize the available scientific information on the following joint-friendly medicinal plants, which have been tested in human studies: Arnica montana, Boswellia spp., Curcuma spp., Equisetum arvense, Harpagophytum procumbens, Salix spp., Sesamum indicum, Symphytum officinalis, Zingiber officinalis, Panax notoginseng, and Whitania somnifera.
... Over the last 60 years, numerous studies have demonstrated that curcumin can be used to treat a wide variety of diseases like cancer (Momtazi & Sahebkar, 2016b;Teymouri, Pirro, Johnston, & Sahebkar, 2017), type 2 diabetes (Panahi et al., 2017a;Panahi et al., 2018), neurodegenerative disease (Ghosh, Banerjee, & Sil, 2015;Monroy, Lithgow, & Alavez, 2013), hepatic disorders (Alappat & Awad, 2010;El-Agamy, 2010;Panahi et al., 2016;Panahi et al., 2017b;Rahmani et al., 2016;Zabihi, Pirro, Johnston, & Sahebkar, 2017), cardiovascular disease (Cicero et al., 2017;Ganjali et al., 2017;Saeidinia et al., 2018), metabolic disorders (Panahi, Khalili, Hosseini, Abbasinazari, & Sahebkar, 2014aa;Sahebkar, 2013), arthritis (Panahi et al., 2014b;Sahebkar & Henrotin, 2016), autoimmune disease (Abdollahi, Momtazi, Johnston, & Sahebkar, 2018;Lelli, Sahebkar, Johnston, & Pedone, 2017;Momtazi-Borojeni et al., 2017), pulmonary disorders (Lelli et al., 2017), thrombotic disorders (Keihanian, Saeidinia, Bagheri, Johnston, & Sahebkar, 2018), and inflammatory diseases (Chandran & Goel, 2012;Funk et al., 2006a;Funk et al., 2006b). ...
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Turmeric extracts contain three primary compounds, which are commonly referred to as curcuminoids. They are curcumin, demethoxycurcumin (DMC), and bisdemethoxycurcumin. While curcumin has been the most extensively studied of the curcuminoids, it suffers from low overall oral bioavailability due to extremely low absorption as a result of low water solubility and instability at acidic pH, as well as rapid metabolism and clearance from the body. However, DMC, which lacks the methoxy group on the benzene ring of the parent structure, has much greater chemical stability at physiological pH and has been recently reported to exhibit antitumor properties. However, the treatment of noncancerous diseases with DMC has not been comprehensively reviewed. Therefore, here we evaluate published scientific literature on the therapeutic properties of DMC. The beneficial pharmacological actions of DMC include anti‐inflammatory, neuroprotective, antihypertensive, antimalarial, antimicrobial, antifungal, and vasodilatory properties. In addition, DMC's ability to ameliorate the effects of free radicals and an environment characterized by oxidative stress caused by the accumulation of advanced glycation end‐products associated with diabetic nephropathy, as well as DMC's capacity to inhibit the migration and proliferation of vascular smooth muscle cells following balloon angioplasty are also addressed. This review collates the available literature regarding the therapeutic possibilities of DMC in noncancerous conditions. Here, our aim was to review the biological and pharmacological activity of demethoxycurcumin relevant to the treatment of noncancerous diseases.
... There are no studies reporting effects of C. longa on production of LPS-induced NO in cartilage explants with which to compare our data, and no studies which seek to identify post-hepatic biotransformation products in this model. However, our data support a mild inhibitory effect of TUR sim on LPS-induced NO production which may contribute to the anti-arthritic effect reported from turmeric [22,23], curcumin [24][25][26], and other turmeric-based compounds [27][28][29]. ...
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Background: Turmeric is commonly used as a dietary treatment for inflammation, but few studies have evaluated the direct effect of turmeric on cartilage. The purpose of this study was to characterize cartilage explants' inflammatory responses to lipopolysaccharide in the presence of a simulated biological extract of turmeric. Methods: Turmeric was incubated in simulated gastric and intestinal fluid, followed by inclusion of liver microsomes and NADPH. The resulting extract (TURsim) was used to condition cartilage explants in the presence or absence of lipopolysaccharide. Explants were cultured for 96 h (h); the first 24 h in basal tissue culture media and the remaining 72 h in basal tissue culture media containing TURsim (0, 3, 9 or 15 μg/mL). Lipopolysaccharide (0 or 5 μg/mL) was added for the final 48 H. media samples were collected immediately prior to lipopolysaccharide exposure (0 h) and then at 24 and 48 h after, and analyzed for prostaglandin E2 (PGE2), glycosaminoglycan (GAG), and nitric oxide (NO). Explants were stained with calcein-AM for an estimate of live cells. Data were analyzed using a 2-way repeated measures (GAG, PGE2, NO) or 1-way ANOVA without repeated measures (viability). Significance accepted at p < 0.05. Results: TURsim significantly reduced PGE2, NO and GAG, and calcein fluorescence was reduced. Conclusions: These data contribute to the growing body of evidence for the utility of turmeric as an intervention for cartilage inflammation.
... The bone metabolism alterations are frequently related to the resorption process either in the form of generalized osteolysis, such as osteoporotic fractures in old age and postmenopause subjects, or focal ones, especially at the level of joints in rheumatoid arthritis and bone metastases [56]. Therefore, the level changes of sex hormones such as oestrogen and testosterone, growth factors, and increased adiposity in the bone marrow, hematopoietic cells, and aged cells could influence the bone resorption processes, producing an increased osteoclast activity stimulated by RANKL [55,[57][58][59][60][61][62][63][64] (Figure 6). ...
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Phenolic compounds are natural phytochemicals that have recently reported numerous health benefits. Resveratrol, curcumin, and quercetin have recently received the most attention among these molecules due to their documented antioxidant effects. The review aims to investigate the effects of these molecules on bone metabolism and their role in several diseases such as osteopenia and osteoporosis, bone tumours, and periodontitis. The PubMed/Medline, Web of Science, Google Scholar, Scopus, Cochrane Library, and Embase electronic databases were searched for papers in line with the study topic. According to an English language restriction, the screening period was from January 2012 to 3 July 2022, with the following Boolean keywords: ("resveratrol" AND "bone"); ("curcumin" AND "bone"); ("quercetin" AND "bone"). A total of 36 papers were identified as relevant to the purpose of our investigation. The studies reported the positive effects of the investigated phenolic compounds on bone metabolism and their potential application as adjuvant treatments for osteoporosis, bone tumours, and periodontitis. Furthermore, their use on the titanium surfaces of orthopaedic prostheses could represent a possible application to improve the osteogenic processes and osseointegration. According to the study findings, resveratrol, curcumin, and quercetin are reported to have a wide variety of beneficial effects as supplement therapies. The investigated phenolic compounds seem to positively mediate bone metabolism and osteoclast-related pathologies. Citation: Inchingolo, A.D.; Inchingolo, A.M.; Malcangi, G.; Avantario, P.; Azzollini, D.; Buongiorno, S.; Viapiano, F.; Campanelli, M.; Ciocia, A.M.; De Leonardis, N.; et al. Effects of Resveratrol, Curcumin and Quercetin Supplementation on Bone Metabolism-A Systematic Review.
... Patient was seated in a specially designed sauna cabin at a temperature of 50e55 C. arthritis [17]. However, the earlier trials used the extract of the curcumin administered internally, whereas we used turmeric paste as a topical application. ...
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A 57 years old male patient was admitted to an inpatient Naturopathy and Yoga (N&Y) hospital, diagnosed with pemphigus vulgaris (PV) for one year and co-morbid type 2 diabetes (T2DM) for 10 years, associated with poor quality of life (QoL). He was administered N&Y therapies for 10 days, along with conventional medicines. There was improved QoL and reduced dosage of insulin, along with reduction in body weight. These changes were sustained and improved further during the 60-day follow-up period. Although there was no improvement in the skin lesions, the improvement in QoL indicate a possible role of N&Y in management of PV and T2DM. This case report also warrants further studies for N&Y in the management of dermatological conditions as well as metabolic syndrome.
... Local activation of NF-κβ and the expression of NFκβ-regulated genes were also prevented, and chemokines, COX-2, and RANKL were decreased. 200 Treatment with turmeric essential oils (TEO, i.p.) for 1 month inhibited joint swelling (90%-100% inhibition) in female rats with the SCW-induced arthritis, but it was accompanied by significant morbidity and mortality. Treatment with a 20-fold higher TEO dose, p.o. was nontoxic, but only showed mildly joint-protective (20% inhibition) effect. ...
Article
Curcuma longa (C. longa) or turmeric is a plant with a long history of use in traditional medicine, especially for treating inflammatory conditions C. longa and its main constituent, curcumin (CUR), showed various pharmacological effects such as antioxidant and anti-microbial properties. The updated knowledge of anti-inflammatory, antioxidant, and immunomodulatory effects of C. longa and CUR is provided in this review article. Pharmacological effects of C. longa, and CUR, including anti-inflammatory, antioxidant, and immunomodulatory properties, were searched using various databases and appropriate keywords until September 2020. Various studies showed anti-inflammatory effects of C. longa and CUR, including decreased white blood cell, neutrophil, and eosinophil numbers, and its protective effects on serum levels of inflammatory mediators such as phospholipase A2 and total protein in different inflammatory disorders. The antioxidant effects of C. longa and CUR were also reported in several studies. The plant extracts and CUR decreased malondialdehyde and nitric oxide levels but increased thiol, superoxide dismutase, and catalase levels in oxidative stress conditions. Treatment with C. longa and CUR also improved immunoglobulin E (Ig)E, pro-inflammatory cytokine interleukin 4 (IL)-4, transforming growth factor-beta, IL-17, interferon-gamma levels, and type 1/type 2 helper cells (Th1)/(Th2) ratio in conditions with disturbance in the immune system. Therefore C. longa and CUR showed anti-inflammatory, antioxidant, and immunomodulatory effects, indicating a potential therapeutic effect of the plant and its constituent, CUR, for treating of inflammatory, oxidative, and immune dysregulation disorders.
... Curcuma longa have adequate amount of volatile oils like tumerone, atlantone and zingiberone, proteins, sugars and resins. This medicinal plant is particularly composed of approximately 2-9 % of curcuminoids among which the most important are curcumin (76.9%), demethoxycurcumin (17.6%), and bis-demethoxycurcumin (5.5%) and curcumin having major therapeutic potential [22,23]. Curcumin is polyphenol which is water insoluble and stable in acidic pH of the stomach [24]. ...
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Medicinal plants are being used for therapeutic purposes since the dawn of human civilization. The therapeutic efficacy of medicinal plants is due to the presence of wide range phytochemical constituents or secondary metabolites. The medicinal plants are traditionally used for several types of ailments. Even in those pathological conditions where other methods of treatment fail to work. Curcuma longa Linn is very common ingredient used as spice in foods as preservative and coloring material in different part of the world. It has been used as a home remedy for a variety of diseases. Curcuma longa and its isolated constituent curcumin are widely evaluated for anticancer activity. Curcumin possesses broad remedial potential due to its multi-targeting effect against many different carcinoma including leukemia, genitourinary cancers, gastrointestinal cancers and breast cancer etc. Hence, Curcumin has potential for the development of new medicine for the treatment of several diseases.
... Animal studies. In an animal arthritis model a preparation from CL lacking essential oil strongly suppressed joint inflammation and periarticular damage in correlation with decreased activation of NF-κB and of the ensuing cascade of events (involving mediators of inflammation and injury such as chemokines, cyclooxygenase 2, and receptor activator of nuclear factor kappa-B ligand-RANKL) [37]. The ability to prevent the destructive changes in joints and periarticular bone seems to be comparable to that of betamethasone [38,39]. ...
Preprint
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Chronic joint inflammatory disorders such as osteoarthritis and rheumatoid arthritis have in common an upsurge of inflammation, and oxidative stress, resulting in progressive histological alterations and disabling symptoms. Currently used conventional medication (ranging from pain-killers to biological agents) is potent, but frequently associated with serious, even life-threatening side effects. Used for millennia in traditional herbalism, medicinal plants are a promising alternative, with lower rate of adverse events and an efficiency frequently comparable with that of conventional drugs. Nevertheless, their mechanism of action is in many cases elusive and/or uncertain. Even many of them have been proved effective in studies done in vitro or on animal models, there is a scarcity of human clinical evidence. The purpose of this review is to summarise the available scientific information on these joint-friendly medicinal plants, which have been already tested in human studies: Arnica montana, Boswelliaspp., Curcuma spp., Equisetum arvense, Harpagophytumprocumbens, Salix spp., Sesamumindicum, Symphytumofficinalis, Zingiberofficinalis, Panaxnotoginseng, Whitaniasomnifera.
... in Currypulver und Gewürzmischungen eingesetzt. Es ist weithin als Gewürz bekannt und findet in der Naturheilkunde als Mittel gegen rheumatoide Arthritis, bei entzündlichen Erkrankungen und Schmerzen Verwendung (Funk, Frye et al. 2006, Schiborr, Kocher et al. 2014. Großes Interesse gilt der Substanz in Bezug auf einen möglichen Einsatz im Rahmen onkologischer Therapien, denn ein antiproliferativer und proapoptotischer Effekt des Curcumins auf verschiedenste bislang getestete Tumorzellarten konnte nachgewiesen werden Sung 2009, Wang, Chen et al. 2017). ...
Thesis
Übergewicht, das als Volkskrankheit ein wachsendes globales Problem darstellt, ist mit mehreren folgenreichen Komorbiditäten behaftet und die Assoziation der Erkrankung mit nachweisbarer Schädigung des Erbguts durch oxidativen Stress ist mittlerweile unangefochten. In der vorliegenden Studie wurden periphere Lymphozyten stark bis morbid adipöser Patienten mit Hilfe des Mikrokern-Assays untersucht und es konnte – begleitend zu der zu erwartenden BMI-Abnahme – eine signifikante Reduktion des Genomschadens durch Magenbypass bzw. Sleeve-Gastrektomie 12 Monate postoperativ detektiert werden. Daneben demonstrierte die Analyse zusätzlich erhobener Patientendaten, die u. a. Nüchternglucose, HbA1c, Blutdruck und Herzfrequenz sowie ein Blutbild der Patienten (inklusive CRP als Entzündungsmarker, Transaminasen, gGT sowie Lipidprofil) umfasste, eine deutliche Besserung vieler Parameter bis auf teilweise wieder physiologische Normwerte. All diese Ergebnisse stützen die These der metabolischen Wirksamkeit sowohl des Roux-en-Y-Magenbypass als auch der Sleeve- Gastrektomie. Ihre Bedeutung liegt nicht zuletzt in der angenommenen Reduktion des Krebserkrankungsrisikos, da jeweils ein Zusammenhang mit der Adipositas an sich, dem Diabetes und durch oxidativen Stress verursachter DNA-Schädigung besteht. Mit Blick auf eine gegenwärtig in der Forschung diskutierte potentielle therapeutische Anwendung von Antioxidantien zur Reduktion von Erbgutschädigungen, die durch oxidativen Stress zustande kommen, wurden die Substanzen Tricetinidin, Curcumin und Resveratrol im Rahmen des Mikrokerntests an HL60- und NRK-Zellen untersucht, in denen mit der Mischung aus Insulin und Angiotensin II eine gentoxische Wirkung erzielt worden war.
... Furthermore, the bone has been shown to contain more aglycone curcumin and curcumin than other tissues when curcumin is ingested, probably because the βglucuronidase expressed in bone marrow cells deconjugates TBP1901 [35,43]. Previous studies on bone diseases using curcumin have reported that the deglucuronidation activity of bone marrow cells has given bone protective effects, despite curcumin having low bioavailability [44,45]. Therefore, TBP1901 may act as a pro-drug that targets the bone. ...
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Background: Curcumin has anti-inflammatory effects. However, curcumin is poorly water-soluble, and when administered orally, formscurcumin conjugates with poor efficacy.Curcumin monoglucuronide (TBP1901) is highly water-soluble and can existinthe free-form in a greater proportion than curcumin in vivo. This study aimed to evaluate the effectiveness of intra-articular TBP1901 injections fora rat model of osteoarthritis (OA). Methods: Sixty-four male Wistar rats (12weeks old) that had receivedthe destabilized medial meniscus(DMM) surgery, were randomly separatedinto the TBP1901 injectionandthe saline solution injection (control) group. They were sacrificedat 1, 2, 6, or 10weeks postoperatively(n = 8 for each). The TBP1901 (30mg/mL) andsaline solutionof 50μLwere administered to the knee joint through the patella tendon twice a week for the rats sacrificedat1 and 2weeks or once a week for at6 and 10weeks. The OA changes were evaluated by micro-computed tomography (micro-CT), histology, and immunohistochemical analysis. Results:Curcumin fluorescence was confirmed in the articular cartilageand synovium of rats with TBP1901 injections at all observation periods.The TBP1901injections significantly reducedthe synovial inflammation at 1 and 2 weeks and the expression of TNFα in thetibialarticular cartilage at 6 weeks postoperatively.Moreover, TBP1901 injections ameliorated the articular cartilage structure, the subchondral bone (SB) plate thickness, and perforations from 6 to 10 weeks.As a result, there were significant differencesbetween groups in OA scores, SB plate thickness, and perforations at 10 weeks postoperatively.In addition, osteophyte formation in the TBP1901group was significantly suppressed after 10 weeks. Conclusion: This study reports the first evidence that TBP1901 injections suppress inflammation and osteophyte formation, and ameliorate the articular cartilage and SB pathologies by absorption in the articular cartilage and synovium in a rat DMM model.Therefore, intra-articular injections of TBP1901may be effective in improving OA pathology.
Article
Curcuma species are well‐known herbal plants used for treatment of various ailments and metabolic disorders. Curcuma longa has been used since long times as a condiment to give flavors in vegetables. Curcuma zedoaria has been used in the Indian traditional system of medicine for the treatments of many human ailments. Curcuma mangga is used as remedy for the treatment of stomach pain, fever, debility, bronchitis, and asthma. The rhizomes and shoots were used as explants for induction of callus in the case of turmeric. Turmeric possesses anticancer activity against skin cancer, breast cancer, oral cancer, and stomach cancers. Turmeric extract prevents animal tumors induced by Dalton’s lymphoma. The Curcuma longa leaves contain essential oils that are used in perfume industry as well as for aromatherapy.
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Since primitive times, herbs have been extensively used in conventional remedies for boosting cognitive impairment and age-associated memory loss. It is mentioned that medicinal plants have a variety of dynamic components, and they have become a prominent choice for synthetic medications for the care of cognitive and associated disorders. Herbal remedies have played a major role in the progression of medicine, and many advanced drugs have already been developed. Many studies have endorsed practicing herbal remedies with phytoconstituents, for healing Alzheimer’s disease (AD). All the information in this article was collated from selected research papers from online scientific databases, such as PubMed, Web of Science, and Scopus. The aim of this article is to convey the potential of herbal remedies for the prospect management of Alzheimer’s and related diseases. Herbal remedies may be useful in the discovery and advancement of drugs, thus extending new leads for neurodegenerative diseases such as AD. Nanocarriers play a significant role in delivering herbal medicaments to a specific target. Therefore, many drugs have been described for the management of age-linked complaints such as dementia, AD, and the like. Several phytochemicals are capable of managing AD, but their therapeutic claims are restricted due to their lower solubility and metabolism. These limitations of natural therapeutics can be overcome by using a targeted nanocarrier system. This article will provide the primitive remedies as well as the development of herbal remedies for AD management.
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Herbal supplements containing curcumin and other ingredients are used for pain management in horses with osteoarthritis (OA). To test the effects of a herbal supplement containing curcumin and other ingredients in horses with lameness due to naturally occurring OA. Two‐period randomised crossover design. Ten Thoroughbreds with naturally occurring chronic OA were randomly assigned to the treatment (BLP; Buteless® Performance) or control (CTR, no supplement) groups and fed daily for 30 days. On Days −1 (before treatment), 15 and 30, lameness examination, range of motion, pain on palpation and force platform data were collected. Plasma curcumin concentration and its metabolites were measured on Days 1 and 14. Gastroscopy, a complete blood count and a serum biochemistry panel were performed on each horse before treatment Day −1 and Day 31. Gastric lesions (ulcers) were scored in real time by a masked investigator. Mean peak vertical force (PVF), measured by the force platform, significantly increased in the lame limb of the BLP‐treated horses on Days 15 (0.40 ± 0.13 N/kg, (p = 0.0025) and 30 (0.63 ± 0.14 N/kg, p < 0.0001) compared to the CTR group. In addition, mean normalised PVF was higher in the BLP group on Day 15 (p = 0.0438) and on day 30 (p = 0.0003) when compared to CTR horses for the same days. The PVF significantly improved (≥5%; range, 5.2–33%) in six of nine individual BLP‐treated horses and did not improve (<5%; range, 0–3.4%) in three of nine BLP‐treated horses. Also, PVF improved (≥5%; range, 7.6–15.4%) in three of nine horses in the CRT group. Squamous gastric lesion scores significantly decreased in both groups by Day 31. Plasma curcumin‐O‐sulphate concentrations (1.2–3.3 ng/ml) were present in 9/10 BLP‐treated horses by Day 14. Small sample size and absence of a positive treatment (non‐steroidal anti‐inflammatory drug) control. The BLP supplement containing curcumin achieved plasma concentrations and improved weight bearing in some treated horses with naturally occurring OA.
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Objective To evaluate the randomized controlled trials (RCTs) of Curcumin and Curcuma longa Extract in the treatment of autoimmune diseases. Methods Databases such as Embase, Web of Science, PubMed and The Cochrane Library were searched from the database establishment to February 2022 to collect RCTs of Curcumin and Curcuma longa Extract in the treatment of autoimmune diseases. Then the literature was screened and the data were extracted. Meta-analysis was performed using RevMan 5.3 software. Results A total of 34 records were included, involving 31 RCTs and 10 types of autoimmune disease. Among them, ankylosing spondylitis (AS) involves one RCT, Behcet ‘s disease (BD) involves one RCT, Crohn ‘s disease involves two RCTs, multiple sclerosis (MS) involves two RCTs, oral lichen planus involves six RCTs, psoriasis involves two RCTs, rheumatoid arthritis (RA) involves five RCTs, systemic lupus erythematosus (SLE) involves two RCTs, arteritis involves one RCT, ulcerative colitis (UC) involves nine RCTs. Among them, most of the RCTs of ulcerative colitis (UC), oral lichen planus, RA showed that curcumin and curcumin extracts improved clinical or laboratory results. Crohn ‘ s disease, MS, SLE, psoriasis included two RCTs; they all showed improvements (at least one RCT reported improvements in clinical outcomes). AS, BD and arteritis included only one RCT, and the clinical results showed improvement. However, due to the small number of RCTs and the small number of patients involved in each disease, there is still a need for more high-quality RCTs. Conclusion Curcumin and Curcuma longa Extract had good clinical efficacy in the treatment of Psoriasis, UC and RA, so Curcumin and Curcuma longa Extract could be used in the treatment of the above diseases in the future. The results of Meta-analysis showed that Curcumin and Curcuma longa Extract did not show efficacy in the treatment of oral lichen planus, while Takayasu arteritis, SLE, MS, AS, BD and CD did not report sufficient clinical data for meta-analysis. Therefore, large-sample, multi-center clinical trials are still needed for revision or validation.
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The aim of this study was to explore the chemical composition and the effect of essential oil of Angelicae dahuricae radix on a nitroglycerin (NTG)-induced rat model of migraine. The CO2 supercritical fluid extraction method was optimized for the extraction of essential oil of A. dahuricae radix (EOAD) and its chemical composition was determined. The migraine model was established by subcutaneous injection of NTG (10 mg/kg) 1 h after the last administration of EOAD. The therapeutic effect of EOAD and its underlying mechanism were assessed by monitoring behavioral changes, levels of nitric oxide (NO) in serum and brain tissues, plasma levels of calcitonin gene-related peptide (CGRP) and endothelin (ET), and ET/NO ratio. The optimal conditions for CO2 supercritical fluid extraction of EOAD, as determined by orthogonal test [L9(3(4))], were as follows: 2 h extraction time, 20 MPa pressure, 40°C temperature, and 30 mesh. The yield of EOAD was 1.8%. On gas chromatography-mass spectrometry, 45 peaks were found in EOAD, and 22 compounds were identified and quantified. The main constituents of EOAD were 1-dodecanol (13.71%), elemene (7.54%), palmitic acid ethyl ester (7.32%), α-pinene (6.25%), and 1-pentadecanol (6.08%). Compared with rat migraine model controls, EOAD (35, 70, and 140 mg/kg) significantly reduced the number of head shaking, head scratching, and hind leg shooting events, decreased serum and brain NO levels, decreased plasma CGRP, and increased ET levels in rats. ET/NO ratio was elevated to 28.68 in the EOAD high-dose group. EOAD ameliorates NTG-induced migraine in rats likely by modulating the levels of vasoactive substances.
Book
Inflammation and Natural Products brings together research in the area of the natural products and their anti-inflammatory action in medical, nutraceutical and food products, addressing specific chronic inflammatory diseases like cancer and the mechanistic aspects of the mode of action of some key natural products. Inflammation is a complicated process, driven by infection or injury or genetic changes, which results in triggering signalling cascades, activation of transcription factors, gene expression, increased levels of inflammatory enzymes, and release of various oxidants and pro-inflammatory molecules in inflammatory cells. Excessive oxidants and inflammatory mediators have a harmful effect on normal tissue, including toxicity, loss of barrier function, abnormal cell proliferation, inhibiting normal function of tissues and organs and finally leading to systemic disorders. The emerging development of natural product formulations utilizing the unique anti-inflammatory compounds such as polyphenols, polysaccharides, terpenes, fatty acids, proteins and several other bioactive components has shown notable successes. Inflammation and Natural Products: Recent Development and Current Status provides a comprehensive resource, ranging from detailed explanation on inflammation to molecular docking strategies for naturally occurring compounds with anti-inflammatory activity. It is useful for graduate students, academic and professionals in the fields of pharmaceutical and medical sciences and specialists from natural product-related industries.
Chapter
In the present chapter the antiinflammatory and antiarthritic effects of extracts, fractions, and/or isolated compounds from several medicinal plants is reviewed, including Boswellia serrata Roxb. (Shallaki), Curcuma longa Linn. (turmeric), Cinnamomum zeylanicum Blume (cinnamon), Echinodorus grandiflorus (Cham. & Schltdl.) Micheli. (Chapéu-de-couro), Colchicum luteum Baker (Suranjan-Talkh), Tripterygium wilfordii Hook F. (Thunder God Vine), Andrographis paniculata (Burm. fil.) Nees (creat or green chiretta), and Nigella sativa L. (black caraway). The revision covers the in vitro and in vivo preclinical data reported to date for the aforementioned species, in addition to clinical trials, antiinflammatory mechanisms of action, and toxicological studies, when available.
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Abstract: Rheumatoid arthritis (RA) is an autoimmune disease particularly affecting elderly people which leads to massive bone destruction with consequent inflammation, pain, and debility. Allopathic medicine can provide only symptomatic relief. However, Zingiberofficinale , Turmeric, Boswellia is a plant , which has traditionally been used for treatment of RA in alternative medicines of many countries. Many of the phytochemical constituents of the rhizomes of this plant have therapeutic benefits including amelioration of RA. This review attempts to list those phytochemical constituents with their reported mechanisms of action. It is concluded that these phytochemicals can form the basis of discovery of new drugs, which not only can provide symptomatic relief but also may provide total relief from RA by stopping RA-induced bone destruction. As the development of RA is a complex process, further research should be continued towards elucidating the molecular details leading to RA and drugs that can stop or reverse these processes by phytoconstituents of ginger, turmeric, boswellia Keywords: ginger, essential oil, gingerol, arthritis, mice, inflammation, rats, turmeric, curcumins, boswellia
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Abstract: Rheumatoid arthritis (RA) is an autoimmune disease particularly affecting elderly people which leads to massive bone destruction with consequent inflammation, pain, and debility. Allopathic medicine can provide only symptomatic relief. However, Zingiberofficinale , Turmeric, Boswellia is a plant , which has traditionally been used for treatment of RA in alternative medicines of many countries. Many of the phytochemical constituents of the rhizomes of this plant have therapeutic benefits including amelioration of RA. This review attempts to list those phytochemical constituents with their reported mechanisms of action. It is concluded that these phytochemicals can form the basis of discovery of new drugs, which not only can provide symptomatic relief but also may provide total relief from RA by stopping RA-induced bone destruction. As the development of RA is a complex process, further research should be continued towards elucidating the molecular details leading to RA and drugs that can stop or reverse these processes by phytoconstituents of ginger, turmeric, boswellia Keywords: ginger, essential oil, gingerol, arthritis, mice, inflammation, rats, turmeric, curcumins, boswellia
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Background: Over-the-counter, natural product-based (nonvitamin, nonmineral) dietary supplement (NVNM DS) use is common in adults with rheumatoid arthritis (RA), a group at risk for drug-DS interactions, due to polypharmacy, but this use is underreported to health care providers. Recent dramatic changes in US sales of specific NVNM DS suggest that the prevalence and types of NVNM DS used in RA populations may also have shifted. Objectives: A study was undertaken to identify current and past use of specific NVNM DS for RA disease treatment and to examine associations between use of NVNM DS, RA pharmaceuticals, and/or vitamin or mineral (VM) DS. Methods: We developed a survey instrument to capture current and ever use of specific NVNM DS, VM DS, and RA pharmaceuticals, with 696 subjects self-reporting an RA diagnosis recruited online or in clinic for survey participation. Analyses were limited to 611 subjects reporting RA diagnosis after age 18 y and treatment with specific RA pharmaceuticals. Results: Most participants reported DS use, with current usage prevalence 49.6% (n = 303), 83.5% (n = 510), or 87.6% (n = 535) for NVNM, VM, or any DS, respectively. While not having appeared in previous RA surveys, turmeric and ginger were among the top 3 NVNM DS in current use, along with fish oil/ω-3 (n-3) PUFA. Concurrent NVNM DS use was reported by 48.2% (n = 243) of participants currently using RA pharmaceuticals (n = 504) and was more common in those using disease-modifying antirheumatic drugs only (no biologics). Most methotrexate users (83%) reported concurrent folate supplementation, with one-third also using turmeric, which is notable because methotrexate and turmeric have been associated with hepatotoxicity. Conclusion: Individuals with RA commonly use NVNM DS in combination with RA pharmaceuticals, including a previously undocumented but popular use of turmeric or ginger supplements with an unclear risk/benefit ratio.
Chapter
The Chemistry inside Spices and Herbs: Research and Development brings comprehensive information about the chemistry of spices and herbs with a focus on recent research in this field. The book is an extensive 2-part collection of 20 chapters contributed by experts in phytochemistry with the aim to give the reader deep knowledge about phytochemical constituents in herbal plants and their benefits. The contents include reviews on the biochemistry and biotechnology of spices and herbs, herbal medicines, biologically active compounds and their role in therapeutics among other topics. Chapters which highlight natural drugs and their role in different diseases and special plants of clinical significance are also included. Part II continues from the previous part with chapters on the treatment of skin diseases and oral problems. This part focuses on clinically important herbs such as turmeric, fenugreek, ashwagandha (Indian winter cherry), basil, Terminalia chebula (black myrobalan). In terms of phytochemicals, this part presents chapters that cover resveratrol, piperine and circumin.
Chapter
Background and objective: It is known that oxidative stress and genomic damage are closely related. Arthrospira maxima (Spirulina, or SP) exhibits an antigenotoxic effect, attributed mainly to its antioxidant capacity. In the present study, the protective effect of SP on mitomycin C (MMC) mutagenicity was evaluated using the dominant lethal assay on male and female mice. Methods: In two independent assays, sexually mature mice of both sexes were orally administered SP at 0, 200, 400 and 800 mg kg-1 for 14 days, followed by five days of intraperitoneally (i.p.) administered MMC (1 mg kg-1). For the male dominant lethal test, treated males were mated with two untreated virgin females during one week, which was carried out three times (in 3 weeks) with distinct females. For the female dominant lethal test, the above doses and schedule of treatments were used, and treated females were caged for seven days with an untreated male (1-2). In all cases, mated females were evaluated at 13-15 days after coitus for incidence of pregnancy, total number of corpora lutea, total implants, and embryonic pre- and post-implantation death. Results: SP orally administered for 14 days previous to MMC exposure inhibited embryonic pre-and post-implantation death when MMC-treated males were mated with healthy females. Conversely, when females exposed to MMC were mated with healthy males, SP pretreatment prevented only post-implantation death. In MMC-exposed males, SP reverted the relative weight loss of male sexual organs and returned sperm quality to basal levels. Conclusion: SP protected germ cells of males and females exposed to MMC. https://www.novapublishers.com/catalog/product_info.php?products_id=65198
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Scope: Curcumin prevents bone loss in resorptive bone diseases and inhibits osteoclast formation, a key process driving bone loss. Curcumin circulates as an inactive glucuronide that can be deconjugated in situ by bone's high β-glucuronidase (GUSB) content, forming the active aglycone. Because curcumin is a common remedy for musculoskeletal disease, effects of microenvironmental changes consequent to skeletal development or disease on bone curcumin metabolism are explored. Methods and results: Across sexual/skeletal development or between sexes in C57BL/6 mice ingesting curcumin (500 mg kg-1 ), bone curcumin metabolism and GUSB enzyme activity are unchanged, except for >twofold higher (p < 0.05) bone curcumin-glucuronide substrate levels in immature (4-6-week-old) mice. In ovariectomized (OVX) or bone metastasis-bearing female mice, bone substrate levels are also >twofold higher. Aglycone curcumin levels tend to increase proportional to substrate such that the majority of glucuronide distributing to bone is deconjugated, including OVX mice where GUSB decreases by 24% (p < 0.01). GUSB also catalyzes deconjugation of resveratrol and quercetin glucuronides by bone, and a requirement for the aglycones for anti-osteoclastogenic bioactivity, analogous to curcumin, is confirmed. Conclusion: Dietary polyphenols circulating as glucuronides may require in situ deconjugation for bone-protective effects, a process influenced by bone microenvironmental changes.
Book
The Chemistry inside Spices & Herbs: Research and Development brings comprehensive information about the chemistry of spices and herbs with a focus on recent research in this field. The book is an extensive 2-part collection of 20 chapters contributed by experts in phytochemistry with the aim to give the reader deep knowledge about phytochemical constituents in herbal plants and their benefits. The contents include reviews on the biochemistry and biotechnology of spices and herbs, herbal medicines, biologically active compounds and their role in therapeutics among other topics. Chapters which highlight natural drugs and their role in different diseases and special plants of clinical significance are also included. Part II continues from the previous part with chapters on the treatment of skin diseases and oral problems. This part focuses on clinically important herbs such as turmeric, fenugreek, ashwagandha (Indian winter cherry), basil, Terminalia chebula (black myrobalan). In terms of phytochemicals, this part presents chapters that cover resveratrol, piperine and circumin. Audience: This book is an ideal resource for scholars (in life sciences, phytomedicine and natural product chemistry) and general readers who want to understand the importance of herbs, spices and traditional medicine in pharmaceutical and clinical research.
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Despite progress that has been made in the treatment of obesity, the epidemic continues to rise worldwide. While pharmacological treatment of obesity may be effective, medications may have significant side effects and can be potentially fatal. This review will provide significant evidence to substantiate the existence of Reward Deficiency Syndrome in Obesity and the role of catecholaminergic pathways in aberrant substance seeking behavior, in particular cravings for carbohydrates. The genetic basis for generalized craving behavior will be established. Evidence to support the augmentation of precursor amino acid therapy and enkephalinase, MOA and COMT inhibition leading to enhanced levels of neurotransmitters: serotonin, enkephalins, GABA and dopamine/norepinephrine as well increasing insulin sensitivity (affecting dopamine neuronal synthesis regulation) through the use of certain neurometabolic optimizers will also be provided. This review article cites many published studies to support a conceptual paradigm shift towards the use of this proposed nutrigenomic formula. The analysis and research preceding this formulation is outlined. This formulation has a generalized anti-craving effect and can inhibit carbohydrate bingeing, inducing significant healthy fat loss and prevention of relapse. This is the first time that components of this formula have been combined, at the dosage levels indicated with the goal of promoting successful and sustainable body recomposition. We are encouraging other laboratories to further evaluate Neuroadtagen Amino-Acid Therapy (NAAT)/Nurometabolic optimizers as a putative anti-obesity complex in larger controlled blinded studies and await interpretation of must these needed studies. Keywords: NAAT, Dopamine, Genes, Polymorphisms, Obesity, Craving Behavior, Overeating, Reward Deficiency Syndome, Nutrigenomics.
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The transcription factor NF-kappaB activates a number of genes whose protein products are proinflammatory. In quiescent cells, NF-kappaB exists in a latent form and is activated via a signal-dependent proteolytic mechanism in which the inhibitory protein IkappaB is degraded by the ubiquitin-proteasome pathway. Consequently, inhibition of the proteasome suppresses activation of NF-kappaB. This suppression should therefore decrease transcription of many genes encoding proinflammatory proteins and should ultimately have an anti-inflammatory effect. To this end, a series of peptide boronic acid inhibitors of the proteasome, exemplified herein by PS-341, were developed. The proteasome is the large multimeric protease that catalyzes the final proteolytic step of the ubiquitin-proteasome pathway. PS-341, a potent, competitive inhibitor of the proteasome, readily entered cells and inhibited the activation of NF-kappaB and the subsequent transcription of genes that are regulated by NF-kappaB. Significantly, PS-341 displayed similar effects in vivo. Oral administration of PS-341 had anti-inflammatory effects in a model of Streptococcal cell wall-induced polyarthritis and liver inflammation in rats. The attenuation of inflammation in this model was associated with an inhibition of IkappaBalpha degradation and NF-kappaB-dependent gene expression. These experiments clearly demonstrate that the ubiquitin-proteasome pathway and NF-kappaB play important roles in regulating chronic inflammation and that, as predicted, proteasome inhibition has an anti-inflammatory effect.
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Disruption of the balance between proteases and protease inhibitors is often associated with pathologic tissue destruction. To explore the therapeutic potential of secretory leukocyte protease inhibitor (SLPI) in erosive joint diseases, we cloned, sequenced, and expressed active rat SLPI, which shares the protease-reactive site found in human SLPI. In a rat streptococcal cell wall (SCW)-induced model of inflammatory erosive polyarthritis, endogenous SLPI was unexpectedly upregulated at both mRNA and protein levels in inflamed joint tissues. Systemic delivery of purified recombinant rat SLPI inhibited joint inflammation and cartilage and bone destruction. Inflammatory pathways as reflected by circulating tumor necrosis factor alpha and nuclear factor kappaB activation and cartilage resorption detected by circulating levels of type II collagen collagenase-generated cleavage products were all diminished by SLPI treatment in acute and chronic arthritis, indicating that the action of SLPI may extend beyond inhibition of serine proteases.
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NF-kappa B plays a critical role in the transcriptional regulation of proinflammatory gene expression in various cells. Cytokine-mediated activation of NF-kappa B requires activation of various kinases, which ultimately leads to the phosphorylation and degradation of I kappa B, the NF-kappa B cytoplasmic inhibitor. The food derivative curcumin has been shown to inhibit NF-kappa B activity in some cell types. In this report we investigate the mechanism of action of curcumin on cytokine-induced proinflammatory gene expression using intestinal epithelial cells (IEC). Curcumin inhibited IL-1 beta-mediated ICAM-1 and IL-8 gene expression in IEC-6, HT-29, and Caco-2 cells. Cytokine-induced NF-kappa B DNA binding activity, RelA nuclear translocation, I kappa B alpha degradation, I kappa B serine 32 phosphorylation, and I kappa B kinase (IKK) activity were blocked by curcumin treatment. Wound-induced p38 phosphorylation was not inhibited by curcumin treatment. In addition, mitogen-activated protein kinase/ERK kinase kinase-1-induced IL-8 gene expression and 12-O-tetraphorbol 12-myristate 13-acetate-responsive element-driven luciferase expression were inhibited by curcumin. However, I kappa B alpha degradation induced by ectopically expressed NF-kappa B-inducing kinase or IKK was not inhibited by curcumin treatment. Therefore, curcumin blocks a signal upstream of NF-kappa B-inducing kinase and IKK. We conclude that curcumin potently inhibits cytokine-mediated NF-kappa B activation by blocking a signal leading to IKK activity.
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While TNF-alpha is pivotal to the pathogenesis of inflammatory osteolysis, the means by which it recruits osteoclasts and promotes bone destruction are unknown. We find that a pure population of murine osteoclast precursors fails to undergo osteoclastogenesis when treated with TNF-alpha alone. In contrast, the cytokine dramatically stimulates differentiation in macrophages primed by less than one percent of the amount of RANKL (ligand for the receptor activator of NF-kappaB) required to induce osteoclast formation. Mirroring their synergistic effects on osteoclast differentiation, TNF-alpha and RANKL markedly potentiate NF-kappaB and stress-activated protein kinase/c-Jun NH(2)-terminal kinase activity, two signaling pathways essential for osteoclastogenesis. In vivo administration of TNF-alpha prompts robust osteoclast formation in chimeric animals in which ss-galactosidase positive, TNF-responsive macrophages develop within a TNF-nonresponsive stromal environment. Thus, while TNF-alpha alone does not induce osteoclastogenesis, it does so both in vitro and in vivo by directly targeting macrophages within a stromal environment that expresses permissive levels of RANKL. Given the minuscule amount of RANKL sufficient to synergize with TNF-alpha to promote osteoclastogenesis, TNF-alpha appears to be a more convenient target in arresting inflammatory osteolysis.
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Curcumin (diferuloylmethane), a yellow substance from the root of the plant Curcuma longa Linn., has been demonstrated to inhibit carcinogenesis of murine skin, stomach, intestine and liver. However, the toxicology, pharmacokinetics and biologically effective dose of curcumin in humans have not been reported. This prospective phase-I study evaluated these issues of curcumin in patients with one of the following five high-risk conditions: 1) recently resected urinary bladder cancer; 2) arsenic Bowen's disease of the skin; 3) uterine cervical intraepithelial neoplasm (CIN); 4) oral leucoplakia; and 5) intestinal metaplasia of the stomach. Curcumin was taken orally for 3 months. Biopsy of the lesion sites was done immediately before and 3 months after starting curcumin treament. The starting dose was 500 mg/day. If no toxicity > or = grade II was noted in at least 3 successive patients, the dose was then escalated to another level in the order of 1,000, 2,000, 4,000, 8,000, and 12,000 mg/day. The concentration of curcumin in serum and urine was determined by high pressure liquid chromatography (HPLC). A total of 25 patients were enrolled in this study. There was no treatment-related toxicity up to 8,000 mg/day. Beyond 8,000 mg/day, the bulky volume of the drug was unacceptable to the patients. The serum concentration of curcumin usually peaked at 1 to 2 hours after oral intake of crucumin and gradually declined within 12 hours. The average peak serum concentrations after taking 4,000 mg, 6,000 mg and 8,000 mg of curcumin were 0.51 +/- 0.11 microM, 0.63 +/- 0.06 microM and 1.77 +/- 1.87 microM, respectively. Urinary excretion of curcumin was undetectable. One of 4 patients with CIN and 1 of 7 patients with oral leucoplakia proceeded to develop frank malignancies in spite of curcumin treatment. In contrast, histologic improvement of precancerous lesions was seen in 1 out of 2 patients with recently resected bladder cancer, 2 out of 7 patients of oral leucoplakia, 1 out of 6 patients of intestinal metaplasia of the stomach, I out of 4 patients with CIN and 2 out of 6 patients with Bowen's disease. In conclusion, this study demonstrated that curcumin is not toxic to humans up to 8,000 mg/day when taken by mouth for 3 months. Our results also suggest a biologic effect of curcumin in the chemoprevention of cancer.
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Rheumatoid arthritis (RA) is characterised by the presence of an inflammatory synovitis accompanied by destruction of joint cartilage and bone. Destruction of cartilage matrix results predominantly from the action of connective tissue proteinases released by RA synovial tissues, chondrocytes, and pannus tissue. Several lines of evidence in RA and in animal models of arthritis support a role for osteoclasts in the pathogenesis of bone erosions. RA synovial tissues produce a variety of cytokines and growth factors that may increase osteoclast formation, activity, and/or survival. These include interleukin 1alpha (IL1alpha) and beta, tumour necrosis factor alpha (TNFalpha), IL11, IL17, and macrophage colony stimulating factor (M-CSF). Receptor activator of NFkappaB ligand (RANKL) is an essential factor for osteoclast differentiation and also functions to augment T cell-dendritic cell cooperative interactions. CD4+ T cells and synovial fibroblasts derived from RA synovium are sources of RANKL. Furthermore, in collagen induced arthritis (CIA), blockade with osteoprotegerin (OPG), a decoy receptor for RANKL, results in protection from bone destruction. To further evaluate the role of osteoclasts in focal bone erosion in arthritis, arthritis was generated in the RANKL knockout mouse using a serum transfer model. Despite ongoing inflammation, the degree of bone erosion in arthritic RANKL knockout mice, as assessed by microcomputed tomography and correlated histopathological analysis, was dramatically reduced compared with that seen in arthritic control mice. Cartilage damage was present in both the arthritic RANKL knockout mice and in arthritic control littermates, with a trend toward milder cartilage damage in the RANKL knockout mice. This study supports the hypothesis that osteoclasts play an important part in the pathogenesis of focal bone erosion in arthritis, and reveals distinct mechanisms of cartilage destruction and bone erosion in this animal model of arthritis. Future directions for research in this area include the further investigation of a possible direct role for the RANKL/RANK/OPG system in cartilage metabolism, and the possible role of other cell types and cytokines in bone erosion in arthritis.
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Numerous studies have indicated that inflammatory cytokines play a major role in osteoclastogenesis, leading to the bone resorption that is frequently associated with cancers and other diseases. Gene deletion studies have shown that receptor activator of NF-kappaB ligand (RANKL) is one of the critical mediators of osteoclastogenesis. How RANKL mediates osteoclastogenesis is not fully understood, but an agent that suppresses RANKL signaling has potential to inhibit osteoclastogenesis. In this report, we examine the ability of curcumin (diferuloylmethane), a pigment derived from turmeric, to suppress RANKL signaling and osteoclastogenesis in RAW 264.7 cells, a murine monocytic cell line. Treatment of these cells with RANKL activated NF-kappaB, and preexposure of the cells to curcumin completely suppressed RANKL-induced NF-kappaB activation. Curcumin inhibited the pathway leading from activation of IkappaBalpha kinase and IkappaBalpha phosphorylation to IkappaBalpha degradation. RANKL induced osteoclastogenesis in these monocytic cells, and curcumin inhibited both RANKL- and TNF-induced osteoclastogenesis and pit formation. Curcumin suppressed osteoclastogenesis maximally when added together with RANKL and minimally when it was added 2 days after RANKL. Whether curcumin inhibits RANKL-induced osteoclastogenesis through suppression of NF-kappaB was also confirmed independently, as RANKL failed to activate NF-kappaB in cells stably transfected with a dominant-negative form of IkappaBalpha and concurrently failed to induce osteoclastogenesis. Thus overall these results indicate that RANKL induces osteoclastogenesis through the activation of NF-kappaB, and treatment with curcumin inhibits both the NF-kappaB activation and osteoclastogenesis induced by RANKL.
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Autoantibodies in sera from patients with autoimmune diseases have long been known and have become diagnostic tools. Analysis of their functional role again became popular with the availability of mice mutant for several genes of the complement and Fcgamma receptor (FcgammaR) systems. Evidence from different inflammatory models suggests that both systems are interconnected in a hierarchical way. The complement system mediators such as complement component 5a (C5a) might be crucial in the communication between the complement system and FcgammaR-expressing cells. The split complement protein C5a is known to inactivate cells by its G-protein-coupled receptor and to be involved in the transcriptional regulation of FcgammaRs, thereby contributing to the complex regulation of autoimmune disease.
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Levels of various serum proteins were found to change in adjuvant induced arthritis. Increased levels of a glycoprotein with an apparent molecular weight of 72 kDa (Gp A72) were observed in the sera of arthritic rats. Gp A72 is an acidic glycoprotein with a pI of 5.1. Gp A72 also showed antitryptic activity. The appearance of Gp A72 in the serum preceded the onset of paw inflammation in arthritic rats and persisted in the chronic phase. Oral administration of the antiinflammatory spice principles-capsaicin (from red pepper) and curcumin (from turmeric) lowered the levels of Gp A72 by 88 and 73% respectively with concomitant lowering of paw inflammation in arthritic rats.
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This report builds on the authors' earlier discovery of bis(5-amidino-2-benzimidazolyl)methane (BABIM) as a strong suppressive agent for streptococcal cell wall fragment-induced arthritis in the Lewis rat. As a synthetic inhibitor of trypsinlike proteases, BABIM opens up a new route to the control of inflammatory joint disease. To gain a deeper insight into the function of the compound, the authors have now studied its influence on the sequential development of the joint changes and the associated lesions in spleen and liver. Bis(5-amidino-2-benzimidazolyl)methane is shown to block acute synovitis, to retard and reduce granuloma formation in spleen and liver, to decrease neutrophilic leukocytosis, and to diminish hemopoietic hyperplasia in the bone, and thus also to mitigate the distinctive osteoclastic and chondroclastic events. The compound does not interfere with the splenic immune response, the temporary rise in hepatocytic mitotic activity, or the organ deposition of streptococcal cell walls.
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The anti-inflammatory activity of curcumin (C), sodium curcuminate (NaC), diacetyl curcumin (DAC), triethyl curcumin (TEC), tetrahydro curcumin (THC) and ferulic acid (FA) was compared with that of phenylbutazone (PB) using the carrageenin-induced rat paw edema and cotton pellet granuloma tests. The rank order of potencies of curcumin analogues and PB in carrageenin-induced inflammation were NaC greater than THC greater than C greater than PB greater than TEC. The curcumin analogues de decreased carrageenin-induced paw edema at low doses, however, at higher doses this effect was partially reversed. FA and DAC were devoid of anti-inflammatory activity. Curcumin analogues were less effective in inhibiting the granulomatous tissue formation. Maximum activity was observed with TEC whereas C, NaC and PB were almost half as effective as TEC. C and NaC possess both anti-inflammatory and irritant properties as was evident from experiments in which drugs were incorporated into carrageenin and the cotton pellets for inducing inflammation. The anti-inflammatory action of NaC is not mediated through release of steroids from the adrenal cortex or inhibition of the biosynthesis of prostaglandins from arachidonic acid. The results of the present study support the rationale for the use of powdered rhizome of tumeric (contains 0.6% of curcumin) for conditions of sprain and inflammation.
Article
PTH-related protein (PTHrP), the peptide that is responsible for most cases of hypercalcemia of malignancy, is also produced under normal circumstances by a variety of tissues. Its role and regulation at these sites are not well understood. Recently, we have shown that PTHrP is induced in the spleen during the host response to endotoxin (LPS) and that tumor necrosis factor (TNF) is a major mediator of this effect. Given the large body of in vitro evidence suggesting that PTHrP can be produced by lymphocytes and act in an autocrine loop to alter their function, studies were undertaken to determine whether lymphocytes were the cells responsible for PTHrP production in the spleen. Both constitutive and LPS-induced PTHrP messenger RNA (mRNA) levels were the same in mice lacking mature T cells (nude mice) and in mice lacking natural killer (NK) cells (due to pretreatment with antibody against NK 1.1) compared to levels in normal mice, suggesting that neither mature T cells nor NK cells were the splenic source of PTHrP. Even scid mice that lack functioning T and B cells responded to TNF with the induction of splenic PTHrP mRNA levels comparable to those in control mice. Localization of PTHrP mRNA in subfractions of rat spleens after in vivo treatment with LPS confirmed the results of the murine studies; PTHrP mRNA was barely detectable in the lymphocyte-rich single cell fraction of the spleen. In contrast, the stromal fraction of the spleen was enriched with PTHrP mRNA both in the basal state and in response to LPS. A similar pattern of distribution was seen for interleukin-6; LPS only increased mRNA levels of this TNF-inducible cytokine in the splenic stroma. In addition, mRNA for the PTH/PTHrP receptor, which decreased in response to LPS, colocalized with PTHrP mRNA in the stromal fraction of the spleen. Immunohistochemical studies identified PTHrP in two populations of splenic cells: 1) smooth muscle cells located in the splenic capsule and trabeculae and 2) a subpopulation of stromal cells located in the red pulp of the spleen, primarily in a subcapsular distribution. Consistent with the localization of PTHrP mRNA, lymphocytes in the white pulp of the spleen did not stain for PTHrP.
Article
A recombinant human TNF receptor Fc fusion protein (rhuTNFR:Fc) was assessed for antiarthritic activity using murine type II collagen-induced arthritis in mice. DBA/1 mice were immunized with bovine type II collagen and treated with rhuTNFR:Fc either from day 21 to day 28 (preventative protocol), or after disease onset for fourteen days (therapeutic protocol). Control mice received either sterile saline or human serum albumin injections. rhuT-NFR:Fc treatment significantly reduced both the incidence and the severity of collagen-induced arthritis in the preventative protocol. Mice receiving rhuTNFR:Fc therapeutically progressed to less severe disease than did control animals, and the arthritis index in rhuTNFR:Fc treated mice was significantly lower than the index in control mice from 7.5 weeks after treatment. The antibody response to collagen was significantly reduced by treatment with rhuTNFR:Fc in both the preventative and therapeutic protocols. No difference was observed in the proliferative response to type II collagen or Con A, but the response to LPS was significantly lower in rhuTNFR:Fc treated mice at the conclusion of both the preventative and therapeutic trials. The results suggest that rhuTNFR:Fc may have both immunosuppressive and antiarthritic properties in this experimental model, and may represent a useful approach to the treatment of autoimmune arthritis.
Article
Levels of various serum proteins were found to change in adjuvant induced arthritis. Increased levels of a glycoprotein with an apparent molecular weight of 72 kDa (Gp A72) were observed in the sera of arthritic rats. Gp A72 is an acidic glycoprotein with a pI of 5.1. Gp A72 also showed antitryptic activity. The appearance of Gp A72 in the serum preceded the onset of paw inflammation in arthritic rats and persisted in the chronic phase. Oral administration of the antiinflammatory spice principles-capsaicin (from red pepper) and curcumin (from turmeric) lowered the levels of Gp A72 by 88 and 73% respectively with concomitant lowering of paw inflammation in arthritic rats.
Article
The transcription factor NF-kappa B plays a significant role in inflammatory diseases. In this study we have investigated the expression of activated NF-kappa B p65 subunit in the rat adjuvant arthritis model in a 28-day time-course experiment using immunohistochemistry. The expression of p65 was detected in the synovial lining layer and around the blood vessels in the inflamed synovium as early as Day 3 post-adjuvant injection. The cells that expressed p65 in the synovial lining were thought to be macrophage-like synoviocytes. The expression was stronger in the injected hindpaw than that in the noninjected hindpaw. Dexamethasone treatment at 1 mg/kg p.o. (Days 0-20) suppressed both the hindpaw edema and increase in p65 expression. Withdrawal of the treatment caused increases in both p65 expression and paw volume. Together these suggest that activated NF-kappa B was specifically expressed in the arthritic synovium and may play a significant role in the development of arthritis.
Article
Interesting, recent studies have suggested a possibility that transcriptional factor NF-kappaB may play a functional role in the survival of mouse osteoclasts. However, it has not been known whether NF-kappaB is involved in apoptosis of and bone resorption by mature osteoclasts. Thus, using NF-kappaB inhibitors, we examined the functional role of NF-kappaB in the induction of apoptosis in rabbit mature osteoclasts. PDTC, a potent inhibitor of NF-kappaB, stimulated markedly apoptosis of the osteoclasts and inhibited bone resorption by these cells. These effects also was observed when three other inhibitors of NF-kappaB were used. And a gel mobility shift assay showed that PDTC also inhibited NF-kappaB binding to its consensus sequence in the cells. These results suggest a regulatory role for NF-kappaB in apoptosis in and bone resorption by rabbit mature osteoclasts.
Article
Curcumin is a potent inhibitor of the transcriptional factors activator protein-1 and nuclear factor-kappaB. Since transcriptional factors may play a functional role in the survival of osteoclasts, it was of interest to us to examine the effect of curcumin on osteoclast apoptosis. We observed that curcumin is a potent stimulator of this process in rabbit osteoclasts, as evidenced by morphological changes in nuclei and DNA fragmentation as criteria of apoptosis. The curcumin stimulation of the osteoclast apoptosis was dose-and treatment time-dependent. In addition, curcumin dramatically inhibited osteoclastic bone resorption, supporting our data that curcumin is a potent stimulator of osteoclast apoptosis.
Article
Recently, The American Journal of Clinical Nutrition (AJCN) began reviewing articles about dietary supplements. The purpose of this commentary is to provide guidelines to authors and reviewers for articles on one category of supplement ingredients, botanicals. The botanicals in the studies published by the AJCN tend to fall into 1 of 2 groups: 1) plants as foods containing nonessential bioactive constituents that may provide health benefits beyond basic nutrition, and 2) plants as herbs, specifically those used as phytomedicines. Research in these areas is relevant to clinical nutrition, but both topics represent relatively new territory to many AJCN reviewers, readers, and contributors. Although studies of botanicals are unique in many respects, the research should be evaluated with the same basic criteria applied to other types of investigations. For example, a study cannot be evaluated or replicated unless the test materials are properly identified and characterized. Investigators must provide an accurate and complete description of the botanical test material regardless of whether it is a finished product, commercial ingredient, extract, or single chemical constituent. For herbal preparations, investigators are advised to follow the criteria used by researchers in the field of pharmacognosy. Finally, the quality of research related to botanical dietary supplements would be improved and cross-study comparisons facilitated if standard reference materials and certified methods of analysis were more broadly available.
Article
Biglycan (bgn) is an extracellular matrix proteoglycan that is enriched in bone and other skeletal connective tissues. Previously, we generated bgn-deficient mice and showed that they developed age-dependent osteopenia. To identify the cellular events that might contribute to this progressive osteoporosis, we measured the number of osteogenic precursors in the bone marrow of normal and mutant mice. The number of colonies, indicative of the colony-forming unit potential of fibroblasts (CFU-F), gradually decreased with age. By 24 weeks of age, colony formation in the bgn knockout (KO) mice was significantly more reduced than that in the wild type (wt) mice. This age-related reduction was consistent with the extensive osteopenia previously shown by X-ray analysis and histological examination of 24-week-old bgn KO mice. Because bgn has been shown previously to bind and regulate transforming growth factor beta (TGF-beta) activity, we also asked whether this growth factor would affect colony formation. TGF-beta treatment significantly increased the size of the wt colonies. In contrast, TGF-beta did not significantly influence the size of the bgn colonies. An increase in apoptosis in bgn-deficient bone marrow stromal cells (BMSCs) was observed also. The combination of decreased proliferation and increased apoptosis, if it occurred in vivo, would lead to a deficiency in the generation of mature osteoblasts and would be sufficient to account for the osteopenia developed in the bgn KO mice. The bgn KO mice also were defective in the synthesis of type I collagen messenger RNA (mRNA) and protein. This result supports the suggestion that the composition of the extracellular matrix may be regulated by specific matrix components including bgn.
Article
Although the cause of rheumatoid arthritis is still unknown, there is convincing evidence that interleukin-1 (IL-1) and tumornecrosis factor (TNF) play a pivotal role in the pathogenesis of the disease. As the targets (IL-1/TNF) are known, the introduction of gene therapy is the logical step in the treatment of chronic joint inflammation. This article will give the latest information about gene therapy in experimental arthritis on IL-1 and TNF modulation using IL-1 receptor antagonist, IL-4 and IL-10. The mechanism of the distal effects using local gene therapy as seen by many researchers will be discussed. Furthermore, the effect of different viral vectors, controlled transgene expression and strategies to enhance the transfection efficiency so it will improve the local gene therapeutic approach will be reviewed.
Article
Recent advances in our understanding of the role of cytokine networks in inflammatory processes have led to the development of novel biological agents for the treatment of chronic inflammatory diseases. At the present time, significant efforts are focused on characterizing the complex signal transduction cascades that are activated by these cytokines and, in turn, regulate their expression. The transcription factor NF-kappaB is a pivotal regulator of the inducible expression of key proinflammatory mediators, and activated NF-kappaB has been observed in several debilitating inflammatory disorders, including rheumatoid arthritis and osteoarthritis. In light of its central role in inflammation, the identification of inhibitors of NF-kappaB should provide novel therapeutics for the treatment of chronic joint disease.
Article
The TNF-family molecule receptor activator of nuclear factor kappa B (NFkappaB) ligand (RANKL) (OPGL, TRANCE, ODF) and its receptor activator of NFkappaB (RANK) are key regulators of bone remodeling and regulate T cell/dendritic cell communications, and lymph node formation. Moreover, RANKL and RANK are expressed in mammary gland epithelial cells and control the development of a lactating mammary gland during pregnancy. Genetically, RANKL and RANK are essential for the development and activation of osteoclasts and bone loss in response to virtually all triggers tested. Inhibition of RANKL function via the natural decoy receptor osteoprotegerin (OPG, TNFRSF11B) prevents bone loss in postmenopausal osteoporosis and cancer metastases. Importantly, RANKL appears to be the pathogenetic principle that causes bone and cartilage destruction in arthritis, and OPG treatment prevents bone loss at inflamed joints and has partially beneficial effects on cartilage destruction in all arthritis models studied so far. Modulation of these systems provides a unique opportunity to design novel therapeutics to inhibit bone loss and crippling in arthritis.
Article
Inflammation is a protective tissue response occurring in three distinct phases, acute, subacute and a chronic proliferative phase. We undertook the present study to understand the overall immune response of the body during adjuvant induced chronic inflammation in rat and the effect of ibuprofen and curcumin on this response. Inflammatory mediators were estimated on day 21 and day 35 after adjuvant injection. The level of C-reactive protein increased to 200% on day 21 and then reduced to 50% on day 35 compared to control. Curcumin and ibuprofen further reduced the increased levels at both the time intervals. Haptoglobin level decreased to 42% on day 21 but increased to 5 times of control on day 35. Curcumin and ibuprofen reduced the increased levels at day 35. No significant change was observed in Prostaglandin-E2 and Leukotriene-B4 levels and in Lymphocyte proliferation. The level of Tumor Necrosis Factor-alpha increased by three folds on day 21, but came down to 88% on day 35. Ibuprofen treatment decreased the raised level on day 21 and increased the reduced level on day 35. Interleukin-1beta increased to 2 folds on day 21 and 10 folds on day 35 which were significantly brought down by curcumin and ibuprofen. Nitric oxide level was reduced at both the time intervals, which were increased by drug treatment.
Article
To determine whether parathyroid hormone-related protein (PTHrP), an interleukin-1beta-inducible, bone-resorbing peptide that is produced in increasing amounts by the synovium in rheumatoid arthritis (RA), may play a role in the pathophysiology of joint destruction in RA. PTHrP expression and the effect of PTHrP 1-34 neutralizing antibody on disease progression were tested in streptococcal cell wall (SCW)-induced arthritis, an animal model of RA. As has been reported in RA, while serum levels of PTHrP did not change during SCW-induced arthritis, PTHrP expression dramatically increased in the arthritic synovium. Treatment with PTHrP neutralizing antibody (versus control antibody) did not affect joint swelling in SCW-treated animals. However, PTHrP antibody significantly inhibited SCW-induced joint destruction, as measured by its ability to block increases in serum pyridinoline (a marker of cartilage and bone destruction), erosion of articular cartilage, decreases in femoral bone mineral density, and increases in the numbers of osteoclasts in eroded bone. Unexpectedly, granuloma formation at sites of SCW deposition in the liver and spleen was also inhibited by PTHrP antibody, an effect associated with significant decreases in the tissue influx of PTH/PTHrP receptor-positive neutrophils and in SCW-induced neutrophilia. In vitro, neutrophil chemotaxis was stimulated by PTHrP 1-34. These findings suggest that PTHrP, consistent with its previously described osteolytic effects in metastatic bone disease, can also be an important mediator of joint destruction in inflammatory bone disorders, such as RA. Moreover, this study reveals heretofore unknown effects of PTHrP peptides on neutrophil function that could have important implications in the pathogenesis of inflammatory granulomatous disorders.
Article
Interleukin-1 is a key inflammatory cytokine that mediates its effects through a type I receptor and a receptor accessory protein. These two molecules are members of a wider family of proteins that have in common the presence of immunoglobulin domains in the extracellular region of the protein and a TIR domain in the cytoplasmic region. The nature of this family of proteins and their signal transduction pathway is discussed in this review.
Article
The complement system comprises a strong defense against various pathogens and is a major component of our innate immune system. While earlier studies have established a crucial role of complement in recognition, opsonization and enhanced phagocytosis of microorganisms by professional phagocytes such as polymorphonuclear leukocytes and macrophages, recent studies delineate an additional role of complement in initiation and maintenance of the acquired immune response. In addition, it seems that opsonization of apoptotic cells by complement may lead to polarization of the response of professional antigen-presenting cells to a more inflammatory or tolerogenic response. The present review summarizes these different contributions of complement to the shaping of the immune balance.
Article
Nuclear factor (NF)-kappaB is a key player in the control of both innate and adaptive immunity. NF-kappaB proteins arc present in the cytoplasm in association with inhibitory proteins called inhibitors of kappaB (IkappaBs). On activation by a large plethora of inducers, the IkappaB proteins are phosphorylated, ubiquitinated, and subsequently degraded in the proteasomes. Degradation of IkappaBs allows translocation of NF-kappaB into the nucleus and bind to their cognate DNA binding sites to regulate the transcription of large numbers of genes including antimicrobial peptides, cytokines, chemokines, stress response proteins, and antiapoptotic proteins. NF-kappaB activity is essential for lymphocyte survival, activation, and mounting normal immune responses. Constitutive activation of NF-kappaB pathways is often associated with inflammatory diseases like rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, and asthma. Better understanding of the regulation of NF-kappaB will provide a platform for development of specific therapeutic agents targeted towards the inflammatory diseases.
Article
Rheumatoid arthritis (RA) is a symmetrical polyarticular disease of unknown aetiology that affects primarily the diarthrodial joints. Characteristic features of RA pathogenesis are synovial hyperplasia and inflammation accompanied by cartilage loss and joint destruction. Synovial hyperplasia and inflammation are a consequence of an increase in the macrophage-like and fibroblast-like synoviocytes of the synovial intimal lining associated with infiltration of leucocytes into the subintimal space. Although therapeutic interventions are available, the disease persists despite therapy in a significant fraction of patients. Several lines of evidence have substantiated a crucial role of activated fibroblast-like synoviocytes (FLS) during RA pathogenesis. The hyperplastic FLS population potentially promotes leucocyte infiltration and retention. The rheumatoid synovium eventually transforms into a pannus that destroys articular cartilage and bone. There are no approved drugs that are known to target the FLS in RA, and the underlying mechanisms driving FLS activation remain unresolved. In this review, the importance of Wnt-frizzled (Fz)-mediated signalling in the autonomous activation of FLS is discussed. Anti-Wnt/anti-Fz antibodies, Fz receptor antagonists or small-molecule inhibitors of Wnt-Fz signalling might be useful for therapeutic interventions in refractory RA.