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Curcumin and muscle wasting-A new role for an old drug?
Abstract
Sepsis, severe injury, and cancer are associated with loss of muscle mass. Muscle wasting in these conditions is mainly caused by increased proteolysis, at least in part regulated by nuclear factor-kappaB. Despite recent progress in the understanding of mediators and mechanisms involved in muscle wasting, effective and universally accepted treatments by which muscle atrophy can be prevented or reversed are still lacking. We review recent evidence suggesting that curcumin (diferuloylmethane), a component of the spice turmeric, may prevent loss of muscle mass during sepsis and endotoxemia and may stimulate muscle regeneration after traumatic injury. Curcumin has been part of the traditional Asian medicine for centuries, mainly because of its anti-inflammatory properties. Studies suggest that inhibition of nuclear factor-kappaB is one of the mechanisms by which curcumin exerts its ant-inflammatory effects. Curcumin is easily accessible, inexpensive, and non-toxic even at high doses, and may therefore offer an important treatment modality in muscle wasting and injury. It should be noted, however, that the muscle-sparing effects of curcumin are not universally accepted, and more studies are therefore needed to further test the role of curcumin in the prevention and treatment of muscle wasting.
... Several studies have investigated the mechanisms by which curcumin exerts its beneficial effect. Early experimental study demonstrated that curcumin suppresses the activation of NF-κB (Jobin C, 1999;Singh S, 1995) [21,29] , an effect of critical relevance in DOMS relief, since NF-κB appears to be involved in the regulation of proteolysis and inflammation in muscle (Alamdari N, 2009) [30] . Therefore, inhibition of NF-κB by curcumin may result in a muscle-protective effect. ...
... Several studies have investigated the mechanisms by which curcumin exerts its beneficial effect. Early experimental study demonstrated that curcumin suppresses the activation of NF-κB (Jobin C, 1999;Singh S, 1995) [21,29] , an effect of critical relevance in DOMS relief, since NF-κB appears to be involved in the regulation of proteolysis and inflammation in muscle (Alamdari N, 2009) [30] . Therefore, inhibition of NF-κB by curcumin may result in a muscle-protective effect. ...
... Therefore, inhibition of NF-κB by curcumin may result in a muscle-protective effect. Consistently, it has been suggested that curcumin may prevent loss of muscle mass during sepsis and endotoxaemia and may stimulate muscle regeneration after traumatic injury (Alamdari N, 2009;Thaloor D, 1999) [30,24] . Other mechanisms possibly responsible for the anti-inflammatory and anti-oxidant properties of curcumin include induction of heat-shock response (Dunsmore KE, 2001) [25] , reduction in the expression of the pro-inflammatory enzyme cyclooxygenase-2 (COX-2) (Chun KS, 2003) and promotion of the antioxidant response by activation of the transcription factor Nrf2 (Shehzad A, 2013) [27] . ...
The aim of this study was to determine the effect of local application of cryotherapy and turmeric to alleviate the physical symptoms of DOMS compared to conventional physical therapy programs. The study had 18 healthy, untrained subjects. Subjects were then randomly assigned to 3 groups, 6 participants in each group. Subject of group A (n=6) received physical therapy, group B (n=6) received physical therapy and cryotherapy, and group C (n=6) received physical therapy in combination to cryotherapy and turmeric cream supplementation. Repeated concentric and eccentric contractions were used to induce DOMS in the elbow flexors. A visual analog scale was used to examine perceived muscle soreness, a flexible tape measure was used to measure muscular girth and markers of muscle damage (creatine kinase, CK and lactate dehydrogenase, LDH) were measured. The VAS ratings of elbow flexor soreness was greatly reduced after 72 hours in subjects receiving physical therapy+ cryotherapy and those receiving physical therapy+ cryotherapy+ turmeric supplementation as compared to those receiving only physical therapy. There was significant improvement in the elbow range of motion only after 72 hours post exercise in both subjects receiving cryotherapy and physical therapy and those receiving combination of both cryotherapy and turmeric supplementation and physical therapy. Although there was increase in the biceps brachii girth but it could reach a statistical level. The increase may be due to inflammatory response leading to swelling from unaccustomed eccentric exercise. Plasma CK (but not LDH) activity was significantly improved in subject receiving cryotherapy and physical therapy and subjects receiving combination of cryotherapy, turmeric supplementation and physical therapy. Our result showed that cryotherapy along with local application of turmeric may be beneficial to attenuate exercise induced DOMS. Local application of turmeric along with cryotherapy adds on to the effect of management of DOM.
... A positive effect on cell atrophy caused by TNF-was shown with resveratrol (in Vitis vinifera) supplementation in a muscle cell line (regulating the Akt/mTOR/FoxO1 signaling pathways together with inhibition of the atrophy-related ubiquitin ligase) [16]. Finally, several studies have investigated the mechanisms by which curcumin, a constituent of turmeric (Curcuma longa L.), exerts its beneficial effect on muscle [62]. Early experimental study demonstrated that curcumin suppresses the activation of NF-B, an effect of critical relevance in DOMS relief, since NF-B appears to be involved in the regulation of proteolysis and inflammation in muscle [62]. ...
... Finally, several studies have investigated the mechanisms by which curcumin, a constituent of turmeric (Curcuma longa L.), exerts its beneficial effect on muscle [62]. Early experimental study demonstrated that curcumin suppresses the activation of NF-B, an effect of critical relevance in DOMS relief, since NF-B appears to be involved in the regulation of proteolysis and inflammation in muscle [62]. Therefore, inhibition of NF-B by curcumin may result in a muscle-protective effect. ...
... Therefore, inhibition of NF-B by curcumin may result in a muscle-protective effect. Consistently, it has been suggested that curcumin may prevent loss of muscle mass during sepsis and endotoxaemia and may stimulate muscle regeneration after traumatic injury [62]. Other mechanisms potentially responsible for the anti-inflammatory and antioxidant properties of curcumin include induction of heat-shock response [62], reduction in the expression of the proinflammatory enzyme cyclooxygenase-2 (COX-2), and promotion of the antioxidant response by activation of the transcription factor Nrf2 [63]. ...
We performed a systematic review to evaluate the evidence-based medicine regarding the main botanical extracts and their nutraceutical compounds correlated to skeletal muscle health in order to identify novel strategies that effectively attenuate skeletal muscle loss and enhance muscle function and to improve the quality of life of older subjects. This review contains all eligible studies from 2010 to 2015 and included 57 publications. We focused our attention on effects of botanical extracts on growth and health of muscle and divided these effects into five categories: anti-inflammation, muscle damage prevention, antifatigue, muscle atrophy prevention, and muscle regeneration and differentiation.
... Curcumin (diferuloylmethane) is a component of the spice turmeric (Curcuma longa), which exhibits anti-inflammatory and antioxidant properties [206]. Curcumin was shown to prevent the induction of signaling pathways (i.e., NF-κB, xanthine oxidase, β-catenin) which are usually activated during unloading/disuse and associated with the induction of the UPS and the apoptotic pathway [207]. ...
... An illustration of the effects of the above-described interventions on the anabolic signaling pathways is provided in Figure 4. Curcumin (diferuloylmethane) is a component of the spice turmeric (Curcuma longa), which exhibits anti-inflammatory and antioxidant properties [206]. Curcumin was shown to prevent the induction of signaling pathways (i.e., NF-κB, xanthine oxidase, β-catenin) which are usually activated during unloading/disuse and associated with the induction of the UPS and the apoptotic pathway [207]. ...
Skeletal muscle fibers have a unique capacity to adjust their metabolism and phenotype in response to alternations in mechanical loading. Indeed, chronic mechanical loading leads to an increase in skeletal muscle mass, while prolonged mechanical unloading results in a significant decrease in muscle mass (muscle atrophy). The maintenance of skeletal muscle mass is dependent on the balance between rates of muscle protein synthesis and breakdown. While molecular mechanisms regulating protein synthesis during mechanical unloading have been relatively well studied, signaling events implicated in protein turnover during skeletal muscle recovery from unloading are poorly defined. A better understanding of the molecular events that underpin muscle mass recovery following disuse-induced atrophy is of significant importance for both clinical and space medicine. This review focuses on the molecular mechanisms that may be involved in the activation of protein synthesis and subsequent restoration of muscle mass after a period of mechanical unloading. In addition, the efficiency of strategies proposed to improve muscle protein gain during recovery is also discussed.
... The anti-inflammatory properties attributed to curcumin are due to its ability to inhibit the nuclear factor kappa (NF-κB), which may be a muscle protective and regeneration agent and plays an important role in controlling physiological mechanisms of inflammation and protein breakdown [15]. Curcumin is capable of blocking the activation of TNF-α-dependent NF-κB and the activation pathway induced by ROS [16][17][18]. Likewise, curcumin could have a low regulatory effect on the expression of the COX-2 enzyme and inhibit pro-inflammatory enzyme 5-LOX (lipoxygenase-5) expression in the leukotriene-producing metabolic pathway [19], as well as the intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1)-a crucial step in the inflammatory response-and decrease inducible nitric oxide synthase (iNOS), which is directly responsible for inflammatory damage by blocking of the cytokines responsible for its activation [19,20]. ...
... It is probably the action of curcumin that is responsible for minimizing the incapacitating tissue effects, as it is a therapeutic agent that blocks the signaling pathway of NF-κB. In addition, reducing leucocyte adhesion and migration, and as a result, relieving pain and swelling, improves joint mobility and stiffness [16,37]. Three studies conducted by Tanabe et al. [1,2,25] evaluated MVC and ROM. ...
Physical activity, particularly high-intensity eccentric muscle contractions, produces exercise-induced muscle damage (EIMD). The breakdown of muscle fibers and the consequent inflammatory responses derived from EIMD affect exercise performance. Curcumin, a natural polyphenol extracted from turmeric, has been shown to have mainly antioxidant and also anti-inflammatory properties. This effect of curcumin could improve EIMD and exercise performance. The main objective of this systematic review was to critically evaluate the effectiveness of curcumin supplementation on EIMD and inflammatory and oxidative markers in a physically active population. A structured search was carried out following Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines in the databases SCOPUS, Web of Science (WOS), and Medline (PubMed) from inception to October 2019. The search included original articles with randomized controlled crossover or parallel design in which the intake of curcumin administered before and/or after exercise was compared with an identical placebo situation. No filters were applied to the type of physical exercise performed, the sex or the age of the participants. Of the 301 articles identified in the search, 11 met the established criteria and were included in this systematic review. The methodological quality of the studies was assessed using the McMaster Critical Review Form. The use of curcumin reduces the subjective perception of the intensity of muscle pain; reduces muscle damage through the decrease of creatine kinase (CK); increases muscle performance; has an anti-inflammatory effect by modulating the pro-inflammatory cytokines, such as TNF-α, IL-6, and IL-8; and may have a slight antioxidant effect. In summary, the administration of curcumin at a dose between 150-1500 mg/day before and during exercise, and up until 72 h' post-exercise, improved performance by reducing EIMD and modulating the inflammation caused by physical activity. In addition, humans appear to be able to tolerate high doses of curcumin without significant side-effects.
... It was demonstrated that curcumin extracts enhance the growth performance of pigs by regulating the gene expression of IGF-1 and up regulating the activity of antioxidant enzymes (Upadhaya et al., 2016). Muscular health and growth are well regulated by curcumin feeding (Alamdari et al., 2009). Botanical extracts can aid muscle regeneration and differentiation, reduce muscle atrophy and enhance anti-inflammatory responses (Rondanelli et al., 2016). ...
... Antioxidant-rich botanical extracts from plants like Aloe vera boost the biological role of IGF-1 to modulate energy kinetics, myoglobin accretion and muscular integrity (Muhammad et al., 2013). Muscle health and growth may be regulated by feeding curcumin, which was shown to improve broiler growth performance by regulating IGF-1 gene expression and enhancing the activity of antioxidant enzymes (Upadhaya et al., 2016;Alamdari et al., 2009). Recently, Rondanelli et al.,(2016) described that botanical extracts may aid muscle regeneration and differentiation, reduce muscle atrophy, and demonstrated it has antiinflammatory and anti-fatigue properties, preventing muscle damage. ...
The objectives of current study were to evaluate the effect of botanical extracts as antioxidants on amino - and fatty acids profile of broiler meat. In total, 200 one-day-old broiler chicks were divided according to a completely randomized design into eight dietary treatments with five replicates of five chicks each. Dietary treatments were: A - positive control (PC) with antibiotics and synthetic antioxidants, B - negative control (NC), C - NC+Trigonellafoenum-graecum, D -NC+Nigella sativa seed, E -NC+Violaodorata, F -NC+Trachyspermumammi, G -PC+Trachyspermumammi+Trigonellafoenum-graecum+Violaodorata, and H -NC+ Trachyspermumammi, Trigonellafoenum-graecum and Viola odorata. Meat amino - and fatty acid contents were analyzed after slaughter at 35 days of age. Data were submitted to one-way analysis of variance and means were compared by Duncan’s Multiple Range test. The levels of histidine, isoleucine, leucine, lysine and threonine were significantly higher (p≤0.05) in the H, F, E, H and F groups respectively. Arginine, tryptophan, valine, methionine, and phenylalanine were significantly higher (p≤0.05) in the C, F, E, G and H groups. Total essential amino acid levels were highest (40.36%) in C group (p≤0.05). The meat of H broilers presented significantly higher (p≤0.05) unsaturated fatty acids (54.8%) and omega-3 contents (2.77%) and the lowest saturated fatty acid content (44.8%). Group F present the highest linoleic acid and omega-6 levels and group H the highest (p≤0.05) arachidonic and eicosapentaenoic acid (EPA) contents. It was concluded that botanical extracts aid health-beneficial meat production and the simultaneous inclusion of Trachyspermumammi, Trigonellafoenum-graecum, and Viola odorata in broiler diets is a more suitable option than the other dietary regimes.
... As a net result, curcumin inhibits the expression of inflammatory cytokines (TNF-a, IL-1b, IL-6) and of the expression and function of inducible inflammatory enzymes (COX2 and mPG2S) [5][6][7] . In particular, NF-kB is involved in the development of muscle wasting during catabolic conditions such as sarcopenia; animal studies have shown that inhibition of NF-kB activity in skeletal muscle allows reducing protein degradation 8 . A similar effect is associated with the inhibition of other pro-inflammatory enzymes exerted by curcumin 8 . ...
... In particular, NF-kB is involved in the development of muscle wasting during catabolic conditions such as sarcopenia; animal studies have shown that inhibition of NF-kB activity in skeletal muscle allows reducing protein degradation 8 . A similar effect is associated with the inhibition of other pro-inflammatory enzymes exerted by curcumin 8 . Moreover, curcumin contributes to reduce the inflammatory burden leading to muscle loss in sarcopenia patients by inducing an inhibition of p38 kinase activity, oxygen radical scavenging, and induction of the heat-shock response 8 . ...
Objective:
Curcumin is known to interrupt pro-inflammatory signalling and increases anti-oxidant protection, thus inhibiting the expression of inflammatory cytokines and the expression and function of inducible inflammatory enzymes. Together, these effects contribute to limit the onset and the progression of sarcopenia, due to the major role played by inflammation in the pathophysiology of this disease. This registry study evaluates the effects of Meriva® supplementation in otherwise healthy elderly subjects.
Patients and methods:
This was a registry, supplement study, conducted in healthy subjects > 65 years with apparent loss of strength and tiredness who freely decided to start one of the following interventions: (1) standard management (exercise, balanced diet including proteins) (n = 33); (2) standard management + Meriva® one tablet/day (n = 31); (3) standard management + Meriva® one tablet/day + other supplementation (n = 22). A number of functional and biochemical parameters were evaluated at baseline and after three months (hand grip, weight lifting, time/distance before feeling tired after cycling, walking and climbing stairs; general fitness, proteinuria, oxidative stress, Karnofsky scale; left ventricular ejection fraction).
Results:
Significant improvements in all parameters, with respect to baseline values, were observed in the two supplementation groups (p < 0.05 for all comparisons). On the other hand, no improvement was observed in the standard management-only group. At three months, inter-group comparison revealed a statistical advantage in all parameters for both supplementation groups compared with the standard management-only group (p < 0.05 for all comparisons).
Conclusions:
Our registry study shows that the addition of Meriva® - either or not combined with other nutritional supplements - to standardized diet and exercise plan contributes to improve strength and physical performance in elderly subjects, potentially preventing the onset of sarcopenia.
... Myricanol has been reported to prevent dexamethasoneinduced skeletal muscle wasting, particularly by activating SIRT1 signaling [153]. Diarylheptanoids extracted from curcumin have also been reported to block protein degradation and decrease NF-kB nuclear translocation in sepsis models [301,302]. In cachexia-induced muscle wasting, curcumin treatment also inhibits muscle loss by attenuating lipopolysaccharide-stimulated atrogin-1 expression [303]. ...
Muscle wasting is a consequence of physiological changes or a pathology characterized by increased catabolic activity that leads to progressive loss of skeletal muscle mass and strength. Numerous diseases, including cancer, organ failure, infection, and aging-associated diseases, are associated with muscle wasting. Cancer cachexia is a multifactorial syndrome characterized by loss of skeletal muscle mass, with or without the loss of fat mass, resulting in functional impairment and reduced quality of life. It is caused by the upregulation of systemic inflammation and catabolic stimuli, leading to inhibition of protein synthesis and enhancement of muscle catabolism. Here, we summarize the complex molecular networks that regulate muscle mass and function. Moreover, we describe complex multi-organ roles in cancer cachexia. Although cachexia is one of the main causes of cancer-related deaths, there are still no approved drugs for cancer cachexia. Thus, we compiled recent ongoing pre-clinical and clinical trials and further discussed potential therapeutic approaches for cancer cachexia.
... Numerous health benefits proven in countless trials have been attributed to curcumin; to date, there has been some evidence that proves these benefits for skeletal muscle (Table 1). For some years, it has been proposed that the use of curcumin may be a viable option for the prevention or therapy of muscle wasting [38]. In particular, in muscle wasting caused by sepsis, curcumin blocks the nuclear translocation of NF-kB subunit p25, as well as p65 DNA binding activity [39]. ...
Citation: Vargas-Mendoza, N.; Madrigal-Santillán, E.; Álvarez-González, I.; Madrigal-Bujaidar, E.; Anguiano-Robledo, L.; Aguilar-Faisal, J.L.; Morales-Martínez, M.; Delgado-Olivares, L.; Rodríguez-Negrete, E.V.; Morales-González, Á.; et al. Phytochemicals in Skeletal Muscle Health: Effects of Curcumin (from Curcuma longa Linn) and Sulforaphane (from Brassicaceae) on Muscle Function, Recovery and Therapy of Muscle Atrophy. Plants 2022, 11, 2517. https://doi.
... e administration of curcumin has not only been attributed to the reduction of muscle loss following sepsis and endotoxemia but also to inducing the regeneration of the wasted muscle after the traumatic injury. Curcumin exerts its antiinflammatory and antioxidant properties via the inhibition of NF-lB signaling, induction of heat shock response, abrogating the p38 kinase activity, inhibition of oxygen free radical formation, and prevention of the biosynthesis and release of pro-inflammatory cytokines (reviewed in [78]). Furthermore, curcumin reduces the inflammation associated with exertive exercise-induced muscle damage. ...
Skeletal muscle mass responds rapidly to growth stimuli, precipitating hypertrophies (increased protein synthesis) and hyperplasia (activation of the myogenic program). For ages, muscle degeneration has been attributed to changes in the intracellular myo ber pathways. ese pathways are tightly regulated by hormones and lymphokines that ultimately pave the way to decreased anabolism and accelerated protein breakdown. Despite the lacunae in our understanding of specific pathways, growing bodies of evidence suggest that the changes in the myogenic/regenerative program are the major contributing factor in the development and progression of muscle wasting. In addition, inflammation plays a key role in the pathophysiology of diseases linked to the failure of skeletal muscles. Chronic inflammation with elevated levels of inflammatory mediators has been observed in a spectrum of diseases, such as inflammatory myopathies and chronic obstructive pulmonary disease (COPD). Although the pathophysiology of these diseases varies greatly, they all demonstrate sarcopenia and dysregulated skeletal muscle physiology as common symptoms. Medicinal plants harbor potential novel chemical moieties for a plenitude of illnesses, and inflammation is no exception. However, despite the vast number of potential antiinflammatory compounds found in plant extracts and isolated components, the research on medicinal plants is highly daunting. is review aims to explore the various phytoconstituents employed in the treatment of inflammatory responses in skeletal muscles, while providing an in-depth molecular insight into the latter.
... The cellular activation of NF-κB mediated by this process stimulates the secretion of products responsible for the production of tissue damage, such as inflammatory cytokines (IL-1, IL-1b, IL-2, IL-15, IL-21, and TNF-α), Oxidative Medicine and Cellular Longevity chemokines (CCL-19, CCR-7), and metalloproteases (MMP-13, ADAMSTS-4) (Wainstein GE 2014). The curcumin action probably minimizes the tissue's disabling effects, blocking the NF-κB signaling pathway and thus providing less muscle damage and a consequently smaller decrease in MVC and ROM [48,49]. ...
Exhaustive and acute unusual physical exercise leads to muscle damage. Curcumin has been widely studied due to the variety of its biological activities, attributed to its antioxidant and anti-inflammatory properties. Furthermore, it has shown positive effects on physical exercise practitioners. However, there is no literature consensus on the beneficial effects of curcumin in acute physical activities performed by sedentary individuals. Therefore, we systematically reviewed evidence from clinical trials on the main effects of curcumin supplementation on inflammatory markers, sports performance, and muscle damage during acute physical exercises in these individuals. We searched PubMed/MEDLINE, Scopus, Web of Science, and Embase databases, and only original studies were analyzed according to the PRISMA guidelines. The included studies were limited to supplementation of curcumin during acute exercise. A total of 5 studies were selected. Methodological quality assessments were examined using the SYRCLE's risk-of-bias tool. Most studies have shown positive effects of curcumin supplementation in sedentary individuals undergoing acute physical exercise. Overall, participants supplemented with curcumin showed less muscle damage, reduced inflammation, and better muscle performance. The studies showed heterogeneous data and exhibited methodological limitations; therefore, further research is necessary to ensure curcumin supplementation benefits during acute and high-intensity physical exercises. Additionally, mechanistic and highly controlled studies are required to improve the quality of the evidence and to elucidate other possible mechanisms. This study is registered with Prospero number CRD42021262718.
... Curcumin, a phytopolyphenol isolated from Curcuma longa L., can interfere with multiple cellular targets; because of that, it is one of the promising candidates for musclewasting diseases [130]. It has been shown that curcumin contributes to the treatment of FSHD at the clinical level [126]. ...
Facioscapulohumeral muscular dystrophy (FSHD) is in the top three list of all dystrophies with an approximate 1:8000 incidence. It is not a life-threatening disease; however, progression of the disease extends over being wheel-chair bound. Despite some drug trials have been continuing, including DUX4 inhibition, TGF-ß inhibition and resokine which promote healthier muscle, there is not an applicable treatment option for FSHD today. Still, there is a need for new agent or agents to heal, to stop or at least to slow down the muscle wasting. Current FSHD studies with nutraceuticals as vitamin C, vitamin E, coenzyme Q10, zinc, selenium, and phytochemicals as curcumin or genistein, daidzein flavonoids provide promising treatment strategies. In this review we will present the clinical and molecular nature of FSHD and focus on nutraceuticals and phytochemicals that may alleviate FSHD. Via interconnection of impaired pathophysiological FSHD pathways together with nutraceuticals and phytochemicals in the light of literature, we present both studied and novel approaches that can contribute FSHD treatment.
... Traditionally, a large number of people in India, China, Indonesia and other Asian countries have applied turmeric powder in therapeutic herbs and as a food additive. [1][2][3][4][5] The curcumin (diferuloylmethane) constituent is a tautomeric compound known to exist as an enolic form in organic solvents, and in keto form in water. 6 The wide range of biological activities are currently being tested in vivo and in vitro to develop the numerous potentials in treating various diseases. ...
Background: Curcumin reduces the proliferation of cancer cells through inhibition of the DYRK2 enzyme, which is a positive regulator of the 26S proteasome.
Methods: In the present work, curcumin analogues have been screened from the MolPort database using a pharmacophore model that comprised a ligand-based approach. The result of the screening was then evaluated by molecular docking and molecular dynamics based on binding the free energy of the interaction between each compound with the binding pocket of DYRK2. The hit compounds were then confirmed by absorption, distribution, metabolism, and excretion (ADME) prediction.
Results: Screening of 7.4 million molecules from the MolPort database afforded six selected hit compounds. By considering the ADME prediction, three prospective curcumin analogues have been selected. These are: 2‐[2‐(1‐methylpyrazol‐4‐yl)ethyl]‐1H,5H,6H,7H,8H‐imidazo[4,5‐c]azepin‐4‐one (Molport-035-369-361), methyl 4‐(3‐hydroxy‐1,2‐oxazol‐5‐yl)piperidine‐1‐carboxylate (Molport-000-004-273) and (1S)‐1‐[5‐(furan‐3‐carbonyl)‐4H,6H,7H‐pyrazolo[1,5‐a]pyrazin‐2‐yl]ethanol (MolPort-035-585-822).
Conclusion: Pharmacophore modelling, combined with molecular docking and molecular dynamics simulation, as well as ADME prediction were successfully applied to screen curcumin analogues from the MolPort database as DYRK2 inhibitors. All selected compounds that have better predicted pharmacokinetic properties than that of curcumin are considered for further study.
... Facing such a scenario, the WP admixtured of CCM seems to meet the demands of consumers, since this spice would increase the nutritional characteristics of WP due to its antioxidant and nutritional potential (21,22) . Furthermore, the potential health benefits of TUR, such as its good safety profile, ease of acquisition, in addition to not being toxic even at high doses, led to the interest in incorporating it into functional food products as a nutraceutical ingredient (23,24) . ...
This work aimed to evaluate the effects of whey protein concentrate admixtured of curcumin on metabolic control, inflammation and oxidative stress in Wistar rats submitted to exhaustive exercise. A total of 48 male rats were divided into 6 experimental groups (n = 8): standard diet group (AIN-93M); standard diet submitted to exhaustion test group (AIN-93M ET); whey protein concentrate admixtured of curcumin group (WPC + CCM); WPC + CCM submitted to exhaustion test group (WPC + CCM ET); CCM group, and CCM subjected to exhaustion test group (CCM ET). The swimming exhaustion test was performed after 4 weeks of experiment. The consumption of WPC + CCM as well as isolated CCM did not alter the biometric measurements, the animals' food consumption and the hepatic and kidney function, as well as the protein balance of the animals (p>0.05), but reduced the glycemia and the gene expression of TNF- α and IL-6, and increased the expression of IL-10 (p<0.05). The animals that were submitted to the exhaustion test (AIN-93M ET) showed higher AST values when compared to the animals that did not perform the exercise (AIN-93 M) (p<0.05). WPC + CCM reduced the concentration of nitric oxide, carbonylated protein and increased the concentration of catalase (p<0.05). Both (WPC + CCM and CCM) were able to increase the concentrations of superoxide dismutase (p<0.05). We concluded that the WPC admixtured of CCM represents a strategy capable of decreasing blood glucose and oxidative and inflammatory damage caused by exhaustive physical exercise in swimming.
... Curcumin is a well-known polyphenolic compound isolated from the rhizomes of Curcuma longa (turmeric) and exerts multiple pharmacological effects, including antioxidant and anti-inflammatory effects, and prevention of muscle wasting (Alamdari et al., 2009). This compound stimulates the expression of glucose-regulated protein 94 kDa (Grp94) in myogenic cells, whose levels decreases in unloaded and atrophied muscles (Vitadello et al., 2014). ...
Frailty is a late life phenotype characterized by a decline in physiological reserve across several organ systems, resulting in the increased susceptibility to endogenous and/or exogenous stressors. Although the etiology of frailty remains poorly understood, an interconnected network of putative mechanisms linked to the ageing process has been proposed. However, frailty is a dynamic process that may be prevented, delayed, or even reversed. The syndromic nature of frailty requires a multidomain approach, such as proper nutrition, as part of modifiable environmental factors, and represents one of the most promising and least costly ways to prevent and reduce frailty among older adults. Nutrient deficiencies have been consistently associated with frailty; however, mounting evidence also supports the hypothesis that beyond the traditional nutritional value, specific dietary components may exert function-enhancing effects and mitigate the extent of frailty. Thus, further mechanistic studies, along with large clinical trials, are imperative to establish the exact role of functional nutrients in the clinical management of frailty. Here, we provide a contemporary discussion of how emerging functional nutrients may contribute to modify the trajectory of the frailty syndrome.
... Curcumin suppresses the activation of NF-B, while NF-B appears to be involved in the regulation of proteolysis and inflammation in muscles. Therefore, inhibition of NF-B by curcumin may result in a muscle-protective effect ( Alamdari et al., 2009 ). Curcumin significantly prevented muscle proteolysis and down-regulated expression levels of two critical musclespecific ubiquitin ligases (Atrogin-1 and MuRF-1) ( Jun et al., 2016 ). ...
Background
Sarcopenia is a disease of progressive loss of muscle mass due to the imbalance of protein synthesis and proteolysis, and tends to emerge with ageing. Currently its treatment consists of non-drug therapies and drug therapies, but some medications can have various side effects. Therefore, it is important to search for effective herbal medicines that can modulate muscle mass.
Purpose
In this study, we investigated the inhibition effects of Cu, De, Bis, CRE, CRE-SD, CRE-Bin, and CRE-Ter on dexamethasone-induced muscle atrophy in differentiation of C2C12 cells.
Methods
C2C12 cells were cultured and treated with various concentrations of curcuminoids including, Cu, De, Bis, CRE, CRE-SD, CRE-Bin, and CRE-Ter. The inhibitory effects were studied using various methods, including MTT and LDH assays for cell viability and cell cytotoxicity, RT-qPCR for gene expression analysis, and Western blots for protein analysis. In this study, dexamethasone-treated C2C12 myotubes (Dex) are the positive drug control and used as in vitro models of muscle atrophy.
Results
The results revealed that treating differentiated C2C12 cells with Cu, CRE, CRE-Bin, and CRE-Ter reduced Atrogin-1 and MuRF-1 expression, whereas CRE-SD reduced only MuRF-1 expression. The Western blot analysis results show that Cu, CRE, CRE-Bin, CRE-Ter, and CRE-SD upregulated the phosphorylation level of Akt, which is an important protein in the mTOR signaling pathway.
Conclusion
Our results show that Cu, CRE, CRE-Bin, CRE-SD, and CRE-Ter tend to inhibit muscle atrophy by decreasing expression of Atrogin-1 and MuRF-1 inhibiting protein degradation, and to upregulate Phospho-Akt to stimulate protein synthesis. These results provide corroborating evidence of therapeutic potential to treat sarcopenia patients.
... An in vivo study using curcumin as the test product found that curcumin prevents muscle damage by regulating NF-jB and Nrf2 signaling pathways and improves endurance. 41 Another previous study has also shown that curcumin has the ability to prevent muscle atrophy by stimulating glucose-related protein expression. 42 A novel bioavailable hydrogenated curcumin formulation was studied for its positive effect on the management of rheumatoid arthritis, revealing that the groups supplemented with hydrogenated curcuminoids showed significant promising results in rheumatoid arthritis management as measured by the American College of Rheumatology (ACR) responses. ...
Sarcopenia represents the progressive loss of skeletal muscles, which occurs as a result of aging. Plant-derived phytochemicals have the potential ability to manage sarcopenial conditions. The randomized, placebo-controlled, double-blind clinical study involving thirty subjects evaluated the efficacy of CureitÔ supplementation in the management of sarcopenial conditions by measuring the variables, such as hand grip strength, weight lift strength, time/distance before feeling tired after cycling, walking and climbing stairs, and Karnofsky performance scale index along with effects on general fitness, such as protein, urea, oxidative stress, and hematology parameters. The results showed that Cureit supplementation resulted in a significant increase of 1.43% (P < .001) in the handgrip strength compared with placebo. The weight-lifting capacity of subjects supplemented with Cureit showed an increase of 6.08%, whereas placebo showed a 4.54% decrease after the end of the study period. The results demonstrated that the Cureit tended to have a positive impact on distance covered before feeling tired as shown by an increase (P = .09) of 5.51%, compared with placebo group, which showed an increase of 2.29%. The time taken to walk the same distance was reduced in the Cureit group (1.15%), whereas in the placebo group, it was increased (2.02%). Cureit plays a significant role in the management of sarcopenia by anti-inflammatory action, increased hand grip strength, antifatigue effects, and muscle protein management. Clinical Trials Registry-India registration no. CTRI/2018/05/014176 KEYWORDS: complete natural turmeric matrix Cureit hand grip strength sarcopenia weight lift strength
... Other reports indicated a beneficial effect of curcumin on muscle cachexia [105,106]. However, further research on curcumin's influence on oncological cachexia is needed [107]. Among other natural STAT3 inhibitors with antitumor properties, butein [108] and ursolic acid [109] are worth mentioning. ...
Muscle cachexia is one of the most critical unmet medical needs. Identifying the molecular background of cancer-induced muscle loss revealed a promising possibility of new therapeutic targets and new drug development. In this review, we will define the signal transducer and activator of transcription 3 (STAT3) protein’s role in the tumor formation process and summarize the role of STAT3 in skeletal muscle cachexia. Finally, we will discuss a vast therapeutic potential for the STAT3-inhibiting single-agent treatment innovation that, as the desired outcome, could block tumor growth and generally prevent muscle cachexia.
... Such an extract has demonstrated a potent antioxidant effect in skeletal muscle both in vitro and in vivo (Vasilaki and Jackson, 2013;Wang et al., 2014;Haramizu et al., 2017). Another substance with powerful antiinflammatory and antioxidant properties is curcumin, a yellow pigment extracted from the rhizome of turmeric (Curcuma longa) (Abrahams et al., 2019) that can also modulate muscle protein degradation (Busquets et al., 2001;Lin, 2007;Alamdari et al., 2009). Due to their activity as reactive oxygen species (ROS) scavengers, these bioactive molecules are of high interest as dietary supplements for fish species, with particular relevance during early developmental stages where growth potential is largely affected by nutritional clues. ...
Somatic growth is a balance between protein synthesis and degradation, and it is largely influenced by nutritional clues. Antioxidants levels play a key role in protein turnover by reducing the oxidative damage in the skeletal muscle, and hence promoting growth performance in the long-term. In the present study, Senegalese sole postlarvae (45 days after hatching, DAH) were fed with three experimental diets, a control (CTRL) and two supplemented with natural antioxidants: curcumin (CC) and grape seed (GS). Trial spanned for 25 days and growth performance, muscle cellularity and the expression of muscle growth related genes were assessed at the end of the experiment (70 DAH). The diets CC and GS significantly improved growth performance of fish compared to the CTRL diet. This enhanced growth was associated with larger muscle cross sectional area, with fish fed CC being significantly different from those fed the CTRL. Sole fed the CC diet had the highest number of muscle fibers, indicating that this diet promoted muscle hyperplastic growth. Although the mean fiber diameter did not differ significantly amongst treatments, the proportion of large-sized fibers (>25 µm) was also higher in fish fed the CC diet suggesting increased hypertrophic growth. Such differences in the phenotype were associated with a significant up-regulation of the myogenic differentiation 2 (myod2) and the myomaker (mymk) transcripts involved in myocyte differentiation and fusion, respectively, during larval development. The inclusion of grape seed extract (GS diet) resulted in a significant increase in the expression of myostatin1. These results demonstrate that both diets (CC and GS) can positively modulate muscle development and promote growth in sole postlarvae. This effect is more prominent in CC fed fish, where increased hyperplastic and hypertrophic growth of the muscle was associated with an upregulation of myod2 and mymk genes.
... The use of curcumin in myalgic encephalomyelitis/ chronic fatigue syndrome as a novel therapeutic option was mentioned . Curcumin inhibited sepsis-induced muscle wasting by inhibiting catabolic response in skeletal muscle via blocking NF-κB (Alamdari, O'Neal, & Hasselgren, 2009). Curcumin (Meriva®, 1 g, 3 months) prevented muscle loss and improved physical performance in healthy elder subjects and delayed the onset of sarcopenia in them (Franceschi et al., 2016). ...
In late December 2019, the outbreak of respiratory illness emerged in Wuhan, China, and spreads worldwide. World Health Organization (WHO) named this disease severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused by a new member of beta coronaviruses. Several medications are prescribed to patients, and some clinical trials are underway. Scientists are trying to find a specific drug against this virus. In this review, we summarize the pathogenesis, clinical features, and current treatments of coronavirus disease 2019 (COVID-19). Then, we describe the possible therapeutic effects of curcumin and its molecular mechanism against coronavirus-19. Curcumin, as an active constituent of Curcuma longa (turmeric), has been studied in several experimental and clinical trial studies. Curcumin has some useful clinical effects such as antiviral, antinociceptive, anti-inflammatory, antipyretic, and antifatigue effects that could be effective to manage the symptoms of the infected patient with COVID-19. It has several molecular mechanisms including antioxidant, antiapoptotic, and antifibrotic properties with inhibitory effects on Toll-like receptors, NF-κB, inflammatory cytokines and chemokines, and bradykinin. Scientific evidence suggests that curcumin could have a potential role to treat COVID-19. Thus, the use of curcumin in the clinical trial, as a new treatment option, should be considered. © 2020 The Authors. Food Science & Nutrition published by Wiley Periodicals LLC.
... Consistently, it has been suggested that curcumin may prevent loss of muscle mass during sepsis and endotoxaemia and may stimulate muscle regeneration after traumatic injury. Other mechanisms potentially responsible for the anti-inflammatory and antioxidant properties of curcumin include induction of heat-shock response, 18 reduction in the expression of the pro-inflammatory enzyme cyclooxygenase-2 (COX-2), and promotion of the antioxidant response by activation of the transcription factor Nrf2. More recent studies confirm that curcumin can reduce inflammation and decrease some of the negative effects associated with eccentric exercise-induced muscle damage, including the release of pro-inflammatory cytokines and markers of muscle injury like creatine kinase (Ck). ...
... Curcumin, the major active component of turmeric (Curcuma longa), is widely used as a kind of spice or food-coloring agent, and has been used widely for the treatment of various diseases, including respiratory and liver diseases, anorexia and arthritis, and which is also taken as a candidate for cancer, etc [23][24][25][26]. Recently, curcumin has been shown special potential to shed light on anti-catabolic and protective effects in muscle wasting related to varied pathological status [27,28]. ...
Curcumin has been reported to attenuate muscle atrophy. However, the underling mechanism remains unclear. The aim of this study was to investigate whether curcumin could improve chronic kidney disease (CKD) - induced muscle atrophy and mitochondrial dysfunction by inhibiting GSK-3β activity. The sham and CKD mice fed either a control diet or an identical diet containing 0.04% curcumin for 12 weeks. The C2C12 myotubes were treated with H2O2 in the presence or absence of curcumin. In addition, wild-type (WT) and muscle-specific GSK-3β knockout (KO) CKD model mice made by 5/6 nephroctomy, and the sham was regarded as control (CTL). Curcumin could exert beneficial effects, including weight maintenance and improved muscle function, increased mitochondrial biogenesis, alleviated mitochondrial dysfunction by increasing ATP levels, activities of mitochondrial electron transport chain (ETC) complexes and basal mitochondrial respiration and suppressing mitochondrial membrane potential. In addition, curcumin modulated redox homeostasis by increasing antioxidant activity and suppressed mitochondrial oxidative stress. Moreover, the protective effects of curcumin had been found to be mediated via inhibiting GSK-3β activity in vitro and in vivo. Importantly, GSK-3β KO contributed to improved mitochondrial function, attenuated mitochondrial oxidative damage, and augmented mitochondrial biogenesis in muscle of CKD. Overall, this study suggested that curcumin alleviated CKD - induced mitochondrial oxidative damage and mitochondrial dysfunction via inhibiting GSK-3β activity in skeletal muscle.
... Curcumin may also be potentially useful to prevent muscle mass loss. By activating the transcription factor Nrf2, curcumin favors antioxidant defense and downregulates NF-kB activity, which is a crucial molecule in the path leading to muscle mass loss [73,74]. ...
The individual response to nutrients and non-nutrient molecules can be largely affected by three important biological layers. The gut microbiome can alter the bioavailability of nutrients and other substances, the genome can influence molecule kinetics and dynamics, while the epigenome can modulate or amplify the properties of the genome. Today the use of omic techniques and bioinformatics, allow the construction of individual multilayer networks and thus the identification of personalized strategies that have recently been considered in all medical fields, including sports medicine. The composition of each athlete’s microbiome influences sports performance both directly by acting on energy metabolism and indirectly through the modulation of nutrient or non-nutrient molecule availability that ultimately affects the individual epigenome and the genome. Among non-nutrient molecules polyphenols can potentiate physical performances through different epigenetic mechanisms. Polyphenols interact with the gut microbiota, undergoing extensive metabolism to produce bioactive molecules, which act on transcription factors involved in mitochondrial biogenesis, antioxidant systems, glucose and lipid homeostasis, and DNA repair. This review focuses on polyphenols effects in sports performance considering the individual microbiota, epigenomic asset, and the genomic characteristics of athletes to understand how their supplementation could potentially help to modulate muscle inflammation and improve recovery.
... In sports nutrition, turmeric and in particular curcumin may be potentially useful to prevent loss of muscle mass. Inhibition of NF-kB activity is of particular interest for the potential use of curcumin in the treatment of muscle wasting since NF-kB activation is a key step in the pathway leading to loss of muscle mass (Alamdari et al., 2009). ...
... In sports nutrition, turmeric and in particular curcumin may be potentially useful to prevent loss of muscle mass. Inhibition of NF-kB activity is of particular interest for the potential use of curcumin in the treatment of muscle wasting since NF-kB activation is a key step in the pathway leading to loss of muscle mass (Alamdari et al., 2009). ...
Since ancient times, nutrition has always been considered an essential condition for
maintaining good health. Hippocrates of Kos, the father of medicine, said in 460 BC:
“Let food be thy medicine and medicine be thy food.” His observations led to associative
evidence between diet and health by highlighting how food is able to interfere with our
body’s physiology by not only acting as an energy provider, but as a modulator of the
health/disease balance in a different way for each individual (Tsiompanou and
Marketos, 2013) depending on the personal characteristics. Somehow it can be considered a precursor of modern nutritional genomics.
It is fundamental to consider that although nutrients act by modulating some physiologic
functions in a dose-dependent manner, each individual responds differently
depending on its genotypic and phenotypic characteristics (Ferguson et al., 2016).
Therefore, the recommended daily doses suggested by the international nutrition
guidelines, based on studies on large populations rather than specific genotypes or phenotypes, should be used with enough flexibility to account for the plethora of genetic,
epigenetic, and environmental factors contributing to health and disease in each
individual.
Nutritional genomics is a new branch of nutritional medicine based on the concepts
of functional genomics and personalized medicine. Empowering the individual biochemical data with genomic data allows the customization of a specific diet for each individual, based on the genotypic characteristics and the nutrients modulatory action on
gene expression (Camp and Trujillo, 2014).
... It is reported that curcumin enhances wound healing by increasing granulation tissue formation, neovascularization, and faster reepithelialization [40]. Mechanisms for the anti-inflammatory effects of curcumin include inhibition of NF-κB activity, activation of the heat-shock response, inhibition of p38 kinase activity and oxygen free radical formation, and prevention of cytokine production and release [41]. Oral administration of curcumin has attenuated skeletal muscle mitochondrial impairment in chronic obstructive pulmonary disease rats [42]. ...
Objective: To compare the effects of curcumin and nanocurcumin oral supplementation on the muscle healing rate of an animal model of surgical muscle laceration.
Methods: Thirty-two male adult rats were randomly divided into sham, control, curcumin, and nanocurcumin groups. Partial transection of the gastrocnemius muscle was made in the right limb of the control and treatment groups. The sham and control groups received normal saline, curcumin group received 500 mg/kg of curcumin and nanocurcumin group received 100 mg curcumin-loaded nanomicelles orally every day. They euthanized two weeks later and the specimens were stained by hematoxylin-eosin (H&E) and Masson’s trichrome methods. Aspartate transaminase (AST) and creatine phosphokinase (CPK) were measured in blood samples.
Results: The percentage of collagen fibers in the nanocurcumin group was significantly lesser than the control and curcumin groups (p=0.000). Muscle fiber regeneration in the treatment groups was significantly higher than the control group (p=0.000). The blood vessels of the nanocurcumin group were significantly more than other groups (p=0.000). Plasma AST had a significant difference in the control group compared to the sham and nanocurcumin groups (p=0.026). The plasma CPK level of the control group was also significantly higher than other groups (p=0.000).
Conclusion: In conclusion, although oral curcumin supplementation has little effects because of its poor bioavailability, embedding it in nanoparticles could enhance its systemic effects in promoting the muscle healing process.
... Curcumin, an ingredient in the spice turmeric, has garnered attention due to its ability to alleviate disease pathologies through its anti-inflammatory, anti-carcinogenic and antioxidant properties [20]. The ability of curcumin to alter the cellular redox status could be particularly beneficial to aging muscle. ...
Oxidative stress resulting from decreased antioxidant protection and increased reactive oxygen and nitrogen species (RONS) production may contribute to muscle mass loss and dysfunction during aging. Curcumin is a phenolic compound shown to upregulate antioxidant defenses and directly quench RONS in vivo. This study determined the impact of prolonged dietary curcumin exposure on muscle mass and function of aged rats. Thirty-two-month-old male F344xBN rats were provided a diet with or without 0.2% curcumin for 4 months. The groups included: ad libitum control (CON; n = 18); 0.2% curcumin (CUR; n = 18); and pair-fed (PAIR; n = 18) rats. CUR rats showed lower food intake compared to CON, making PAIR a suitable comparison group. CUR rats displayed larger plantaris mass and force production (vs. PAIR). Nuclear fraction levels of nuclear factor erythroid-2 related-factor-2 were greater, and oxidative macromolecule damage was lower in CUR (vs. PAIR). There were no significant differences in measures of antioxidant status between any of the groups. No difference in any measure was observed between CUR and CON rats. Thus, consumption of curcumin coupled with reduced food intake imparted beneficial effects on aged skeletal muscle. The benefit of curcumin on aging skeletal muscle should be explored further.
... Curcumin being easily available, inexpensive, non-toxic and antioxidant has gained much attention and has been considered as an important modality in treatment of muscle atrophy [39,40] under various catabolic conditions. However, since the musclesparing effects of curcumin are not universally accepted [41] and there is lack of extensive studies on role of curcumin in inhibiting hypobaric hypoxia mediated muscle atrophy, more studies are needed to further test the role of curcumin in treatment of muscle wasting under high altitude hypoxia. The aim of the present study was therefore to explore the therapeutic efficacy of curcumin in ameliorating muscle mass loss by reducing oxidative stress under hypobaric hypoxia. ...
Chronic hypobaric hypoxia induced muscle atrophy results in decreased physical performance at high altitude. Curcumin has been shown to have muscle sparing effects under cachectic conditions. However, the protective effects of curcumin under chronic hypobaric hypoxia have not been studied till now. Therefore, the present study aims at evaluating the effects of curcumin administration on muscle atrophy under chronic hypobaric hypoxia. Male Sprague Dawley rats were divided into four groups: Control (C)-normoxia exposed, Control Treated (CT)-normoxia exposed and administered with curcumin at a dose of 100 mg/kg body weight for 14 days, Hypoxia (H)-exposed to hypobaric hypoxia for 14 days and Hypoxia Treated (HT)-exposed to hypobaric hypoxia and administered with curcumin for 14 days. Oxidative stress, muscle protein degradation, proteolytic pathways, myosin heavy chain (MHC), CPK activity and muscle histology were performed in gastrocnemius muscle samples of the exposed rats. In addition, fatigue time on treadmill running was also evaluated to observe the effects of curcumin administration on physical performance of the rats. As previously shown, hypobaric hypoxia increased muscle protein degradation via upregulated calpain and ubiquitin-proteolytic pathways. An enhanced oxidative stress has been linked to upregulation of these pathways under hypoxic conditions. Curcumin administration resulted in reduced oxidative stress as well as reduced activity of the proteolytic pathways in HT group as compared to H group thereby resulting in reduced muscle protein degradation under hypobaric hypoxia. Histology of rat muscle revealed an increased number of muscle fibres in HT as compared to H group. Thus, increased number of muscle fibres and decreased muscle proteolysis following curcumin administration, lead to enhanced muscle mass under hypobaric hypoxia resulting in improved physical performance of the rats. © 2018 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM)
... A possible role of curcumin in muscle mass loss has already been described, notably by blocking the NF-kB pathway or inhibiting the activity of p38 kinase in catabolismenhanced patterns such as sepsis, endotoxemia, or stimulating muscle fibers regeneration after trauma [29]. This protective role of curcumin on muscle in hypermetabolism states could be the explanation of our experimental evidence, as ALS is a well-known condition of hypermetabolism [30]. ...
Objective:
To investigate the efficacy of curcumin oral supplementation (600 mg/day, Brainoil), a natural antioxidant compound, in Amyotrophic Lateral Sclerosis (ALS).
Methods:
Patients were randomized into two groups: Group A received placebo for 3 months, then Brainoil for the following 3 months, Group B took Brainoil for 6 months. The evaluations were conducted at basal (T0), after 3 months of double blinded Brainoil or placebo treatment (T1), and after the 3 month open-label phase (T2). Clinical evaluations and oxidative stress biomarkers, including oxidative protein products (AOPPs), ferric reducing ability (FRAP), total thiols (T-SH) and lactate, were evaluated, compared to a control group, during an incremental forearm exercise test.
Results:
Over the entire study Group B showed a stable score of the ALS-FRS-r which decreased in Group A (p<0.01), in parallel with a reduction of AOPPs (p<0.01) which was not detected into Group A. Also FRAP exercise values remained stable in Group B, while in Group A they were reduced without treatment at T1 (0.05<p<0.01), for then increase at T2 with introduction of therapy (p<0.05). In Group B T1>T0 exercise lactate was lower compared to Group A (p<0.01). Compared to controls, the whole ALS population showed a greater oxidative stress (p<0.001), those treated with curcumin (Group B) exhibiting decreased exercise AOPPs at T2 with values approaching those of controls.
Conclusion:
Although further studies are needed to confirm these data, treatment with curcumin shows encouraging results indicating a slight slowdown in disease progression, improving aerobic metabolism and oxidative damage, this also contributing to deepen knowledge into the pathogenic mechanisms of ALS.
... GFPu is a surrogate marker to monitor dynamic changes in the proteolytic function of UPS in the living cells [22]. Elevated GFPu expression (Fig 4A and 4B) and decreased chymotrypsin-like activity of the proteasome (Fig 4C) indicate that UPS function was blocked by curcumin treatment [23][24][25]. In addition, broad-spectrum caspase inhibitor Boc-D-FMK also did not affect Akt protein expression under concomitant treatment of curcumin (S2 Fig). ...
Previous studies have evidenced that the anticancer potential of curcumin (diferuloylmethane), a main yellow bioactive compound from plant turmeric was mediated by interfering with PI3K/Akt signaling. However, the underlying molecular mechanism is still poorly understood. This study experimentally revealed that curcumin treatment reduced Akt protein expression in a dose- and time-dependent manner in MDA-MB-231 breast cancer cells, along with an activation of autophagy and suppression of ubiquitin-proteasome system (UPS) function. The curcumin-reduced Akt expression, cell proliferation, and migration were prevented by genetic and pharmacological inhibition of autophagy but not by UPS inhibition. Additionally, inactivation of AMPK by its specific inhibitor compound C or by target shRNA-mediated silencing attenuated curcumin-activated autophagy. Thus, these results indicate that curcumin-stimulated AMPK activity induces activation of the autophagy-lysosomal protein degradation pathway leading to Akt degradation and the subsequent suppression of proliferation and migration in breast cancer cell.
... Curcumin is easily available, inexpensive, and has proven to be non-toxic even when administered at high doses. [43] Various studies have clearly pointed out that methylprednisolone enhances functional recovery and induces regenerative responses after SCI in humans and experimental animals, [2,4] but it is not effective enough and is sometimes associated with some side effects. ...
Sarcopenia is the progressive loss of muscle mass, strength, and functions as we age. The pathogenesis of sarcopenia is underlined by oxidative stress and inflammation. As such, it is reasonable to suggest that a natural compound with both antioxidant and anti-inflammatory activities could prevent sarcopenia. Curcumin, a natural compound derived from turmeric with both properties, could benefit muscle health. This review aims to summarise the therapeutic effects of curcumin on cellular, animal, and human studies. The available evidence found in the literature showed that curcumin prevents muscle degeneration by upregulating the expression of genes related to protein synthesis and suppressing genes related to muscle degradation. It also protects muscle health by maintaining satellite cell number and function, protecting the mitochondrial function of muscle cells, and suppressing inflammation and oxidative stress. However, it is noted that most studies are preclinical. Evidence from randomised control trials in humans is lacking. In conclusion, curcumin has the potential to be utilised to manage muscle wasting and injury, pending more evidence from carefully planned human clinical trials.
After the devastating Spanish Flu epidemics of 1918–1920, a new deadly virus strikes the world in late December 2019 and is first detected in China in early January 2020. There are 153 lakh active cases of corona virus worldwide (Worldometer data). Improving nutritional patterns is a successful strategy for combating coronavirus pandemic. The most effective natural antibiotics against viruses are spices like turmeric, ginger, black pepper and garlic.Curcumin, a hydrophobic polyphenol is an active constituent of turmeric rhizomes, has antioxidant, antiapoptotic and anti-fibrotic properties. It also has inhibitory effects on TLRs, NF-Kβ, cytokines, chemokines and bradykinin. Curcumin inhibited 3CLprotease and prevented SARS-CoV replication. It not only blocks ligand-receptor binding at entry point but blocks replication and gene expression of viruses. Ginger extracts containing compounds such as gingerol, shogoal and paradols have been found to be effective against SARS-CoV. These chemicals have anti-bacterial effect that can help to prevent nausea. They inhibit ACE2 gene receptor, in the same way that curcumin does. Piperine presents in black pepper slows the breakdown of curcumin in the liver, thus helping its absorption through intestine and increases its level in bloodstream. Garlic contains flavonoid (e.g. quercetin) and organosulfur (e.g.allicin and alliin) compounds that have immunomodulatory properties which inhibit the virus spread.
Muscle atrophy is a reduction of muscle mass and size that occurs after the age of 30. The effects of the solid dispersions of curcumin (CURSD) and gamma-oryzanol (GOSD) were investigated on skeletal muscle of middle-aged Sprague-Dawley rats (12 months old) and compared to young rats (4 months old). A mixture of CURSD and GOSD supplements (GO-CURSD) increased antioxidant enzymes through the Nrf2 pathway which caused a reduction in lipid peroxidation and pro-inflammations, resulting in less muscle damage. The GO-CURSD increased IRS1-AKT-mTOR activity and suppressed Atrogin-1 and MuRF-1 genes, resulting in increased muscle mass and cross-sectional area. In addition, the GO-CURSD increased muscular glucose uptake and glycogen via IRS1-Akt up-regulated GLUT4 expression. These results suggest that the synergistic effect of CURSD and GOSD against age-related muscle atrophy regulated by increasing the antioxidant and anti-inflammatory activities, as well as improving muscle energy storage via the Nrf2 and IGF1/Insulin-Akt-mTOR signaling pathway.
Cachexia, a multifactorial and often irreversible wasting syndrome, is often associated with the final phase of several chronic disorders. Although cachexia is characterized by skeletal muscle wasting and adipose tissue loss, it is a syndrome affecting different organs, which ultimately results in systemic complications and impaired quality of life. The pathogenesis and underlying molecular mechanisms of cachexia are not fully understood, and currently there are no effective standard treatments or approved drug therapies to completely reverse cachexia. Moreover, adequate nutritional interventions alone cannot significantly improve cachexia. Other approaches to ameliorate cachexia are urgently needed, and thus, the role of medicinal plants has received considerable importance in this respect due to their beneficial health properties. Increasing evidence indicates great potential of medicinal plants and their phytochemicals as an alternative and promising treatment strategy to reduce the symptoms of many diseases including cachexia. This article reviews the current status of cachexia, the molecular mechanisms of primary events driving cachexia, and state-of-the-art knowledge that reports the preventive and therapeutic activities of multiple families of phytochemical compounds and their pharmacological mode of action, which may hold promise as an alternative treatment modality for the management of cachexia. Based on our review of various in vitro and in vivo models of cachexia, we would conclude that phytochemicals may have therapeutic potential to attenuate cachexia, although clinical trials are required to unequivocally confirm this premise.
Background
COVID-19 pandemic has made the disease a major global problem by creating a significant burden on health, economic, and social status. To date, there are no effective and approved medications for this disease. Curcumin as an anti-inflammatory agent can have a positive effect on the control of COVID-19 complications. This study aimed to assess the efficacy of curcumin-piperine supplementation on clinical symptoms, duration, severity, and inflammatory factors in patients with COVID-19.
Methods
Forty-six outpatients with COVID-19 disease were randomly allocated to receive two capsules of curcumin-piperine; each capsule contained 500 mg curcumin plus 5 mg piperine or placebo for 14 days.
Results
Mean changes in complete blood count, liver enzymes, blood glucose levels, lipid parameters, kidney function, and c-reactive protein (CRP) were not significantly different between the two groups. There was a significant improvement in health status, including dry cough, sputum cough, ague, sore throat, weakness, muscular pain, headache, and dyspnea at week 2 in both curcumin-piperine and placebo groups ( P value < 0.05); however, the improvement in weakness was more in the curcumin-piperine group than with placebo group ( P value 025).
Conclusion
The present study results showed that curcumin-piperine co-supplementation in outpatients with COVID-19 could significantly reduce weakness. However, in this study, curcumin-piperine co-supplementation could not significantly affect the other indices, including biochemical and clinical indices.
Trial registration
Iranian Registry of Clinical Trials IRCT20121216011763N46 . 2020-10-31
The skeletal muscle (SkM) is the largest organ, which plays a vital role in controlling musculature, locomotion, body heat regulation, physical strength, and metabolism of the body. A sedentary lifestyle, aging, cachexia, denervation, immobilization, etc. Can lead to an imbalance between protein synthesis and degradation, which is further responsible for SkM atrophy (SmA). To date, the understanding of the mechanism of SkM mass loss is limited which also restricted the number of drugs to treat SmA. Thus, there is an urgent need to develop novel approaches to regulate muscle homeostasis. Presently, some natural products attained immense attraction to regulate SkM homeostasis. The natural products, i.e., polyphenols (resveratrol, curcumin), terpenoids (ursolic acid, tanshinone IIA, celastrol), flavonoids, alkaloids (tomatidine, magnoflorine), vitamin D, etc. exhibit strong potential against SmA. Some of these natural products have been reported to have equivalent potential to standard treatments to prevent body lean mass loss. Indeed, owing to the large complexity, diversity, and slow absorption rate of bioactive compounds made their usage quite challenging. Moreover, the use of natural products is controversial due to their partially known or elusive mechanism of action. Therefore, the present review summarizes various experimental and clinical evidence of some important bioactive compounds that shall help in the development of novel strategies to counteract SmA elicited by various causes.
The goal of this study was to evaluate if combinations of ingredients with known anti-cachexia benefits (Fish oil-FO with either curcumin or Green tea extract-GTE), have adverse effects on tumor growth, using human carcinoma xenograft mice models. FO (EPA/DHA 360 mg/kg bw), GTE (90 mg/kg bw), and curcumin (180 mg/kg bw) were administered orally, alone or in combination, to nude mice bearing either A549 human non-small cell lung carcinoma or SW620 human colon carcinoma tumors. Bodyweight, tumor growth, survival time, and other clinical endpoints were assessed. The ingredients either alone or in combinations were well tolerated in both lung and colon tumor-bearing mice. There were no significant group differences between individual or combination treatments for tumor growth (A549 or SW620) as measured by the median time in days to endpoint of tumor volume (TTE). TTE results indicate that these ingredients (alone or combinations) did not adversely impact tumor growth. No significant differences in body weights or survival were observed between controls and treatment groups indicating no adverse health effects of the ingredients. In conclusion, FO, GTE or curcumin administered as monotherapies and in combination were well tolerated and displayed no adverse effects on tumor growth in mouse xenograft models of lung and colon cancer.
Background
Curcumin, a natural polyphenolic compound, is proposed as a potential treatment option for patients with coronavirus disease by inhibiting the entry of virus to the cell, encapsulation of the virus and viral protease, as well as modulating various cellular signaling pathways. In this study, the efficacy and safety of nanocurcumin oral formulation has been evaluated in patients with mild-moderate Coronavirus disease 2019 (COVID-19) in outpatient setting.
Methods
In this triple-blind randomized placebo-controlled clinical trial, sixty mild to moderate COVID-19 patients in outpatient setting who fulfilled the inclusion criteria were randomly allocated to treatment (n = 30) group to receive oral nanocurcumin formulation (Sinacurcumin soft gel which contains 40 mg curcuminoids as nanomicelles), two soft gels twice a day after food for 2 weeks or placebo (n = 30) group. Patients’ symptoms and laboratory data were assessed at baseline and during follow-up period and compared between two groups.
Results
All symptoms except sore throat resolved faster in the treatment group and the difference was significant for chills, cough and smell and taste disturbances. The CRP serum level was lower in the treatment group at the end of two weeks and the lymphocyte count was significantly higher in treatment group. No significant adverse reaction reported in the treatment group.
Conclusion
Oral nanoformulation of curcumin can significantly improve recovery time in patients with mild to moderate COVID-19 in outpatient setting. Further studies with larger sample size are recommended.
Turmeric rhizome (root) used as a pulverized powder is an ancient herb used daily in cooking in turmeric-consuming nations. Many Ayurvedic and modern dietary supplements (>800) contain turmeric or its extracts. Low doses of turmeric may modulate persistent dysregulated chronic immune inflammation in the body, including eyes and brain. Turmeric contains more than 235 active ingredients, including curcuminoids (>89), noncurcuminoids (turmerosaccharides, essential oils, tumerones, and fiber). These diverse and complex phytochemicals and fibers in turmeric root and their potential metabolites may act in an additive or synergistic fashion as a modulator of aging-related chronic immune inflammation in the digestive system, eyes, joints, brain, as well as in cardiometabolic disorders. Preclinical pharmacological studies in animal models of various diseases suggest that low doses of turmeric or its active ingredients (curcumin, curcuminoids, turmerosaccharides, turmerones) may have potential utility in the prevention and management of immune-inflammatory diseases. Standardized turmeric (ST such as ADRxSynergy) contains a predetermined (specific) amount of curcumin while still retaining all of the phytochemicals and fibers of native turmeric. ST and the novel formulations of curcumin, curcuminoids, turmerones, and turmerosaccharides may reduce the need for medications for immune inflammation (steroids), chronic pain (opiates, NSAIDs), depression, and anticancer medicines. These products act via multiple mechanisms of actions in a disease-specific manner. The clinical potential of these products is warranted using well-designed clinical trials. Herbs and spices, including turmeric, or its extracts or active ingredients, are not a panacea, meaning they are not a cure for all diseases.
Background
curcumin consumption may have a protective effect against exercise‐induced muscle damage (EIMD) through stabilization of the cell membrane via inhibition of free radical formation. Evidence supporting a protective role of curcumin after physical activity induced muscle injury in humans, however, it is inconsistent.
Methods
Medline, Scopus, and Google scholar were systematically searched up to May 2020. The Cochrane Collaboration tool for assessing the risk of bias was used for assessing the quality of studies. Random effects model, weighted mean difference (WMD), and 95% confidence interval (CI) were used for estimating the overall effect. Between‐study heterogeneity was assessed using the chi‐squared and I² statistic.
Results
The results revealed a significant effect of curcumin supplementation on reducing creatine kinase (CK) (weighted mean difference [WMD] = −48.54 IU.L⁻¹; 95% CI: −80.667, −16.420; p = .003) and muscle soreness index decrease (WMD = −0.476; 95% CI: −0.750, −0.202; p = .001). Moreover, a subgroup analysis resulted in a significant decrease in CK concentrations and muscle soreness index, according to follow‐ups after exercise, dose of curcumin, duration of studies, exercise type, train status and study design.
Conclusions
The current evidence revealed a efficacy of curcumin in reducing CK serum levels and muscle soreness index among adults. Therefore, curcumin may be known as a priority EIMD recovery agent in interventions.
Le muscle squelettique est le réservoir principal d’acides aminés libres de l’organisme. Ainsi, l’atrophie musculaire induite par l’immobilisation peut entraîner un affaiblissement et un allongement des périodes de récupération générant des coûts de santé publique élevés. Une aggravation de l’atrophie caractérise de façon surprenante le muscle tibialis anterior (TA) après le déplâtrage, retardant la récupération. Mon objectif a été de comprendre les mécanismes à l’origine de l’aggravation de l’atrophie du TA pendant les phases précoces de récupération en étudiant i) la structure et le phénotype des muscles, ii) la composition de la matrice extracellulaire (MEC), iii) la protéolyse et l’apoptose, et iv) les processus de signalisation via les intégrines. Des rats ont été soumis à une immobilisation par plâtrage pendant 8 jours d’une des deux pattes arrière, l’autre servant de témoin, et placés en récupération pendant 10 jours. L’aggravation de l’atrophie du TA apparaît dès déplâtrage, corrélée avec i) une baisse de l’aire des fibres associée à leur déformation, ii) une redistribution des isoformes des chaines lourdes de myosines, iii) une augmentation de l’apoptose localisée dans le tissu conjonctif, iv) un épaississement de l’endomysium pendant la remobilisation, v) des adaptations au niveau des processus de remodelage des collagènes, et vi) une activation prononcée et persistante du système protéolytique ubiquitine-protéasome (UPS) et de l’apoptosome. Nous montrons également une élévation des niveaux ARNm dans le TA remobilisé vii) de la ténascine-C et de Sparc dès le déplâtrage, et viii) de marqueurs de l’autophagie à partir du moment où l’atrophie se stabilise. Enfin, nous montrons également une élévation des ARNm dans le TA immobilisé ix) des facteurs myogéniques, et x) des intégrines membranaires et de leurs partenaires pendant l’immobilisation et après le déplâtrage. En conclusion, mon travail de thèse a permis de montrer que l'aggravation de l’atrophie du TA est précoce, associée à un remodelage important de la structure et de la composition de la MEC et du phénotype des fibres musculaires, et pourrait résulter de l’augmentation persistante et prononcée de la voie UPS et de l’apoptose. Ce travail suggère que des modifications au niveau des molécules matricielles pendant la remobilisation pourraient influencer la signalisation dépendante des intégrines et la régénération musculaire.
Significance:
Regular contractile activity plays a critical role in maintaining skeletal muscle morphological integrity and physiological function. If the muscle is forced to stop contraction, such as during limb immobilization (IM), the IGF/Akt/mTOR signaling pathway that normally stimulates protein synthesis and inhibits proteolysis will be suppressed, whereas the FoxO-controlled catabolic pathways such as ubiquitin-proteolysis and autophagy/mitophagy will be activated and dominate, resulting in muscle fiber atrophy. Recent Advances. Mitochondria occupy a central position in regulating both protein synthesis and degradation via several redox-sensitive pathways including PGC-1α, mitochondrial fusion/fission proteins, mitophagy, and sirtuins. Prolonged IM downregulates PGC-1α due to AMPK and FoxO activation thus decreasing mitochondrial biogenesis and causing oxidative damage. Decline of mitochondrial inner membrane potential and increased mitochondrial fission can trigger cascades of mitophagy leading to loss of mitochondrial homeostasis (mitostasis), inflammation, and apoptosis. The phenotypic outcomes of these disorders are compromised muscle function and fiber atrophy.
Critical issues:
Given the molecular mechanism of the pathogenesis, it is imperative that the integrity of intracellular signaling be restored to prevent the deterioration. So far, overexpression of PGC-1α via transgene and in vivo DNA transfection has been found to be effective in ameliorating mitostasis and reduces IM-induced muscle atrophy. Nutritional supplementation of select amino acids and phytochemicals also provides mechanistic and practical insights into the prevention of muscle disuse atrophy.
Future directions:
In light of the importance of mitochondria in regulating the various critical signaling pathways, future work should focus on exploring new epigenetic strategies to restore mitostasis and redox balance.
Skeletal muscle wasting is highly correlated with not only the reduced quality of life but also higher morbidity and mortality. Although increasing patients are suffering from various kinds of muscle atrophy and weakness, there’s still no effective therapy available, and skeletal muscle is considered as an under-medicated organ. Food provided not only essential macronutrients but functional substances involved in modulation of physiological systems of our body. Natural constituents from commonly-consumed dietary plants, either extracts or compounds, have attracted more and more attention to be developed as agents for preventing and treating muscle wasting due to their safety and effectiveness, as well as structural diversity. This review provides an overview of the mechanistic aspects of muscle wasting, and summarizes the extracts and compounds from food sources as potential therapies against muscle wasting.
Diarylheptanoids exhibit numerous biological activities and have been used as traditional medicine in Asian countries. However, their effects on myogenesis are still unknown. This study determined the effects of eight different diarylheptanoid compounds including 1,7-diphenyl-(6E)-6-hepten-3-one (compound 1) and its analogs (compounds 2–8) isolated and purified from Curcuma comosa Roxb. on mouse myoblasts (C2C12 cells) proliferation and differentiation. All compounds (10⁻⁹–10−5 M) were non-toxic to C2C12 cells, and had no anti-oxidant activity except (3S)-1-(3,4–dihydroxyphenyl)-7-phenyl-(6E)-6-hepten-3-ol (compound 8), which showed higher activity compared to that of ascorbic acid. Additionally, this compound (10−8 M) effectively prevented the toxic effect of H2O2 on C2C12 cells. Proliferation of C2C12 cells was significantly increased by all compounds except compound 1 and (3R)-1,7-diphenyl-(4E,6E)-4,6-heptadien-3-ol (compound 4), whereas differentiation of myoblasts was enhanced by all compounds. The effect on proliferation was not blocked by ICI 182,780, but this blocker completely inhibited the effects of diarylheptanoids on differentiation. In addition, silencing the transcription of oestrogen receptor α (ERα), but not estrogen receptor β (ERβ), completely abolished the enhancement of differentiation. Together, the results indicate that diarylheptanoids enhance proliferation of C2C12 cells by a non-estrogenic mechanism, but induce differentiation selectively via ERα. These compounds may have potential for further development as therapeutic agents for treatment of muscle injury and/or diseases.
Prolonged high-intensity training seems to result in increased systemic inflammation, which might explain muscle injury, delayed onset muscle soreness, and overtraining syndrome in athletes. Furthermore, an impaired immune function caused by strenuous exercise leads to the development of upper respiratory tract infections in athletes. Nutraceuticals might help counteract these performance-lowering effects. The use of nanotechnology is an interesting alternative to supply athletes with nutraceuticals, as many of these substances are insoluble in water and are poorly absorbed in the digestive tract.
The present chapter starts with a brief review of the effects of exercise on immunity, followed by an analysis on how nutraceuticals such as omega-3 fatty acids, glutamine, BCAAs, or phytochemicals can counteract negative effects of strenuous exercise in athletes. Finally, how nanostructured delivery systems can constitute a new trend in enhancing bioavailability and optimizing the action of nutraceuticals will be discussed, using the example of food beverages.
EPA has been clinically shown to reduce muscle wasting during cancer cachexia. This study investigates whether curcumin or green tea extract (GTE) enhances the ability of low doses of eicosapentaenoic acid (EPA) to reduce loss of muscle protein in an in vitro model. A low dose of EPA with minimal anti-cachectic activity was chosen to evaluate any potential synergistic effect with curcumin or GTE. Depression of protein synthesis and increase in degradation was determined in C2C12 myotubes in response to tumour necrosis factor-α (TNF-α) and proteolysis-inducing factor (PIF). EPA (50 μM) or curcumin (10 μg ml−1) alone had little effect on protein degradation caused by PIF but the combination produced complete inhibition, as did the combination with GTE (10 μg ml−1). In response to TNF-α (25 ng ml−1)-induced protein degradation, EPA had a small, but not significant effect on protein degradation; however, when curcumin and GTE were combined with EPA, the effect was enhanced. EPA completely attenuated the depression of protein synthesis caused by TNF-α, but not that caused by PIF. The combination of EPA with curcumin produced a significant increase in protein synthesis to both agents. GTE alone or in combination with EPA had no effect on the depression of protein synthesis by TNF-α, but did significantly increase protein synthesis in PIF-treated cells. Both TNF-α and PIF significantly reduced myotube diameter from 17 to 13 μm for TNF-α (23.5%) and 15 μm (11.8%) for PIF However the triple combination of EPA, curcumin and GTE returned diameters to values not significantly different from the control. These results suggest that either curcumin or GTE or the combination could enhance the anti-catabolic effect of EPA on lean body mass.
Previous study has shown that curcumin directly or indirectly suppresses insulin signaling in 3T3-L1 adipocytes. However, the underlying mechanism remains unclear. Here we experimentally demonstrate that curcumin inhibited the ubiquitin-proteasome system (UPS) function, activated autophagy, and reduced protein levels of protein kinase B (Akt) in a dose- and time-dependent manner in 3T3-L1 adipocytes, accompanied with attenuation of insulin-stimulated Akt phosphorylation, plasma membrane translocation of glucose transporter type 4 (GLUT4), and glucose uptake. These in vitro inhibitory effects of curcumin on Akt protein expression and insulin action were reversed by pharmacological and genetic inhibition of autophagy but not by inhibition of the UPS and caspases. In addition, Akt reduction in adipose tissues of mice treated with curcumin could be recovered by administration of autophagy inhibitor bafilomycin A1 (BFA). This new finding provides a novel mechanism by which curcumin induces insulin resistance in adipocytes.
Approximately half of all cancer patients present with cachexia, a condition in which disease-associated metabolic changes lead to a severe loss of skeletal muscle mass. Working toward an integrated and mechanistic view of cancer cachexia, we investigated the hypothesis that cancer promotes mitochon-drial uncoupling in skeletal muscle. We subjected mice to in vivo phosphorous-31 nuclear magnetic resonance (31 P NMR) spec-troscopy and subjected murine skeletal muscle samples to gas chromatography/mass spectrometry (GC/MS). The mice used in both experiments were Lewis lung carcinoma models of cancer cachexia. A novel 'fragmented mass isotopomer' approach was used in our dynamic analysis of 13 C mass isotopomer data. Our 31 P NMR and GC/MS results indicated that the adenosine triphosphate (ATP) synthesis rate and tricarboxylic acid (TCA) cycle flux were reduced by 49% and 22%, respectively, in the cancer-bearing mice (p<0.008; t-test vs. controls). The ratio of ATP synthesis rate to the TCA cycle flux (an index of mitochon-drial coupling) was reduced by 32% in the cancer-bearing mice (p=0.036; t-test vs. controls). Genomic analysis revealed aberrant expression levels for key regulatory genes and transmission electron microscopy (TEM) revealed ultrastructural abnormalities in the muscle fiber, consistent with the presence of abnormal, giant mitochondria. Taken together, these data suggest that mitochondrial uncoupling occurs in cancer cachexia and thus point to the mitochondria as a potential pharmaceutical target for the treatment of cachexia. These findings may prove relevant to elucidating the mechanisms underlying skeletal muscle wasting observed in other chronic diseases, as well as in aging.
Skeletal muscle is often the site of tissue injury due to trauma, disease, developmental defects or surgery. Yet, to date, no effective treatment is available to stimulate the repair of skeletal muscle. We show that the kinetics and extent of muscle regeneration in vivo after trauma are greatly enhanced following systemic administration of curcumin, a pharmacological inhibitor of the transcription factor NF-κB. Biochemical and histological analyses indicate an effect of curcumin after only 4 days of daily intraperitoneal injection compared with controls that require >2 wk to restore normal tissue architecture. Curcumin can act directly on cultured muscle precursor cells to stimulate both cell proliferation and differentiation under appropriate conditions. Other pharmacological and genetic inhibitors of NF-κB also stimulate muscle differentiation in vitro. Inhibition of NF-κB-mediated transcription was confirmed using reporter gene assays. We conclude that NF-κB exerts a role in regulating myogenesis and that modulation of NF-κB activity within muscle tissue is beneficial for muscle repair. The striking effects of curcumin on myogenesis suggest therapeutic applications for treating muscle injuries.
When activated, NF-κB, a ubiquitous transcription factor, binds DNA as a heterodimeric complex composed of members of the
Rel/NF-κB family of polypeptides. Because of its intimate involvement in host defense against disease, this transcription
factor is an important target for therapeutic intervention. In the present report we demonstrate that curcumin (diferuloylmethane),
a known anti-inflammatory and anticarcinogenic agent, is a potent inhibitor of NF-κB activation. Treatment of human myeloid
ML-1a cells with tumor necrosis factor (TNF) rapidly activated NF-κB, which consists of p50 and p65 subunits, and this activation
was inhibited by curcumin. AP-1 binding factors were also found to be down-modulated by curcumin, whereas the Sp1 binding
factor was unaffected.
Besides TNF, curcumin also blocked phorbol ester- and hydrogen peroxide-mediated activation of NF-κB. The TNF-dependent phosphorylation
and degradation of IκBα was not observed in curcumin-treated cells; the translocation of p65 subunit to the nucleus was inhibited
at the same time. The mechanism of action of curcumin was found to be different from that of protein tyrosine phosphatase
inhibitors. Our results indicate that curcumin inhibits NF-κB activation pathway at a step before IκBα phosphorylation but
after the convergence of various stimuli.
Skeletal muscle is often the site of tissue injury due to trauma, disease, developmental defects or surgery. Yet, to date, no effective treatment is available to stimulate the repair of skeletal muscle. We show that the kinetics and extent of muscle regeneration in vivo after trauma are greatly enhanced following systemic administration of curcumin, a pharmacological inhibitor of the transcription factor NF-kappaB. Biochemical and histological analyses indicate an effect of curcumin after only 4 days of daily intraperitoneal injection compared with controls that require >2 wk to restore normal tissue architecture. Curcumin can act directly on cultured muscle precursor cells to stimulate both cell proliferation and differentiation under appropriate conditions. Other pharmacological and genetic inhibitors of NF-kappaB also stimulate muscle differentiation in vitro. Inhibition of NF-kappaB-mediated transcription was confirmed using reporter gene assays. We conclude that NF-kappaB exerts a role in regulating myogenesis and that modulation of NF-kappaB activity within muscle tissue is beneficial for muscle repair. The striking effects of curcumin on myogenesis suggest therapeutic applications for treating muscle injuries.
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.
Nuclear factor-kappaB (NF-kappaB) regulates the transcription of a variety of genes involved in immune responses, cell growth, and cell death. However, the role of NF-kappaB in muscle biology is poorly understood. We recently reported that tumor necrosis factor-alpha (TNF-alpha) rapidly activates NF-kappaB in differentiated skeletal muscle myotubes and that TNF-alpha acts directly on the muscle cell to induce protein degradation. In the present study, we ask whether NF-kappaB mediates the protein loss induced by TNF-alpha. We addressed this problem by creating stable, transdominant negative muscle cell lines. C2C12 myoblasts were transfected with viral plasmid constructs that induce overexpression of mutant I-kappaBalpha proteins that are insensitive to degradation via the ubiquitin-proteasome pathway. These mutant proteins selectively inhibit NF-kappaB activation. We found that differentiated myotubes transfected with the empty viral vector (controls) underwent a drop in total protein content and in fast-type myosin heavy-chain content during 72 h of exposure to TNF-alpha. In contrast, total protein and fast-type myosin heavy-chain levels were unaltered by TNF-alpha in the transdominant negative cell lines. TNF-alpha did not induce apoptosis in any cell line, as assessed by DNA ladder and annexin V assays. These data indicate that NF-kappaB is an essential mediator of TNF-alpha-induced catabolism in differentiated muscle cells.
Muscle wasting is a debilitating consequence of fasting, inactivity, cancer, and other systemic diseases that results primarily from accelerated protein degradation by the ubiquitin-proteasome pathway. To identify key factors in this process, we have used cDNA microarrays to compare normal and atrophying muscles and found a unique gene fragment that is induced more than ninefold in muscles of fasted mice. We cloned this gene, which is expressed specifically in striated muscles. Because this mRNA also markedly increases in muscles atrophying because of diabetes, cancer, and renal failure, we named it atrogin-1. It contains a functional F-box domain that binds to Skp1 and thereby to Roc1 and Cul1, the other components of SCF-type Ub-protein ligases (E3s), as well as a nuclear localization sequence and PDZ-binding domain. On fasting, atrogin-1 mRNA levels increase specifically in skeletal muscle and before atrophy occurs. Atrogin-1 is one of the few examples of an F-box protein or Ub-protein ligase (E3) expressed in a tissue-specific manner and appears to be a critical component in the enhanced proteolysis leading to muscle atrophy in diverse diseases.
The potential for inhibitors of nuclear factor-kappaB (NF-kappaB) activation to act as inhibitors of muscle protein degradation in cancer cachexia has been evaluated both in vitro and in vivo. Activation of NF-kappaB is important in the induction of proteasome expression and protein degradation by the tumour factor, proteolysis-inducing factor (PIF), since the cell permeable NF-kappaB inhibitor SN50 (18 microM) attenuated the expression of 20S proteasome alpha-subunits, two subunits of the 19S regulator MSS1 and p42, and the ubiquitin-conjugating enzyme, E2(14k), as well as the decrease in myosin expression in murine myotubes. To assess the potential therapeutic benefit of NF-kappaB inhibitors on muscle atrophy in cancer cachexia, two potential inhibitors were employed; curcumin (50 microM) and resveratrol (30 microM). Both agents completely attenuated total protein degradation in murine myotubes at all concentrations of PIF, and attenuated the PIF-induced increase in expression of the ubiquitin-proteasome proteolytic pathway, as determined by the 'chymotrypsin-like' enzyme activity, proteasome subunits and E2(14k). However, curcumin (150 and 300 mg kg(-1)) was ineffective in preventing weight loss and muscle protein degradation in mice bearing the MAC16 tumour, whereas resveratrol (1 mg kg(-1)) significantly attenuated weight loss and protein degradation in skeletal muscle, and produced a significant reduction in NF-kappaB DNA-binding activity. The inactivity of curcumin was probably due to a low bioavailability. These results suggest that agents which inhibit nuclear translocation of NF-kappaB may prove useful for the treatment of muscle wasting in cancer cachexia.
Unloading of skeletal muscle causes atrophy and loss of contractile function. In part, this response is believed to be mediated by the transcription factor nuclear factor-kappa B (NF-kappaB). Both curcumin, a component of the spice turmeric, and N-acetylcysteine (NAC), an antioxidant, inhibit activation of NF-kappaB by inflammatory stimuli, albeit by different mechanisms. In the present study, we tested the hypothesis that dietary curcumin or NAC supplementation would inhibit unloading-induced NF-kappaB activity in skeletal muscle and thereby protect muscles against loss of mass and function caused by prolonged unloading.
We used hindlimb suspension to unload the hindlimb muscles of adult mice. Animals had free access to drinking water or drinking water supplemented with 1% NAC and to standard laboratory diet or diet supplemented with 1% curcumin. For 11 days, half the animals in each dietary group were suspended by the tail (unloaded) and half were allowed to ambulate freely.
Unloading caused a 51-53% loss of soleus muscle weight and cross-sectional area relative to freely-ambulating controls. Unloading also decreased total force and force per cross-sectional area developed by soleus. Curcumin supplementation decreased NF-kappaB activity measured in peripheral tissues of ambulatory mice by gel shift analysis. In unloaded animals, curcumin supplementation did not inhibit NF-kappaB activity or blunt the loss of muscle mass in soleus. In contrast, NAC prevented the increase in NF-kappaB activity induced by unloading but did not prevent losses of muscle mass or function.
In conclusion, neither dietary curcumin nor dietary NAC prevents unloading-induced skeletal muscle dysfunction and atrophy, although dietary NAC does prevent unloading induced NF-kappaB activation.
Curcumin is the major yellow pigment extracted from turmeric, a commonly-used spice in India and Southeast Asia that has broad anticarcinogenic and cancer chemopreventive potential. However, few systematic studies of curcumin's pharmacology and toxicology in humans have been performed.
A dose escalation study was conducted to determine the maximum tolerated dose and safety of a single dose of standardized powder extract, uniformly milled curcumin (C3 Complextrade mark, Sabinsa Corporation). Healthy volunteers were administered escalating doses from 500 to 12,000 mg.
Seven of twenty-four subjects (30%) experienced only minimal toxicity that did not appear to be dose-related. No curcumin was detected in the serum of subjects administered 500, 1,000, 2,000, 4,000, 6,000 or 8,000 mg. Low levels of curcumin were detected in two subjects administered 10,000 or 12,000 mg.
The tolerance of curcumin in high single oral doses appears to be excellent. Given that achieving systemic bioavailability of curcumin or its metabolites may not be essential for colorectal cancer chemoprevention, these findings warrant further investigation for its utility as a long-term chemopreventive agent.
NF-kappaB is a major pleiotropic transcription factor modulating immune, inflammatory, cell survival, and proliferative responses, yet the relevance of NF-kappaB signaling in muscle physiology and disease is less well documented. Here we show that muscle-restricted NF-kappaB inhibition in mice, through targeted deletion of the activating kinase inhibitor of NF-kappaB kinase 2 (IKK2), shifted muscle fiber distribution and improved muscle force. In response to denervation, IKK2 depletion protected against atrophy, maintaining fiber type, size, and strength, increasing protein synthesis, and decreasing protein degradation. IKK2-depleted mice with a muscle-specific transgene expressing a local Igf-1 isoform (mIgf-1) showed enhanced protection against muscle atrophy. In response to muscle damage, IKK2 depletion facilitated skeletal muscle regeneration through enhanced satellite cell activation and reduced fibrosis. Our results establish IKK2/NF-kappaB signaling as an important modulator of muscle homeostasis and suggest a combined role for IKK inhibitors and growth factors in the therapy of muscle diseases.
In the present study, the BCAAs (branched-chain amino acids) leucine and valine caused a significant suppression in the loss of body weight in mice bearing a cachexia-inducing tumour (MAC16), producing a significant increase in skeletal muscle wet weight, through an increase in protein synthesis and a decrease in degradation. Leucine attenuated the increased phosphorylation of PKR (double-stranded-RNA-dependent protein kinase) and eIF2alpha (eukaryotic initiation factor 2alpha) in skeletal muscle of mice bearing the MAC16 tumour, due to an increased expression of PP1 (protein phosphatase 1). Weight loss in mice bearing the MAC16 tumour was associated with an increased amount of eIF4E bound to its binding protein 4E-BP1 (eIF4E-binding protein 1), and a progressive decrease in the active eIF4G-eIF4E complex due to hypophosphorylation of 4E-BP1. This may be due to a reduction in the phosphorylation of mTOR (mammalian target of rapamycin), which may also be responsible for the decreased phosphorylation of p70(S6k) (70 kDa ribosomal S6 kinase). There was also a 5-fold increase in the phosphorylation of eEF2 (eukaryotic elongation factor 2), which would also decrease protein synthesis through a decrease in translation elongation. Treatment with leucine increased phosphorylation of mTOR and p70(S6k), caused hyperphosphorylation of 4E-BP1, reduced the amount of 4E-BP1 associated with eIF4E and caused an increase in the eIF4G-eIF4E complex, together with a reduction in phosphorylation of eEF2. These changes would be expected to increase protein synthesis, whereas a reduction in the activation of PKR would be expected to attenuate the increased protein degradation.
Myostatin is a negative regulator of myogenesis, and inactivation of myostatin leads to muscle growth. Here we have used modified RNA oligonucleotides targeting the myostatin mRNA and examined the therapeutic potential in normal and cancer cachexia mouse models. We found that the RNA oligonucleotides could suppress the myostatin expression in vivo, leading to the increase in muscle growth both in normal and cachectic mice. We also established that the effect of myostatin inhibition caused by the RNA oligonucleotides may be through the MyoD pathway, as evidenced by a significant upregulation of MyoD expression. Taken together, these results demonstrate the feasibility using antisense strategy for the treatment of muscle wasting conditions.
We tested the hypothesis that treatment of rats with curcumin prevents sepsis-induced muscle protein degradation. In addition, we determined the influence of curcumin on different proteolytic pathways that are activated in septic muscle (i.e., ubiquitin-proteasome-, calpain-, and cathepsin L-dependent proteolysis) and examined the role of NF-kappaB and p38/MAP kinase inactivation in curcumin-induced inhibition of muscle protein breakdown. Rats were made septic by cecal ligation and puncture or were sham-operated. Groups of rats were treated with three intraperitoneal doses (600 mg/kg) of curcumin or corresponding volumes of solvent. Protein breakdown rates were measured as release of tyrosine from incubated extensor digitorum longus muscles. Treatment with curcumin prevented sepsis-induced increase in muscle protein breakdown. Surprisingly, the upregulated expression of the ubiquitin ligases atrogin-1 and MuRF1 was not influenced by curcumin. When muscles from septic rats were treated with curcumin in vitro, proteasome-, calpain-, and cathepsin L-dependent protein breakdown rates were reduced, and nuclear NF-kappaB/p65 expression and activity as well as levels of phosphorylated (activated) p38 were decreased. Results suggest that sepsis-induced muscle proteolysis can be blocked by curcumin and that this effect may, at least in part, be caused by inhibited NF-kappaB and p38 activities. The results also suggest that there is not an absolute correlation between changes in muscle protein breakdown rates and changes in atrogin-1 and MuRF1 expression during treatment of muscle wasting.
NF-kappaB activation is classically defined as a transient response initiated by the degradation of IkappaB inhibitor proteins leading to nuclear import of NF-kappaB and culminating with the resynthesis of IkappaBalpha and subsequent inactivation of the transcription factor. Although this type of regulation is considered the paradigm for NF-kappaB activation, other regulatory profiles are known to exist. By far the most common of these is chronic or persistent activation of NF-kappaB. In comparison, regulation of NF-kappaB in a biphasic manner represents a profile that is scarcely documented and whose biological significance remains poorly understood. Here we show using differentiated skeletal muscle cells, that tumor necrosis factor (TNF) induces NF-kappaB activation in a biphasic manner, Unlike the first transient phase, which is terminated within 1 h of cytokine addition, the second phase persists for an additional 24-36 h. Biphasic activation is mediated at both the levels of NF-kappaB DNA binding and transactivation function, and both phases are dependent on the IKK/26 S proteasome pathway. We find that regulation of the first transient phase is mediated by the degradation and subsequent resynthesis of IkappaBalpha, as well as by a TNF-induced expression of A20. Second phase activity correlates with persistent down-regulation of both lkappaBalpha and IkappaBbeta proteins, derived from a continuous TNF signal. Finally, we demonstrate that inhibition of NF-kappaB prior to initiation of the second phase of activity inhibits cytokine-mediated loss of muscle proteins. We propose that the biphasic activation of NF-kappaB in response to TNF may play a key regulatory role in skeletal muscle wasting associated with cachexia.
Muscle wasting is commonly seen in patients with sepsis, severe injury, and cancer [1, 2]. The loss of muscle mass in these conditions mainly reflects ubiquitin-proteasome-dependent degradation of myofibrillar
proteins although other proteolytic mechanisms may be involved as well [3]. Muscle atrophy is regulated by multiple factors, including glucocorticoids [4], the pro-inflammatory cytokines, interleukin (IL)-1(3 and tumor necrosis factor (TNF)-α [5, 6], and myostatin [7]. In addition to these catabolic factors, a lack of anabolic signals, such as insulin-like growth factor (IGF)-1 and insulin,
is probably also important for the development of muscle wasting in various catabolic conditions.
Radioactivity was detectable in blood, liver and kidney following dosage with 400, 80 or 10 mg of [3H]curcumin. The major route of elimination of the label was the feces; the urinary excretion of the label was very low regardless of the dose. At the lower doses of 80 mg and 10 mg of [3H]-curcumin, most of the label was excreted within 72 h, while with 400 mg, considerable amounts of the label was present in the tissues 12 days after dosage. The percentage of curcumin absorbed (60-66% of the given dose) remained constant regardless of the dose administered.
When activated, NF-kappa B, a ubiquitous transcription factor, binds DNA as a heterodimeric complex composed of members of the Rel/NF-kappa B family of polypeptides. Because of its intimate involvement in host defense against disease, this transcription factor is an important target for therapeutic intervention. In the present report we demonstrate that curcumin (diferuloylmethane), a known anti-inflammatory and anticarcinogenic agent, is a potent inhibitor of NF-kappa B activation. Treatment of human myeloid ML-1a cells with tumor necrosis factor (TNF) rapidly activated NF-kappa B, which consists of p50 and p65 subunits, and this activation was inhibited by curcumin. AP-1 binding factors were also found to be down-modulated by curcumin, whereas the Sp1 binding factor was unaffected. Besides TNF, curcumin also blocked phorbol ester- and hydrogen peroxide-mediated activation of NF-kappa B. The TNF-dependent phosphorylation and degradation of I kappa B alpha was not observed in curcumin-treated cells; the translocation of p65 subunit to the nucleus was inhibited at the same time. The mechanism of action of curcumin was found to be different from that of protein tyrosine phosphatase inhibitors. Our results indicate that curcumin inhibits NF-kappa B activation pathway at a step before I kappa B alpha phosphorylation but after the convergence of various stimuli.
To determine the effects of recombinant human insulin-like growth factor-1 (IGF-1) complexed with its principal binding protein, IGFBP-3, on skeletal muscle metabolism in severely burned children.
Severe burns are associated with a persistent hypermetabolic response characterized by hyperdynamic circulation and severe muscle catabolism and wasting. Previous studies showed that nutritional support and pharmacologic intervention with anabolic agents such as growth hormone and insulin abrogated muscle wasting and improved net protein synthesis in the severely burned. The use of these agents, however, has several adverse side effects. A new combination of IGF-1 and IGFBP-3 is now available for clinical study.
Twenty-nine severely burned children were prospectively studied before and after treatment with 0.5, 1, 2, or 4 mg/kg/day IGF-1/IGFBP-3 to determine net balance of protein across the leg, muscle protein fractional synthetic rates, and glucose metabolism. Another group was studied in a similar fashion without IGF-1/IGFBP-3 treatment as time controls.
Seventeen of 29 children were catabolic before starting treatment. The infusion of 1.0 mg/kg/day IGF-1/IGFBP-3 increased serum IGF-1, which did not further increase with 2.0 and 4.0 mg/kg/day. IGF-1/IGFBP-3 treatment at 1 to 4 mg/ kg/day improved net protein balance and increased muscle protein fractional synthetic rates. This effect was more pronounced in catabolic children. IGF-1/IGFBP-3 did not affect glucose uptake across the leg or change substrate utilization.
IGF-1/IGFBP-3 at doses of 1 to 4 mg/kg/day attenuates catabolism in catabolic burned children with negligible clinical side effects.
To review present knowledge of intracellular mechanisms and molecular regulation of muscle cachexia.
Muscle cachexia, mainly reflecting degradation of myofibrillar proteins, is an important clinical feature in patients with severe injury, sepsis, and cancer. The catabolic response in skeletal muscle may result in muscle wasting and weakness, delaying or preventing ambulation and rehabilitation in these patients and increasing the risk for pulmonary complications.
Muscle cachexia, induced by severe injury, sepsis, and cancer, is associated with increased gene expression and activity of the calcium/calpain- and ubiquitin/proteasome-proteolytic pathways. Calcium/calpain-regulated release of myofilaments from the sarcomere is an early, and perhaps rate-limiting, component of the catabolic response in muscle. Released myofilaments are ubiquitinated in the N-end rule pathway, regulated by the ubiquitin-conjugating enzyme E2(14k) and the ubiquitin ligase E3 alpha, and degraded by the 26S proteasome.
An understanding of the mechanisms regulating muscle protein breakdown is important for the development of therapeutic strategies aimed at treating or preventing muscle cachexia in patients with severe injury, sepsis, cancer, and perhaps other catabolic conditions as well.
Sepsis is associated with increased muscle proteolysis and upregulated transcription of several genes in the ubiquitin-proteasome proteolytic pathway. Glucocorticoids are the most important mediator of sepsis-induced muscle cachexia. Here, we examined the influence of sepsis in rats on the transcription factors NF-kappaB and AP-1 in skeletal muscle and the potential role of glucocorticoids in the regulation of these transcription factors. Sepsis was induced by cecal ligation and puncture (CLP). Control rats were sham-operated. NF-kappaB and AP-1 DNA binding activity was determined by electrophoretic mobility shift assay (EMSA) in extensor digitorum longus muscles at different time points up to 16 h after sham-operation or CLP. Sepsis resulted in an early (4 h) upregulation of NF-kappaB activity followed by inhibited NF-kappaB activity at 16 h. AP-1 binding activity was increased at all time points studied during the septic course. When rats were treated with the glucocorticoid receptor antagonist RU38486, NF-kappaB activity increased, whereas AP-1 activity was not influenced by RU38486. The results suggest that NF-kappaB and AP-1 are differentially regulated in skeletal muscle during sepsis and that glucocorticoids may regulate some but not all transcription factors in septic muscle.
Systemic administration of curcumin [1,7-bis(4-hydroxy-3-methoxyphenil)1,6-heptadiene-3,5-dione] (20 microg/kg body weight) for 6 consecutive days to rats bearing the highly cachectic Yoshida AH-130 ascites hepatoma resulted in an important inhibition of tumor growth (31% of total cell number). Interestingly, curcumin was also able to reduce (24%) in vitro tumor cell content at concentrations as low as 0.5 microM without promoting any apoptotic events. Although systemic administration of curcumin has previously been shown to facilitate muscle regeneration, administration of the compound to tumor-bearing rats did not result in any changes in muscle wasting, when compared with the non-treated tumor-bearing animals. Indeed, both the weight and protein content of the gastrocnemius muscle significantly decreased as a result of tumor growth and curcumin was unable to reverse this tendency. It is concluded that curcumin, in spite of having clear antitumoral effects, has little potential as an anticachectic drug in the tumor model used in the present study.
Skeletal muscle adapts to decreases in activity and load by undergoing atrophy. To identify candidate molecular mediators
of muscle atrophy, we performed transcript profiling. Although many genes were up-regulated in a single rat model of atrophy,
only a small subset was universal in all atrophy models. Two of these genes encode ubiquitin ligases: Muscle RING Finger 1 (MuRF1), and a gene we designate Muscle Atrophy F-box(MAFbx), the latter being a member of the SCF family of E3 ubiquitin ligases. Overexpression of MAFbx in myotubes produced atrophy, whereas mice deficient in either MAFbx orMuRF1 were found to be resistant to atrophy. These proteins are potential drug targets for the treatment of muscle atrophy.
There is interest in developing pharmacologic inducers of the heat shock response as a means to confer cytoprotection in the clinical setting. We propose that a potential strategy for screening novel pharmacologic inducers of the heat shock response is to examine known inhibitors of the transcription factor nuclear factor-kappaB. Curcumin, derived from the tropical herb Curcuma longa, is a recently described inhibitor of nuclear factor-kappaB and is widely used in Eastern medicinal practices. We tested the hypothesis that curcumin can induce expression of heat shock protein 70.
Experimental.
University laboratory.
HeLa cells.
HeLa cells were exposed to varying concentrations of curcumin and analyzed for expression of heat shock protein 70 by Western blot.
Activation of the transcription factor, heat shock factor-1, was analyzed by electromobility shift assays. Curcumin-mediated inhibition of nuclear factor-kappaB activation was measured by transiently transfecting cells with a nuclear factor-kappaB luciferase reporter plasmid. The role of heat shock factor-1 in curcumin-mediated expression of heat shock protein 70 was tested in embryonic fibroblasts derived from heat shock factor-1 knockout mice. Induction of the heat shock response was quantified by transiently transfecting cells with a heat shock protein 70 promoter-luciferase reporter plasmid. Cell viability was measured by using the tetrazolium dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. Curcumin induced expression of heat shock protein 70, the major inducible heat shock protein in cells undergoing the heat shock response, in a dose-dependent and time-dependent manner. Curcumin induced specific nuclear translocation and activation of heat shock factor-1. Curcumin-mediated expression of heat shock protein 70 was reduced substantially in fibroblasts having genetic ablation of heat shock factor-1. The extent of induction of the heat shock response correlated, in part, with cellular toxicity.
Curcumin, a widely used medicinal compound, induces the heat shock response in vitro as measured by expression of heat shock protein 70. The mechanism of heat shock protein 70 induction depends on activation of heat shock factor-1. Examining known inhibitors of nuclear factor-kappaB for their ability to induce heat shock protein 70 may be a valid screening method to discover novel pharmacologic inducers of the heat shock response.
Previous studies suggest that insulin-like growth factor-I (IGF-I) inhibits burn-induced muscle wasting mainly by reducing muscle protein degradation. The intracellular mechanisms of this effect of IGF-I are not known. In the present study, we examined the influence of IGF-I on individual proteolytic pathways in muscles from burned rats. Extensor digitorum longus muscles from burned rats were incubated with specific blockers of lysosomal, calcium-calpain-dependent, and ubiquitin-proteasome-dependent proteolytic pathways in the absence or presence of IGF-I. In addition, cathepsin B and L activities and 20S proteasome activity were determined. IGF-I inhibited lysosomal and ubiquitin-proteasome-dependent protein breakdown in skeletal muscle from burned rats by 70 and 90%, respectively, but did not influence calcium-calpain-dependent protein breakdown. The hormone blocked the burn-induced increase in cathepsin B and L activities but did not reduce 20S proteasome activity. Results are important because they provide novel information about intracellular mechanisms by which IGF-I inhibits the catabolic response to burn injury in skeletal muscle.
NF-kappaB activation is classically defined as a transient response initiated by the degradation of IkappaB inhibitor proteins leading to nuclear import of NF-kappaB and culminating with the resynthesis of IkappaBalpha and subsequent inactivation of the transcription factor. Although this type of regulation is considered the paradigm for NF-kappaB activation, other regulatory profiles are known to exist. By far the most common of these is chronic or persistent activation of NF-kappaB. In comparison, regulation of NF-kappaB in a biphasic manner represents a profile that is scarcely documented and whose biological significance remains poorly understood. Here we show using differentiated skeletal muscle cells, that tumor necrosis factor (TNF) induces NF-kappaB activation in a biphasic manner. Unlike the first transient phase, which is terminated within 1 h of cytokine addition, the second phase persists for an additional 24-36 h. Biphasic activation is mediated at both the levels of NF-kappaB DNA binding and transactivation function, and both phases are dependent on the IKK/26 S proteasome pathway. We find that regulation of the first transient phase is mediated by the degradation and subsequent resynthesis of IkappaBalpha, as well as by a TNF-induced expression of A20. Second phase activity correlates with persistent down-regulation of both IkappaBalpha and IkappaBbeta proteins, derived from a continuous TNF signal. Finally, we demonstrate that inhibition of NF-kappaB prior to initiation of the second phase of activity inhibits cytokine-mediated loss of muscle proteins. We propose that the biphasic activation of NF-kappaB in response to TNF may play a key regulatory role in skeletal muscle wasting associated with cachexia.
Muscle wasting during sepsis reflects increased expression and activity of the ubiquitin-proteasome proteolytic pathway and is at least in part mediated by glucocorticoids. The ubiquitination of proteins destined to be degraded by the proteasome is regulated by multiple enzymes, including ubiquitin ligases. We tested the hypothesis that sepsis upregulates the gene expression of the newly described ubiquitin ligases, MuRF1 and atrogin-1/MAFbx. Sepsis was induced in rats by cecal ligation and puncture. Control rats were sham-operated. In some experiments, rats were treated with the glucocorticoid receptor antagonist RU 38486 before induction of sepsis. At various time points after induction of sepsis, mRNA levels for MuRF1 and atrogin-1/MAFbx were determined in extensor digitorum longus muscles by real-time PCR. Sepsis resulted in a 10-16-fold increase in gene expression of the ubiquitin ligases studied here. These changes were much greater than those observed previously for another ubiquitin ligase, E3alpha, in muscle during sepsis. Treatment of rats with RU 38486 prevented the sepsis-induced increase in mRNA levels for MuRF1 and atrogin-1/MAFbx, suggesting that glucocorticoids participate in the upregulation of these genes in muscle during sepsis. The present results lend further support to the concept that the ubiquitin-proteasome pathway plays an important role in sepsis-induced muscle proteolysis and suggest that multiple ubiquitin ligases may participate in the development of muscle wasting during sepsis.
Tumeric is a spice that comes from the root Curcuma longa, a member of the ginger family, Zingaberaceae. In Ayurveda (Indian traditional medicine), tumeric has been used for its medicinal properties for various indications and through different routes of administration, including topically, orally, and by inhalation. Curcuminoids are components of tumeric, which include mainly curcumin (diferuloyl methane), demethoxycurcumin, and bisdemethoxycurcmin.
The goal of this systematic review of the literature was to summarize the literature on the safety and anti-inflammatory activity of curcumin.
A search of the computerized database MEDLINE (1966 to January 2002), a manual search of bibliographies of papers identified through MEDLINE, and an Internet search using multiple search engines for references on this topic was conducted. The PDR for Herbal Medicines, and four textbooks on herbal medicine and their bibliographies were also searched.
A large number of studies on curcumin were identified. These included studies on the antioxidant, anti-inflammatory, antiviral, and antifungal properties of curcuminoids. Studies on the toxicity and anti-inflammatory properties of curcumin have included in vitro, animal, and human studies. A phase 1 human trial with 25 subjects using up to 8000 mg of curcumin per day for 3 months found no toxicity from curcumin. Five other human trials using 1125-2500 mg of curcumin per day have also found it to be safe. These human studies have found some evidence of anti-inflammatory activity of curcumin. The laboratory studies have identified a number of different molecules involved in inflammation that are inhibited by curcumin including phospholipase, lipooxygenase, cyclooxygenase 2, leukotrienes, thromboxane, prostaglandins, nitric oxide, collagenase, elastase, hyaluronidase, monocyte chemoattractant protein-1 (MCP-1), interferon-inducible protein, tumor necrosis factor (TNF), and interleukin-12 (IL-12).
Curcumin has been demonstrated to be safe in six human trials and has demonstrated anti-inflammatory activity. It may exert its anti-inflammatory activity by inhibition of a number of different molecules that play a role in inflammation.
We have shown that SLH induces tolerance to endotoxin in vivo and in vitro, and is associated with alterations in MAP kinase (p38, p44/42, and SAPK/JNK) activation and TNF production. This study investigates the effect of sublethal hemorrhage (SLH) on cecal ligation and puncture (CLP) polymicrobial sepsis and examined the effect of the bioflavinoid, curcumin, a MAP kinase inhibitor, on this relationship.
Sprague-Dawley rats underwent SLH (hemorrhage and MAP = 30 mm Hg for 15 min, with shed blood returned) or sham operation. After 24 h, rats had CLP (cecal base ligation with double puncture). Survival was determined +/- curcumin pretreatment (n = 10/group). Lung tissue, serum, and bronchoalveolar lavage (BAL) fluid were obtained 30 min after SLH and 4 and 12 h after CLP (n = 8/group). Lung tissue was analyzed for p38, p44/42 SAPK/JNK, and HSP-70 phosphorylation (Western). Lung myeloperoxidase (MPO) activity was measured as an index of neutrophil infiltration. TNF ELISA was performed on serum and BAL sample.
SLH significantly improved survival after CLP (21.5 vs. 7.5 h vs. sham, p = 0.008), and curcumin reversed this benefit (7.3 h, p = 0.0007 vs. SLH + CLP). MAP kinase activity was significantly greater in SLH rats 4 h post-CLP (p38: 720 vs. 331, p = 0.03, p44/42: 2759 vs. 1295, p = 0.006, SAPK: 413 vs. 254). Curcumin significantly inhibited MAPK activity both 30 min after SLH (p38: 297 vs. 3260, p44/42: 370 vs. 2628, SAPK: 748 vs. 1764, all p < 0.01 vs. SLH 30 min) and 4 h post CLP (p38: 146 vs. 720, p44/42: 616 vs. 2759, all p < 0.01 vs. SLH + CLP4 h). Four hours after CLP, SLH rats expressed more HSP72. Lung MPO activity was significantly lower in SLH + CLP rats at both 4 h (9.5 vs. 15.6, p = 0.02 vs. sham) and 12 h (18.1 vs. 37.5, p = 7 x 10(-5), vs. sham). Serum and BAL TNF levels were higher in SLH rats initially (serum: 145 vs. 28 pg/mL, p = 2 x 10(-5) BAL: 83 vs. 57 vs. sham + CLP4h); however, BAL TNF was significantly lower in SLH animals 12 h post-CLP (37 vs. 72.7 pg/mL, p = 0.003 vs. sham + CLP12h).
SLH induces tolerance to CLP. This tolerance is dependent on early MAP kinase activation, since the survival benefit is reversed by curcumin. Decreases in tissue cytokine levels and neutrophil infiltration are potential mechanisms by which SLH induces tolerance to CLP (polymicrobial sepsis), attenuates acute lung injury, and improves survival.
Muscle wasting accompanies aging and pathological conditions ranging from cancer, cachexia, and diabetes to denervation and immobilization. We show that activation of NF-kappaB, through muscle-specific transgenic expression of activated IkappaB kinase beta (MIKK), causes profound muscle wasting that resembles clinical cachexia. In contrast, no overt phenotype was seen upon muscle-specific inhibition of NF-kappaB through expression of IkappaBalpha superrepressor (MISR). Muscle loss was due to accelerated protein breakdown through ubiquitin-dependent proteolysis. Expression of the E3 ligase MuRF1, a mediator of muscle atrophy, was increased in MIKK mice. Pharmacological or genetic inhibition of the IKKbeta/NF-kappaB/MuRF1 pathway reversed muscle atrophy. Denervation- and tumor-induced muscle loss were substantially reduced and survival rates improved by NF-kappaB inhibition in MISR mice, consistent with a critical role for NF-kappaB in the pathology of muscle wasting and establishing it as an important clinical target for the treatment of muscle atrophy.