Study on Powdered Turmeric for Inflammation

Turmeric is mainly cultivated in tropical and subtropical regions and produced primarily in India. It has traditionally been used to flavor food, dye fabrics, and treat various human diseases [1]. Curcumin is extracted from turmeric by various methods (e.g., Soxhlet, ultrasound, microwave, and supercritical carbon dioxide) in solvent extraction (ethanol preferred) followed by purification by column chromatography [2].

This extract, in addition to other macro- and micronutrients, contains 77% curcuminoids, 17% demethoxycurcumin and 3% bisdemethoxycurcumin, collectively named curcumin (Cur cumin), which gives the yellow turmeric its different shades of yellow [3]. Curcumin is a lipophilic polyphenol, soluble in water, and stable at acidic pH [4]. Doses of up to 8 g/d have been reported in human studies with no evidence of resistance [5]. Since the identification of curcumin as the major constituent of turmeric, a wide range of pharmacological activities including antioxidant, anti-inflammatory, anti-tumor and anti-diabetic activities have been reported for curcumin, which has a number of molecular targets and therefore a complex mechanism of action.

1 Pharmacological effects of curcumin

1.1 Antioxidant effects

Curcumin is considered an antioxidant due to the presence of a β-diketone group in its structure [6]. Joe and Lokesh determined in 1994 that the most important mechanism by which curcumin exerts most of its activity is the inhibition of superoxide radicals, hydrogen peroxide and nitric oxide [7]. Other researchers have suggested that curcumin activates antioxidant enzymes such as glutathione-S-transferase (GST), quinine reductase and haem oxygenase-1 [8].

Curcumin therefore has a protective effect against reactive oxygen species (ROS). In an in vitro model of ischemia-reperfusion using rat cortical neurons, curcumin was found to protect neurons from death caused by oxygen and glucose deprivation.

The authors of this study suggest that curcumin activates the antioxidant protein thioredoxin in the Nrf2 pathway [9]. In a study on curcumin by Wang et al. [10], the authors further investigated the role of curcumin in regulating cellular redox homeostasis. The seahorse bioenergetics analyzer was used to study changes in oxygen consumption and aerobic glycolysis rates. The results showed that curcumin enhanced the cellular oxidative stress of cancer cells by disrupting mitochondrial homeostasis and inducing severe apoptosis. Moreover, curcumin significantly reduced mt DNA content and DNA polymerase γ (POLG), which helped to reduce mitochondrial oxygen consumption and aerobic glycolysis. We found that curcumin induced POLG depletion through ROS production, and that POLG knockout also reduced oxidative phosphorylation (OX PHOS) activity and cellular glycolysis rate, which was partially rescued by the ROS scavenger NAC.

1.2 Anti-inflammatory effect

Curcumin can reduce inflammation by interacting with many inflammatory processes, which plays an important role in the development of chronic diseases such as autoimmune, cardiovascular, endocrine, neurodegenerative and tumor diseases in the inflammatory cascade. Oxidative stress can lead to chronic inflammation, and ROS production regulates the expression of the nuclear factor κB (NF-κβ) and tumor necrosis factor α (TNF-α) pathways, which play an important role in the inflammatory response [12].

On the one hand, the downregulation of the gene products of matrix degradation (matrix metalloproteinases -1, -9 and -13), prostaglandin production (cyclooxygenase -2), apoptosis (Bax and activated caspase -3) and stimulation of cell survival (Bcl-2), are known as NF-κB regulation. Buhrmann C et al. [13] investigated the anti-inflammatory effect of curcumin using an in vitro model of human tendon cells and found that curcumin inhibits the IKK (inhibitor of NF-κB nuclear factor κ-light chain enhancer) kinase (IKK) and the phosphorylation of AKT induced by IL-1β and the association between the two signal molecules passes through, and this leads to the inhibition of the phosphorylation and degradation of the nuclear factor of the κ light polypeptide gene enhancer in B cells inhibitor, α-(I KBα), an endogenous inhibitor of NF-κB.

They therefore showed that curcumin can inhibit the translocation of NF-κB into the nucleus, thereby preventing the inflammatory response of the cell. Curcumin also prevents the down-regulation of Bcl-2 and Bcl-XL expression stimulated by IL-1β and the increase in Bax and caspase-3 expression. The reduction in Bcl-2/Bax and Bcl-XL/Bad ratio is associated with a loss of mitochondrial membrane potential. Fu et al. [14] further found that curcumin also inhibits the phosphorylation of p38 and C-Jun N-terminal kinase (JNK) and increases the pro-survival signals of ERK and AKT, thereby suppressing the expression of apoptosis.

On the other hand, curcumin can reduce TNFα production and the cell signaling mediated by TNFα in various types of cells. In vitro and in vivo studies have suggested that curcumin acts as an NF-κB inhibitor because it directly binds to TNF-α [15]. In this sense, curcumin regulates TNF-α expression by inhibiting p300/CREB-specific acetyltransferase, which leads to the inhibition of histone/non-histone protein acetylation and thus transcription [16]. Li et al. [17] also showed in in vivo and in vitro experiments that curcumin induces higher levels of anti-inflammatory cytokines and reduces the production of pro-inflammatory cytokines, and can inhibit Ti particle-induced inflammation by regulating macrophage polarization. In addition, curcumin can also act as a free radical scavenger [18]. These data provide preliminary evidence that curcumin has good antioxidant stress and anti-inflammatory effects in experimental animals and humans.

1.3 Anti-tumor effect

Several preclinical studies have shown that curcumin is relatively safe for normal cells, but can induce apoptosis in tumor cells through different pathways [19]. The anti-tumor effects of curcumin are thought to be achieved through many different signaling pathways, such as cell proliferation [20], apoptosis [21], autophagy [22], angiogenesis [23], immune regulation [24], infiltration [25], and metastasis [26].

Some research data suggest that curcumin can induce G2/M cell cycle arrest and apoptosis, and recent work has attempted to explain how this cell cycle arrest occurs. Wu et al. [27] treated the U251 GBM cell line with curcumin in 2012 and found a dose-dependent increase in DAPK1 mRNA by real-time RT-PCR, and confirmed a corresponding increase in protein expression by western blot analysis. In addition, they used siRNA (si-DAPK1-1 and si-DAPK1-2) to transfect and inhibit DAPK1, and found that curcumin had the ability to inhibit the phosphorylation of STAT3 and NF-κB. They also showed that they knocked down DAP K1 to inhibit curcumin-mediated caspase-3 activation, resulting in a decrease in apoptosis (33.0% apoptotic cells versus 58.3% in the control group). These findings suggest that DAPK1 plays an important role in curcumin-mediated cell death.

In recent studies, micro RNAs, small non-coding RNA molecules associated with cancer progression, have been shown to be regulated by curcumin. Curcumin-induced micro RNA dysregulation may activate or inactivate a set of signaling pathways, such as the Akt, Bcl-2, PTEN, p53, Notch and Erbb signaling pathways [28]. Lelli D et al. [29] also found that the potential anticancer activity of curcumin and its analogues is mediated through miRNA regulation, for example, miRNA-21, which affects cell cycle regulation and apoptosis by downregulating the PTEN and PDCD4 proteins.

1.4 Anti-diabetic effect

Recent studies have shown that curcumin can improve obesity-related insulin resistance. In their study, Rains et al. [30] observed that curcumin has immunomodulatory effects on obesity and insulin resistance, as it reduces the cytokines TNF-α, MCP-1, glucose and glycosylated haemoglobin in diabetic rats [31].

A study using C57BL/Ks-db/db diabetic mice [32] showed that curcumin reduced blood glucose and glycosylated hemoglobin levels and increased plasma insulin levels and hepatic glucokinase activity. In addition, curcumin reduced glucose-6-phosphatase and phosphoenolpyruvate carboxykinase activities, lowered blood glucose levels and improved glucose tolerance.

Genq S et al. [33] found that treatment of HepG2 cells with 100 nM BPA for 5 days induced a significant reduction in glucose consumption, impaired insulin signaling, elevated proinflammatory cytokines and oxidative stress, and activation of signaling pathways; inhibition of the JNK and p38 pathways, rather than the ERK and NF-κB pathways, improved glucose consumption and insulin signaling in BPA-treated HepG2 cells.

In addition, we found that curcumin effectively attenuated the spectrum of insulin resistance induced by BPA, and pretreatment with the JNK and p38 activator anisomycin significantly compensated for the effects caused by curcumin. Meanwhile, some researchers [34] found that in rats with induced diabetes, compared with untreated rats, those treated with zinc and curcumin had significantly increased catalase, significantly reduced glucose, lipid profile components and arylsulfatase activity. Therefore, zinc and curcumin are protective agents against metabolic defects in diabetes.

1.5 Other

In addition to the above effects, curcumin has good therapeutic effects for preventing bronchial inflammation in asthmatic patients [35], treating rheumatoid arthritis [36], pancreatitis [37], liver fibrosis [38], cardiovascular disease, etc., and the pharmacological mechanisms of action in various fields have also been reported.

2 Carrier types and development of curcumin

The poor solubility, bioavailability and stability of curcumin limit its in vivo efficacy for disease treatment. Therefore, nanoscale drug delivery systems, including solid lipid nanoparticles (SLNs) [39], liposomes [40], liquid crystals [41], nanoemulsions [42] and phospholipid complexes [43], have been used as a means to overcome these shortcomings. In particular, S LN have been considered promising drug nanocarriers for curcumin and many other chemotherapeutic drugs due to the potential for improved bioavailability. However, the explosive release of curcumin in an acidic environment limits its use as an oral drug delivery system. Therefore, Baek JS et al. [44] prepared N-carboxymethylchitosan (NCC)-coated curcumin-loaded SLNs (NCC-SLNs) to inhibit the rapid release of curcumin in an acidic environment and improve bioavailability.

NCC-SLN showed inhibition of burst release in simulated gastric fluid, while sustained release was observed in simulated intestinal fluid. In addition, NCC-SLN showed increased cytotoxicity and cellular uptake in MCF-7 cells, and it was found that the lymphatic uptake and oral bioavailability of NCC-SLN were 6.3 and 9.5 times higher than those of curcumin solution, respectively. These results indicate that NCC-SLN can be an effective oral delivery system for curcumin. Sugasini D et al. [45] used a phospholipid core material (Lipoid TM) to prepare curcumin nanomicelles and explore ways to improve their bioavailability. Curcumin was dissolved in coconut oil (rich in MCFA, rich in fumaric acid), sunflower oil (SNO, n-6 PUFA rich) or linseed oil (LSO, n-3 PUFA rich), mixed with Lipoid TM using a high-pressure homogenizer to form a nanoemulsion, and fed to weaned rats together with an AIN-93 diet for 60 days. Rats fed a nanoemulsion containing curcumin from LSO showed high levels of curcumin in their serum, liver, heart and brain.

3 Conclusion

Curcumin, as a natural medicine, has a good therapeutic effect on various diseases that are of great concern in modern society. In order for curcumin to be better applied in clinical practice, its mechanism of action and dosage form deserve in-depth research and have good research prospects.

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