Anti-inflammatory properties of curcumin and silver (I) nanocomplexes in inflammatory bowel diseases: in vitro and in vivo examination

doi:10.21203/rs.3.rs-1758974/v1

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Research Article

Anti-inflammatory properties of curcumin and silver (I) nanocomplexes in inflammatory bowel diseases: in vitro and in vivo examination

https://doi.org/10.21203/rs.3.rs-1758974/v1

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published 01 Sep, 2023

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Purpose

Inflammatory bowel disease (IBD) is characterized by chronic and relapsing inflammation of the gastrointestinal tract. Current treatment strategies of IBD are insufficient, expensive and connected with high toxicity. In search for alternatives that could help in the management of IBD without causing serious side effects, natural compounds attracted much attention recently. Curcumin is a natural, inexpensive compound with anti-inflammatory properties derived from rhizomes of Curcuma longa L. Concurrently, silver can suppress microbial activity and promote wound healing. Taking into consideration properties of both compounds, we decided to combine, with the use of nanotechnology, silver and curcumin to synergistically enhance their activity.

Methods

We obtained two formulations: curcumin and silver (I) nanoparticles complex (curcumin + nAg) and curcumin nanoparticles and silver (I) nanoparticles complex (ncurcumin + nAg). We assessed the anti-inflammatory effect of formulations in vitro in the LPS-stimulated RAW264.7 macrophages and in vivo in the mouse model of dextran sulfate sodium (DSS)-induced colitis.

Results

In vitro, both formulations inhibited nitric oxide (NO) release and in vivo complexes alleviated colitis.

Conclusion

In conclusion, our research showed that combination of curcumin with nAg improves curcumin’s anti-inflammatory properties and that using nanocurcumin instead of curcumin further enhanced this effect. Curcumin and silver (I) nanocomplexes may become a new treatment option in inflammatory bowel diseases.

inflammatory bowel disease

colitis

silver nanoparticles

curcumin

nanotechnology

Inflammatory bowel diseases (IBD) consist of Crohn’s disease (CD) and ulcerative colitis (UC) and are characterized by chronic, relapsing inflammation of the gastrointestinal tract. It is estimated that IBD currently affects several millions of people worldwide and about 2.5-3 million people in Europe [1]. Moreover, there is an increasing incidence of IBD reported in newly industrialized countries, which is associated with influences of the Western lifestyle[2]. This disease has detrimental impact on patients’ quality of life by causing persistent symptoms such as rectal bleeding, vomiting, diarrhea, abdominal pain, anemia and weight loss, which leads to frequent hospitalizations[3]. The etiology of IBD still remains unclear but it has been shown that factors such as epithelial barrier dysfunction, immune system imbalance, gut microbiota dysbiosis and environmental influences can be implicated in its pathogenesis[4]. Despite intense research there is no satisfying therapeutic method which could simultaneously induce remission and avoid serious side effects. Current treatment strategies in IBD are based on anti-inflammatory and immunosuppressive drugs, such as 5-aminosalicylic acid, corticosteroids, antibiotics and biological agents[5]. However, these strategies are connected with relatively low efficacy and high risk of side effects[6].

Recent studies have shown that plants may have positive impact on the treatment of inflammatory diseases, mainly because of bioactive compounds that exhibit anti-inflammatory and antioxidant properties[7], [8]. Turmeric (Curcuma longa) is one of these plants with several beneficial actions, including anti-inflammatory effects. Rhizomes of C. longa are widely used in the Southeast Asia in the treatment of many diseases, including arthritis and atherosclerosis[9], [10]. There are three primary compounds that are found in rhizome of C. longa: curcumin, bisdemethoxycurcumin, and demethoxycurcumin. These compounds are named curcuminoids and occur in concentrations of 77, 17, and 3%, respectively[11]. Curcumin is the principal compound in the rhizomes and its properties are the most widely studied. It was showed that curcumin possesses a wide range of medical activities such as anti-inflammatory, antioxidant, hepatoprotective and antibacterial[12].

The mechanism of its anti-inflammatory activity, connected with phenolic groups which are present in the curcumin molecule, is exhibited by inhibition of interleukin 2 (Il-2) and Il-12 synthesis, activation of leukocytes and decrease of proinflammatory molecules expression[13]. Contrary to current IBD pharmacological treatment, curcumin is regarded as safe, nontoxic and not associated with severe side effects[14]. The research conducted by Hanai et al. [15] has shown that patients with UC who received 1 g of curcumin after breakfast and 1 g after the evening meal presented improved clinical activity index (CAI) and suppressed morbidity connected with UC. Moreover, the study conducted on 50 patients with active mild-to-moderate UC has presented that almost 54% of the patients that received curcumin (3 g per day) achieved clinical remission, while remission was not observed in the placebo group[16]. The endoscopic remission was achieved by 38% of curcumin group and by none of the placebo group.

Although curcumin seems to be a promising remedy, its therapeutic efficacy is limited by its poor absorption and rapid metabolism, so it is difficult to use it as a systemic drug[12]. Nanotechnology based on silver is proved to increase bioavailability of many substances[17]. For example, it has been demonstrated that silver nanoparticles loaded with imatinib, a drug used in breast cancer treatment effectively improved its bioavailability[18]. What is more, silver has been widely used since antiquity as a therapeutic agent mainly due to its antimicrobial properties[19]. The most common medical use of silver is treatment of ulcers, burns and open wounds[20]. Furthermore, in the late nineteenth century Crede started treatment of eye infections in new-borns with eye drops containing 1% silver nitrate[21].

We hypothesized that a combination of the antibacterial properties of silver and the anti-inflammatory properties of curcumin would allow the generation of a complex with a wide spectrum of healing qualities. By synthesizing a product consisting of both components with the use of nanotechnology, it might be possible to reduce its side effects and improve bioavailability, while synergistically enhancing positive activity of both compounds.

In this study we synthesized and characterized the anti-inflammatory activity of curcumin and silver complexes that were formulated with the use of nanotechnology. We investigated their anti-inflammatory properties in vitro on RAW264.7 macrophages and in vivo in the DSS-induced mouse model of colitis.

2.1 Synthesis of suspensions

Synthesis of suspensions of silver nanoparticles with curcumin was performed using silver acetate (99%, Sigma Aldrich, Munich, Germany), curcumin (≥ 94% (curcuminoid content), ≥ 80% (Curcumin) Sigma Aldrich), gallic acid (≥ 98%, Sigma Aldrich) and sodium hydroxide (≥ 98%, Merck). Concentrations of silver nanoparticle and curcumin in suspension were 100 mg/dm³ and 5000 mg/dm³, respectively.

In the first step, a suspension of silver nanoparticles with curcumin (curcumin + nAg) was obtained. For this purpose, 500 mg curcumin was mixed with 75 ml of an aqueous solution of silver acetate (${C}_{0,C{H}_{3}COOAg}$= 1.235 mM) for 30 min at 20^oC, so that the sorption process of Ag⁺ on the surface of curcumin particles occurred. The stirring speed of the suspension was 400 rpm. The use of silver acetate, was to increase the affinity to the surface of curcumin, whose solubility in water is limited. Afterwards, a solution of gallic acid, acting as a reducing agent, was added to the suspension (the molar ratio of silver ions to gallic acid was 1:1). Using 0.1 mol/dm³ NaOH, the pH of the suspension was adjusted to 6-6.5. The suspension was stirred for 30 min at 20^oC to obtain the final product.

In order to improve the bioavailability of curcumin, in a further step, curcumin nanoparticles were obtained onto which silver nanoparticles were deposited. The process to obtain the suspension of silver nanoparticles with curcumin nanoparticles (ncurcumin + nAg) consisted, in the first step, in dissolving 500 mg curcumin in 10 ml of acetic acid (80%) in the presence of ultrasound by 2 min. Then, a solution of silver acetate (${C}_{0,C{H}_{3}COOAg}$= 1.235 mM) was dropped in, resulting in the precipitation of curcumin in the form of nanoparticles. The further process was similar to the preparation of curcumin + nAg.

To compare the activity of pure silver nanoparticle suspensions with curcumin-containing suspensions, a 100 mg/l nAg suspension was prepared using gallic acid (the molar ratio of Ag⁺ to gallic acid was 1:1). Silver nanoparticles was 100 mg/l and the molar ratio of silver ions to gallic acid was 1:1.

2.2 Extract characterization Instrumental analysis

The characteristic of the obtained suspensions was determined. The presence of nanoparticles in solution was confirmed by spectrophotometric method (RayLeigh UV-1800). The antioxidant activity of curcumin was determined by DPPH (1,1-diphenyl-2-picrylhydrazyl) radical scavenging activity. The shape, size, and dispersion of the materials were examined using scanning transmission electron microscopy (STEM).

UV-VIS spectrometry analysis

UV-VIS spectrometry analysis was conducted in a wavelength range of λ = 300–1100 nm. Spectrophotometric analysis was performed in order to select those extracts in which characteristic absorption bands would not obscure the peaks originating from the nanosilver.

XRD

The formed nAg nanoparticles on the surface of curcumin were examined by X-ray diffraction (XRD) (Philips X'Pert camera with monochromator PW1752/00). The analysis was performed for samples prepared by centrifugation which were dried in 110°C.

FTIR

The FTIR technique was used for the identification of various functional groups and chemical structures in the obtained solutions. Samples were scanned in spectrophotometer (Nicolet 380) over the range of 400–3900 cm^− 1.

DPPH - antioxidant activity

The percentage of antioxidant activity of each substance was assessed by DPPH free radical assay. The samples (20 µl) were mixed with DPPH radical in an ethanol solution and after 30 minutes the changes in color were read at 517 nm using spectrophotometer. The stronger the antioxidant properties of a given sample, the greater the change in absorbance of the DPPH radical. The antioxidant activity of the solutions was expressed as a percentage reduction of the DPPH radical relative to the control sample. The activity percentage was determined with the use of following formula:

$$I \left[\%\right]=\frac{{A}_{0}-{A}_{i}}{{A}_{0}}\bullet 100\%$$

where A_i –examined suspension’s absorbance, A₀ –control group’s absorbance.

STEM

The effectivity of binding silver nanoparticles with curcumin and size of particles were defined using scanning transmission electron microscopy STEM (FEI NOVA NanoSEM).

2.3 Cytotoxicity assessment

The RAW264.7 murine macrophage cell line (from the American Type Culture Collection) were cultured in Dulbecco's Modified Eagle Medium (Gibco, Waltham, MA, USA) supplemented with 10% BCS, 2 mM Ala-Gln, 0,5% P/S, 1 mM sodium pyruvate, 25 mM HEPES. Cells were grown in a humidified atmosphere of 5% CO₂ at 37°C. RAW264.7 cells used in the experiment were from passage 4 to 8.

The cytotoxicity of suspensions was assessed using neutral red uptake (NRU) test after 48h exposure of preparations on RAW264.7 cell line. The neutral red uptake assay is based on the ability of living cells to bind neutral red (NR). NR accumulates intracellularly in lysosomes, where pH becomes more acidic due to a proton gradient and as a result the dye becomes charged. Substances introduced into cell affect the surface of cells or lysosomal membrane, which leads to decreased binding of NR. As a result, the NRU assay makes it possible to evaluate lysosomal activity and permeability of membrane and allows to diversify viable, damaged or dead cells. Cytotoxicity is expressed as a concentration-dependent reduction of the uptake of NR after exposure to the added substances, which supplies a sensitive signal of cell integrity and cell growth inhibition.

In the first step, the cells were seeded on 96-well plates at the density of 20000 per well and then incubated with examined suspensions or without the studied formulations (control group). After 48 hours of incubation, the medium was removed from the plates and 100 µl of 0,05mg/l NR solution was added to each well. The cells were left for 1h of incubation and after that were washed once with PBS. Then, 40% ethanol and 10% acetic acid in water solution was added in volume 100 µl/well and plates were shaken for 10 minutes. The absorbance was measured at 540 nm in a microplate reader (iMARK Microplate Reader, Biorad, Hertfordshire, UK). Cytotoxicity was expressed as a percentage of negative control (medium without the studied suspensions).

2.4 Griess assay

Griess assay is an analytical test which measures the presence of nitrite in solution. Lipopolysaccharide (LPS) is used as stimulus upon which NO is released by the cells and then rapidly converted to nitrite detectable by the Griess assay. This assay is used to evaluate the anti-inflammatory potential of tested compounds - the less production of NO is reported, the better anti-inflammatory effect[22].

The RAW264.7 murine macrophage cell line were seeded on 96-well plates at the density of 20 000/well and incubated for 24 h. The control group was incubated only with medium, the positive control group with budesonide and 1 µg/ml LPS and the examined groups with 1 µg/ml LPS and tested suspensions. After incubation the medium was removed from the plates and suspensions and budesonide without LPS were added to wells with examined groups. The plates were left for another 24h of incubation and then 40mg/ml Griess reagent solution was added to an equal volume of cell culture supernatant. In the last step, the plates were left in the dark for 15 minutes. The absorbance was measured at 540 nm in the microplate reader.

2.5 Animals

Naive male BalbC mice obtained from Animal Facility of University of Lodz, Poland were used in all experiments. The animals were approximately 8 weeks of age and weighed 22–27g. The animals were housed at a constant temperature (22–23°C) and maintained under a 12-h light/dark cycle in sawdust-lined plastic cages. The tap water and laboratory chow were provided. Mice were divided into four groups: control group, DSS only group, and two groups treated with tested solutions (n = 8–9 per experimental group). Animal protocols were approved by the Local Ethical Committee for Animal Research at the Medical University of Lodz (#12/ŁB129/2019 from April 15, 2019). All efforts were made to minimize animal suffering and to reduce the number of animals used.

2.6 Induction of colitis

Dextran sulfate sodium (DSS; 4% wt/vol; molecular weight 40 000; Biochemica, PanReac AppliChem, Darmstadt, Germany) was added to drinking water from day 0 to day 5 to induce colitis in DSS treated groups. The animals in control group were drinking only water throughout the whole experiment. On day 5, DSS was changed for tap water, which was available for animals till day 7. The animals body weight and disease progression were assessed every day.

2.7 Pharmacological Treatment

In vivo, two suspensions were examined: curcumin + nAg and ncurcumin + nAg. The suspensions were administered intragastrically at the dose of 2 mg/kg (100 µL/mouse) once daily from day 3 to day 6 after colitis induction.

2.8 Evaluation of Colonic Damage

On day 7, mice were sacrificed by cervical dislocation and the macroscopic score was evaluated. The colon was isolated and weighed with fecal content. Then, the colon was opened longitudinally and washed. Total macroscopic score was calculated in a blind manner taking into consideration the following parameters: colon length and weight scores (0–4), macroscopic damage score (0–3), stool score (0–3) and fecal blood (0–1).

2.9 The statistical analysis

The statistical analysis was performed in Prism 8.0 (GraphPad Software Inc., La Jolla, CA, USA) with the use of one-way ANOVA followed by Newman-Keuls post hoc test. The data are presented as mean ± standard error of the mean (SEM). P values < 0.05 were considered statistically significant.

3.1 Charactristics of suspensions

Figure 1. presents FTIR spectra of curcumin, curcumin with silver nanoparticles (curcumin + nAg) and curcumin nanoparticles with silver nanoparticles (ncurcumin + nAg). Presented spectra are recorded for the main groups including hydroxyl group (-OH), etheric (-OCH₃), carbonyl (C = O), unsaturated double bounds and aromatic ring. The stability of the spectra confirmed that the structure of curcumin was maintained.

As a result of spectrophotometric analysis, UV-Vis spectra were obtained (Fig. 2). The similarity of spectra between curcumin + nAg and nAg samples can be noticed, which indicates a similar process of silver ion reduction. However, the efficiency of the bond between curcumin and silver nanoparticles is limited. The absorbance maximum of nAg is higher compared to the spectrum of the nAg sample, which is due to the raised background associated with the presence of curcumin in the suspension. The convergence of examined spectra suggests that the silver ions reduction process is similar also without presence of curcumin.

In the spectrum of ncurcumin + nAg sample, the nAg-characteristic peak was not observed that suggests high efficiency of binding nAg particles on the surface of ncurcumin. Moreover, size reduction of ncurcumin caused by its dissolving in acetic acid following by its progressive precipitation in the presence of ultrasound waves resulted in active surface increase and therefore higher curcumin fraction bound with nAg particles. The binding efficiency was confirmed with XRD analysis – in case of ncurcumin + nAg sample two Ag-related peaks were detected (2Theta = 38.0 and 44.40) (Fig. 3).

On the basis of STEM analysis for all suspensions, particles size and shape were determined. The average particle size of curcumin in the ncurcumin + nAg sample ranged from 20 to 100 nm, while in the curcumin + nAg, larger agglomerates were observed whose size exceeded 1 µm. The presence of silver was confirmed in both samples. The nanosilver particles were characterized by an irregular shape with an average size of about 35 nm in the curcumin + nAg, about 24 nm in the ncurcumin + nAg and 12 nm in the nAg sample. It is worth noting that unsupported silver nanoparticles exhibit a particle size of less than 5 nm, which increases the exposure of cells, both cancerous and healthy, to enter them causing damage. The photographs from STEM analysis are presented in Fig. 4.

In the present study, all substances exhibited the DPPH-mediated reduction of free radicals. The solution with ncurcumin + nAg presented the highest antioxidant activity. The results are presented in Table 1.

Table 1

Antioxidant activity of the tested suspensions.
	curcumin + nAg	ncurcumin + nAg	curcumin	nAg
Abs (517 nm)	0.373	0.279	0.330	0.487
% DPPH	66.19%	75.85%	70.61%	54.47%

3.2 In vitro anti-inflammatory activity of suspensions

The in vitro studies consisted of a neutral red uptake (NRU) test to verify the cytotoxicity of the suspensions and a Griess test to assess the production of nitric oxide (NO).

To evaluate at which concentrations tested formulations do not reduce cell viability of RAW264.7 cells, the NRU test was conducted. NRU assay is a method that assesses the cellular uptake of a dye by viable cells in the presence of a tested compound. Curcumin + nAg did not decrease cell viability up to 50.0 + 1.0 ppm, whereas ncurcumin + nAg showed cytotoxicity at 25.0 + 0.5 ppm (Fig. 5). The NRU test presented no decrease in viability for curcumin up to 125 ppm.

Consequently, the ability of the tested suspensions to regulate inflammatory responses was evaluated. The production of NO was measured based on the concentration of nitrite in cell culture supernatants in RAW264.7 cells stimulated by LPS and treated with tested preparations compared with control. The efficacy of formulations was assessed at concentrations which do not cause cytotoxicity. We observed that NO production was suppressed by all tested suspensions. In case of curcumin, NO production was decreased at the concentration 25 ppm (down to 47.00%, where 100.00% is the value for untreated, LPS-stimulated cells), and the inhibition was concentration-dependent. Furthermore, curcumin + nAg suppressed NO production more efficiently than curcumin alone (56.83% vs. 90.13%; same concentration of curcumin in both solutions). When compared at the same concentration (5.0 + 0.1ppm), ncurcumin + nAg showed greater inhibition of NO production than curcumin + nAg (19.03% vs. 56.83%, respectively). However, contrary to ncurcumin + nAg, curcumin + nAg exhibited lower cytotoxicity at higher concentrations (25.0 + 0.5 ppm, 50.0 + 1.0 ppm), which are the most effective. All results described above are presented in Fig. 6.

3.3 In vivo anti-inflammatory activity of suspensions

In the DSS-induced mouse model of colitis, the tested suspensions were administered intragastrically in dose 2 mg/kg once daily from day 3 to day 6 after colitis induction.

Total score was increased in DSS-only treated animals (11.84 ± 1.71) compared to control group (0.5 ± 0.0), what evidences that DSS treatment induced colitis. Both curcumin + nAg and ncurcumin + nAg decreased colon damage score (1.33 ± 0.55 and 1.08 ± 0.33 for curcumin + nAg and ncurcumin + nAg, respectively) (Fig. 7). Furthermore, the group treated with ncurcumin + nAg had lower stool score than DSS group (Fig. 7). Total score was significantly decreased in both treated groups (10.47 ± 1.4 and 9.18 ± 1.18 for curcumin + nAg and ncurcumin + nAg, respectively). Interestingly, ncurcumin + nAg decreased total score more effectively than curcumin + nAg (Fig. 7).

Inflammatory bowel disease is an incurable condition and there is still no satisfying therapeutic method which could induce remission and provide effective treatment. Currently available therapies are insufficient and connected with high risk of many serious adverse effects such as myelosuppression[23]. In many cases, remission is so difficult to achieve that surgical intervention is necessary[24]. Taking into consideration all facts mentioned above, there is an urgent need for new, safe and effective therapeutics.

By dissolving curcumin in a small volume of acetic acid and then precipitating curcumin nanoparticles, it was possible to increase the functional surface of the compound and improve its bioavailability compared to raw curcumin (which is practically insoluble in water). It provides an opportunity for a compound with high anti-inflammatory activity to be used in the future despite its limited biocompatibility. By combining curcumin with silver nanoparticles, the effectiveness of the material was increased, with the toxic effects of silver nanoparticles minimized. The widespread use of nanosilver in anti-cancer treatments is limited due to the possible toxic effects of nAg on both cancer and healthy cells[25]. Immobilization of silver on the surface of the curcumin nanoparticles strongly reduces uncontrolled release of silver increasing the safety of its use.

Here we tested anti-inflammatory properties of two novel complexes: curcumin + nAg and ncurcumin + nAg. In vitro, both complexes inhibited NO production, whereas ncurcumin + nAg was more effective than curcumin + nAg. However, curcumin + nAg could be used at a higher concentration than ncurcumin + nAg without causing cytotoxicity. Interestingly, combination of curcumin with nAg significantly increased curcumin’s anti-inflammatory properties. We also observed that using nanocurcumin instead of curcumin further enhanced curcumin’s anti-inflammatory activity. In vivo, total score was significantly decreased in both groups: treated with curcumin + nAg and ncurcumin + nAg, whereas ncurcumin + nAg decreased total score more effectively than curcumin + nAg.

The beneficial effect of tested preparations was obtained by combining two active substances, which synergistically enhanced their positive properties. Additionally, further improvement of anti-inflammatory activity was achieved due to the use of nanotechnology. The anti-inflammatory properties of curcumin are well-known and associated with suppression of nuclear factor - kappa B (NF-κB) in B-lymphocytes, and downregulation in the production of tumor necrosis factor-α (TNF-α), interferon-c (IFN-c), interleukin-1β (IL-1β), IL-6, IL-12, and IL-17[26], [27]. Curcumin also inhibits the activity of pro-inflammatory proteins such as activated protein-1, peroxisome proliferator-activated receptor gamma (PPAR-γ), as well as the expression of β-catenin, cyclooxygenase 2 (COX-2), 5-lipoxygenase (5-LOX), and inducible nitric oxide synthase isoform, which is a key factor in inflammation[28]. Interestingly, curcumin has also shown ability to modulate gut microbiota in irritable bowel syndrome [29]. The study conducted by Gong et al. has demonstrated that curcumin inhibits NLRP3 inflammasome activation in DSS-stimulated macrophages [30], as evidenced by reduced secretion of IL-1β and decreased caspase-1 activation. Curcumin has proven its therapeutic activity in many conditions. For example, several studies demonstrated that curcumin has positive impact on cartilage in osteoarthritis (OA). Pinsornsak and Niempoog reported that adjuvant therapy of curcumin with diclofenac exhibited beneficial effects in the treatment of primary knee OA[31]. What is more, treatment of OA patients with curcuminoids (1500 mg/day in three doses) caused reduction in pain and physical function scores[32]. Curcumin can also be used as an effective approach for bronchial asthma. Abidi et al. have shown that administration of curcumin improves airway obstruction and hematological parameters in patients who suffer from asthma [33]. Curcumin has also been found to be highly effective in management of metabolic diseases. In high-fat-diet–induced obese mice, curcumin ameliorates inflammation and improves insulin sensitivity [34]. In overweight diabetic patients, curcuminoids contributed to a decrease in blood glucose levels [35] and delayed the development of type 2 diabetes mellitus [36]. Curcumin exerts positive impact on obese patients’ health by reducing oxidative stress and exhibiting an immunomodulatory effect[37], [38]. The advantageous effect of curcumin has also been proven in neurological disorders such as Alzheimer's disease and depression in humans[39], [40]. In DSS-induced colitis, administration of curcumin significantly improved colitis by reducing weight loss, disease activity index (DAI) and colon length shortening[30]. The research conducted by Singla et al. has demonstrated that oral administration of curcumin (500 mg per day) for 8 weeks resulted in significant amelioration in clinical scores of UC patients[41].

As it is presented, there is a clear evidence for curcumin as a potential effective therapeutic agent. Although it seems to be a promising remedy, there are difficulties in clinical development of curcumin as therapeutic drug. The health benefits of curcumin are limited by its poor oral bioavailability which can be due to the weak absorption, high rate of metabolism and rapid systemic elimination from the body[42]. The research conducted by Yang et al. on rats has indicated that after oral administration of curcumin (500 mg/kg) a maximum plasma concentration of 0.06 ± 0.01 µg/mL was achieved, whereas after intravenous administration (10 mg/kg) a maximum serum concentration of 0.36 ± 0.05 µg/mL was reached[43]. This comparison demonstrated that oral bioavailability of curcumin was only 1%. What is more, another study has shown that intraperitoneal administration of curcumin (0.1 g/kg) to mice resulted in 2.25 µg/mL of curcumin in the plasma, but when curcumin was administered orally (0.1 g/kg), only 0.22 µg/mL appeared in plasma[44]. There have also been many studies that examined the pharmacokinetics profile of curcumin in human body. It has been indicated that the highest plasma concentration reported in human is 0.051 µg/mL from 12 g of curcumin[45]. Recent studies have revealed that poor absorption and rapid metabolism are considered to be responsible for reduced bioavailability of this compound[42]. Noteworthy, curcumin has poor water solubility (about 11 ng/mL) and is susceptible to degradation especially in of pH > 7[46]. When curcumin is administered orally, the considerable part is excreted through feces and only minor part is absorbed within the intestine. The absorbed portion of curcumin is rapidly metabolized in the liver and plasma[47]. Curcumin is extensively converted to its water-soluble metabolites (glucuronides and sulfates) and excreted through urine[48].

Taking into consideration beneficial properties of curcumin, several attempts have been made to overcome the limitations described above. For example, adjuvants which can block metabolic pathways of curcumin have been used to improve its bioavailability. Shoba et al. have examined the effect of combining piperine (inhibitor of hepatic and intestinal glucuronidation) with curcumin in rats and healthy human volunteers[49]. Their study has shown that piperine enhances the serum concentration and bioavailability of curcumin. Another research proposed that production of curcumin-loaded microsponges might work as a promising delivery system for curcumin[50]. Furthermore, liposomes, which are described as phospholipid bilayers widely used for the delivery of different pharmaceutical agents, have also been suggested as potential delivery systems that can provide significant improvement of curcumin’s oral absorption[51]. The pharmacokinetic study of curcumin liposome indicated that plasma curcumin concentration was significantly higher in rats treated with liposome than in those receiving curcumin only[52]. The positive impact on curcumin bioavailability has also been displayed by polymeric micelles, phospholipid complexes and microemulsions, which appear to provide longer circulation, better permeability, and resistance to metabolic processes[53], [54].

Interestingly, it has been observed that the nanoformulations not only achieve increased solubilization of curcumin, but also provide protection against inactivation by hydrolysis at the same time[55]. Nanoparticle-based systems are particularly useful in the delivery of hydrophobic agents because their small size (less than 1000 nm) can increase the absorption and bioavailability of the delivered drug[56]. Several studies have been conducted to improve the solubility and oral bioavailability of curcumin by using nanoparticles. Ji et al. have created curcumin solid lipid nanoparticles (Cur-SLNs), which presented significantly improved permeability value comparing to curcumin solution[57]. Noteworthy, after administration of curcumin it has not been detected in the whole brain homogenate, whereas Cur-SLNs formulation provided curcumin to the brain tissue, what seems to be a promising and effective option for treatment of neurological diseases. Shaikh et al. have formulated biodegradable nanoparticles that encapsulated curcumin and examined their bioavailability comparing to curcumin and curcumin with piperine suspensions[58]. The research has shown that curcumin nanoparticles had at least 9-fold increase in oral bioavailability when compared to curcumin with piperine suspension. However, it was observed that after administration of curcumin nanoparticles, increase of plasma concentration of curcumin is relatively slow. It has been suggested that encapsulated curcumin needs more time to evacuate from its vehicle.

In recent studies, synthesis of metal nanoparticles has attracted considerable attention in matter of disease treatment. The most broadly described nanomaterials are silver nanoparticles, which are used as additives to enhance the biocidal activity of medical agents. Sedat et al. have formulated imatinib (drug used in treatment of breast cancer)-loaded silver nanoparticles, which have potentialized bioavailability of the drug and helped control the drug delivery[18]. Another research has presented that mannan sulphate capped silver nanoparticles appeared to have enhanced cytocompatibility and increased site specific delivery[59]. Silver nanoparticles based on petals extract of Rosa indica inhibited NO production in RAW264.7 macrophages[60]. Crisan et al. have shown that biomaterials based on silver nanoparticles carrying polyphenols-rich extracts (Cornus mas) modulate inflammation in psoriasis at cellular and molecular level[61]. Silver nanoparticles have also been observed to possess a potent anti-HIV activity in cells that had been previously infected[17]. Vasanth et al. have found that Moringa oleifera stem bark extract mediated silver nanoparticles displayed excellent anticancer activity against human cervical carcinoma cells[62]. It has also been demonstrated that agents created with the use of silver nanotechnology can contribute to amelioration of colitis[63].

Although nanotechnology based on silver has many advantages, there is an urgent need to expand knowledge about its potential harmful effects on organisms, including the determination of its toxicity. Our study provides significant information about enhancing curcumin’s anti-inflammatory properties by increasing its bioavailability with the use of silver-based nanotechnology. This study is a step toward introducing curcumin and silver-based nanotechnology into IBD treatment, which can increase the treatment efficiency and contribute to improvement of patients’ quality of life.

5-LOX - 5-lipoxygenase

CAI - clinical activity index

CD - Crohn’s disease

COX-2 - cyclooxygenase 2

curcumin+nAg - curcumin and silver (I) nanoparticles complex

Cur-SLNs - curcumin solid lipid nanoparticles

DAI - disease activity index

DPPH - 1,1-diphenyl-2-picrylhydrazyl

DSS - dextran sulfate sodium

FTIR - Fourier-transform infrared spectroscopy

IBD - inflammatory bowel disease

IFN-c - interferon-c

IL-2 - interleukin 2

LPS - lipopolysaccharide

nAg - silver (I) nanoparticles

NF-κB - nuclear factor- kappa B

ncurcumin+nAg - curcumin nanoparticles and silver (I) nanoparticles complex

NO - nitric oxide

NRU - neutral red uptake

NR - neutral red

OA - osteoarthritis

PPAR-γ - peroxisome proliferator-activated receptor gamma

STEM - scanning transmission electron microscopy

TNF-α - tumor necrosis factor-α

UC - ulcerative colitis

XRD - X-ray diffraction

Consent to Participate

No individuals participated in this research

Consent to Publish

No individuals participated in this research

Authors’ contributions:

Conceptualization: M.P, J.K., M.B., J.F. , Formal analysis: M.P., J.K., M.T., Synthesis and analysis of physicochemical properties of obtained products: O.D., M.B. ,Investigation: M.P., J.K., J.F., Supervision: M.B., J.F., Writing—original draft preparation, M.P., Writing—review and editing, J.K., J.F., M.B., All authors read and approved the manuscript and all data were generated in-house and that no paper mill was used.

Ethics approval

Animal protocols were approved by the Local Ethical Committee for Animal Research at the Medical University of Lodz (#12/ŁB129/2019 from April 15, 2019). All institutional and national guidelines for the care and use of laboratory animals were followed

Funding

This work was supported by statutory funds of Department of Biochemistry Faculty of Medicine, Medical University of Lodz (503/1-156-04/503-11-001-19 to Jakub Fichna).

Competing Interests

All authors declare they have no financial interests.

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Anti-inflammatory properties of curcumin and silver (I) nanocomplexes in inflammatory bowel diseases: in vitro and in vivo examination

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Abstract

Purpose

Methods

Results

Conclusion

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1. Introduction

2. Materials And Methods

2.1 Synthesis of suspensions

2.2 Extract characterization Instrumental analysis

2.3 Cytotoxicity assessment

2.4 Griess assay

2.5 Animals

2.6 Induction of colitis

2.7 Pharmacological Treatment

2.8 Evaluation of Colonic Damage

2.9 The statistical analysis

3. Results

3.1 Charactristics of suspensions

3.2 In vitro anti-inflammatory activity of suspensions

3.3 In vivo anti-inflammatory activity of suspensions

4. Discussion

Abbreviations

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References

Additional Declarations

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