The Effect of Nanocurcumin Supplementation on Protein C,Partial Thromboplastin Time,Transforming Growth Factor-β1,and Simplified Acute Physiology Score II in Patients With Systemic Inflammatory Response Syndrome: A Randomized Clinical Trial

Abstract

Systemic inflammatory response syndrome (SIRS) is a general inflammation that involves many patients’ organs in intensive care units and significantly affects the risk of morbidity and mortality. This study aimed to investigate the effect of nanocurcumin on protein C, partial thromboplastin time (PTT), transforming growth factor-β1 (TGF-β1), and simplified acute physiology score II (SAPS II) in patients with SIRS. In this randomized, clinical trial, 40 SIRS-positive patients were randomly assigned to the intervention group who received 160 mg/day of nanocurcumin and the control group that received routine treatment for 10 days. Before, the 5th and 10th days of the study, the SAPS II questionnaire was completed, and protein C, PTT, and TGF-β1 levels were measured. At the end of the study, the PTT levels in the intervention and control groups increased and decreased, respectively. However, the significant increase of protein C levels was shown only in the intervention group. SAPS II scores were also decreased significantly only in the intervention group. There was no significant difference in serum levels of TGF-β1 in both groups. According to the results of this study, supplementation with nanocurcumin can decrease the SAPS II and improve the coagulation status in patients with SIRS.

Keywords

coagulation curcumin transforming growth factor-beta1 phenolic protein C thromboplastin time

Introduction

Systemic inflammatory response syndrome (SIRS) is defined as an extensive inflammation that can result from infection, pancreatitis, ischemia, burns, multiple injuries, and hemorrhagic shock or immunological mediators of organ damage. Sepsis means the body's systemic inflammatory response to infection, a combination of SIRS and the infectious process, and patients with SIRS are at risk for sepsis.^1-3 Sepsis, as a chronic and detrimental inflammatory response to infection, results in organ dysfunction (OD).⁴ It is one of the main reasons for hospitalization and is significantly associated with morbidity and mortality of patients.⁵ Numerous researchers have reported an association between infection, inflammation, and coagulation in sepsis.^6-10 Even though diffuse intravascular coagulation can also arise in 30% to 50% of patients with sepsis, coagulation cascade activation is the first and most common response to infectious challenges.^11-19 Platelet depletion is common in the first 4 days of intensive care unit (ICU) admission, and the severity of sepsis is severely associated with a drop in platelet number.^{10, 12, 13, 20} In addition, most of the molecules contained within the pre-coagulation conditions that characterize sepsis produce or potently enhance the inflammatory response.^{14, 15} Findings from a multinational study have shown that coagulation disorders occur in patients with sepsis before multifocal dysfunction, and constant coagulation abnormalities through the primary day of severe sepsis can increase the danger of new ODs, which can eventually lead to death.²⁰ Activation of the coagulation system and impaired immune response during sepsis is the leading cause of organ failure and sepsis complication. Indeed, the severity of organ failure in sepsis has a prognostic value shown by sequential organ failure assessment score (SOFA). Moreover, platelet has a vital role in the SOFA score and represents hematological function.²¹ In a study, it has been demonstrated that levels of activated partial thromboplastin time (aPTT) and PT is higher in SIRS than in non-SIRS patient.²²

Protein C, an endogenous protein that speeds up fibrinolysis and prevents thrombosis and inflammation, is an inflammatory and coagulation modifier associated with severe sepsis.¹⁹ Decreased protein C levels are seen in most patients with sepsis and relate to an elevated risk of mortality. On the other hand, activated protein C, a protein with anticoagulant action, enhance survival in severe sepsis.²³ Also, this factor has been accepted as a drug in more than 30 countries worldwide. In a study of septic patients, it has been found that the level of protein C and antithrombin activities in patients with OD is lower than in patients without OD. These factors can be a good standard for individualizing patients with OD from patients with no OD.¹¹

Simplified acute physiology score (SAPS) is a scale used to assess disease severity and predict the risk of nosocomial mortality in ICU patients. The SAPS II score is calculated from the worst value of 12 ordinary physiological modules during the first 24 h of ICU admission, information about the former health condition, and some data obtained at admission.²⁴ It has 17 parameters including, age, heart rate, systolic blood pressure, white blood cells (WBC) number, Glasgow coma score (GCS), cause of hospitalization.²⁵ Measurement is completed in the first 24 h after admission to the ICU. These results are between 0 and 163 and predict hospital mortality between 0% to 100%. The higher number indicates a higher mortality rate.²⁴ In a study entitled the power of simplified acute physiological instrument of SAPS in predicting the mortality rate of patients hospitalized in ICU, it has been concluded that the simplified acute physiology tool of SAPS can be used as a valid tool and predict better patient's death in ICUs.²⁶

Transforming growth factor-beta (TGF-β) is a protein that has 4 isoforms with different functions: TGF-β1, TGF-β2, TGF-β3, and TGF-β4. TGF-β, along with other cytokines such as IL-10 and IL-4, has anti-inflammatory properties that have diagnostic value in infectious disease and acute conditions.^{16, 17} Activation of this protein is related to the propagation and activation of various immune cells, such as WBC. TGF-β1 plays a crucial role in stem cell and T cell regulation and differentiation. It is also one of the important factors in inhibiting inflammatory cytokines, along with IL-10 in infections and trauma. Once activated, TGF-β combines with other elements to build a serine/threonine kinase complex, which combines with the TGF-β receptor eventually.¹⁸

Despite recent medical advances, no specific treatment has been discovered for patients with sepsis, and the incidence of this disease has been increasing over the past 20 years.^{27, 28}

Furthermore, curcumin is an active ingredient and hydrophobic polyphenol of turmeric, which belongs to the ginger family, and has been given as a medicine to treat various diseases for more than 6000 years. Many of the beneficial therapeutic effects of curcumin relate to its antioxidant, anti-inflammatory, and anticoagulant attributes.^{16, 29-32} It also has a wide range of antibacterial, antiseptic, wound healing, and lipid-lowering activities.^{30, 31, 33, 34} The inhibitory effect of curcumin on thrombin production supports its anticoagulant effect.¹⁶ Moreover, it reduces diffuse intravascular coagulation by reducing platelet and fibrinogen counts and inhibiting the construction of intravascular fibrin stores in the kidney.¹⁷ Curcumin also prolongs blood clotting time, determined by the breakdown of partial thromboplastin time (PTT), PT, and aPTT.¹³ Regardless of the efficacy of curcumin in multiple diseases, it has low bioavailability due to meager absorption and intestinal and hepatic metabolism. Today, to increase the bioavailability and absorption of curcumin, it is converted into liposomes and nanoparticles, and as a result, side effects and dosage needed for treatment have been reduced.³⁵

Taking into account the increase in SIRS (prone to sepsis) in patients admitted to the ICU, the coagulation disorders and infections as the main problems in patients with SIRS, and the lack of evidence and sufficient studies on the effects of curcumin in improving the symptoms of patients with SIRS, motivated us to determine the influence of nanocurcumin on coagulation factors (PTT, Protein C), anti-inflammatory factor (TGF-β1), and SAPS II in patients with SIRS, hospitalization in the ICU.

Materials and Methods

Subjects and Study Design

We performed a randomized clinical trial (RCT) on 40 patients with SIRS admitted to Shohada and Imam Reza Hospitals (Tabriz University of Medical Sciences, Tabriz, Iran) eligible for the study from November 2017 to November 2018.

Inclusion criteria were as follows: patients admitted to the ICU with APACHE II score 15 to 30, patients whose sepsis was confirmed by a physician, 18 to 60 years old, expecting hospitalization for at least 10 days in the ICU, and receiving enteral nutrition.

Exclusion criteria included: HIV-positive patients, pregnant and lactating women, intestinal obstruction, immunodeficiency, diabetes mellitus, short bowel syndrome, pancreatitis, using non-steroidal anti-inflammatory drugs, and vasopressors.

After approval of the Medical Ethics Committee of Tabriz University of Medical Sciences (IR.TBZMED.REC.1397.762), written informed consent was obtained from the patients (40 patients: 20 patients in the control group and 20 patients in the intervention group) or their legal guardians. This study was registered on the Iranian Registry of Clinical Trials (IRCT) website (available at http://www.irct.ir, identifier: IRCT20110123005670N27).

The sample size was based on the levels of protein C and according to the previously reported data on its mean and standard deviation. With a 90 power and confidence interval of 95%, the sample size of 20 patients per group was considered.³⁶

The present study was performed as an RCT on 40 patients aged 18 to 55 years with SIRS in the ICU. Eligible patients (according to APACHE II ranking on the first day for patient homogenization) were selected from patients with SIRS positive among ICU patients. All relatives or the patient's caregivers gave written consent after being informed of all stages. During the intervention, the patient’s caregivers were assured of study details and any cases of problem or complication related to the intervention.

The duration of supplementation in this study was 10 days. At the beginning of the study, demographic questionnaires were completed by the researcher. For randomizing, RAS software was employed. The patients were divided into 4 blocks by using the random block method. They were also placed in 1 of the 2 complementary groups, intervention and control. The intervention group received standard treatment plus 160 mg/day nanocurcumin orally (2 80 mg capsules every 12 h (at 10 am and 10 pm with a given guide) at least 1 h apart from the patient's formula (to avoid possible food-drug interactions). The control group received standard treatment. Nanocurcumin capsules were prepared by Exir-Nano-Sina Company of Iran (Batch number: 17003). Each nanocurcumin capsule contains curcumin (72%), demethoxycurcumin (25%), and bis-demethoxycurcumin (3%) associated with nanocurcumin.

Biochemical Analysis

On the day before, the 5th and 10th days of the study, the SAPS II questionnaire was completed. Meanwhile, 5 mL blood samples were taken from patients to determine and compare the effects of nanocurcumin supplementation on the level of coagulation factors (Protein C, PTT), anti-inflammatory factor (TGF-β1), and SAPS II.

Statistical Analysis

The findings of the study were analyzed using SPSS software version 24. Descriptive evidence and the Kolmogorov–Smirnov test (K–S) were used to investigate the distribution of variables (normal, abnormal). Moreover, qualitative data were presented as frequency and percentage. Quantitative data were reported with a mean (standard deviation) for normal and median (minimum–maximum) for abnormal distributions. An independent t-test was performed to compare quantitative variables with normal distribution between the 2 groups. Also, the Mann–Whitney test was employed to compare quantitative variables with the abnormal distribution. Covariance analysis was utilized to modify the confounders. Repeated measure analysis of variance was also used to measure the trend of changes in biochemical variables. Values less than 0.05 were considered significant for all tests.

Results

In this study, among 81 enrolled patients, 17 patients from the control group and 24 patients from the intervention group were excluded because of multiple reasons like refusing to participate, initiation of parenteral nutrition, intolerance to enteral nutrition, and discharge from the hospital. Consequently, 40 patients completed the study (Figure 1). The characteristics of study subjects are listed in Table 1. None of the variables had a significant difference between the 2 groups at baseline.

Figure 1.

Study design and flow diagram.

Table 1.

Baseline Characteristics of Patients With SIRS.

Variables		Intervention (n = 20)	Control (n = 20)
Gender ^a	Male	11 (55)^f	13 (65)^f
Gender ^a	Female	9 (45)^f	7 (35)^f
Age (year) ^b		48.75(7.19)^d	49.10(5.01)^d
BMI (kg.m²) ^b		26.21(2.74)^d	26.23(1.23)^d
APACHE II ^c		17 (13-21)^e	16.60 (13-19)^e
ICU admission reason ^a	Trauma	16 (80)^f	15 (75)^f
ICU admission reason ^a	Medical reasons	4 (20)^f	5 (25)^f
Mechanical ventilation ^a		18 (90)^f	16 (80)^f

BMI, body mass index; APACHE II, acute physiology and chronic health evaluation.

Values presented as percentage.

Values presented as mean (standard deviation).

Values presented as median (minimum–maximum).

Independent sample T-Test.

Mann–Whitney U-Test.

Chi-square.

P-value: NS.

The effects of nanocurcumin supplementation on PTT, protein C, TGFβ levels, and SAPS II scores are shown in Figures 2–5. The results showed that PTT increased in the intervention group (P = .001) and decreased in the control group (P = .042) during the study period. The amount of PTT on the 5th and 10th day, based on the analysis of covariance test and adjustment based on baseline values of age, sex, and type of disease, demonstrated a significant difference between the 2 groups (P = .03) (P < .001).

Figure 2.

Effect of curcumin supplementation on PTT in SIRS. Data are presented as mean ± SD.

Figure 3.

Effect of curcumin supplementation on TGF-β1 in SIRS. Data are presented as mean ± SD.

Figure 4.

Effect of curcumin supplementation on protein C in SIRS.

Figure 5.

Effect of curcumin supplementation on SAPS II in SIRS. Data are presented as mean ± SD. *P = .61, **P = .42, ***P = .03.

In the intervention group, the protein C levels increased (P = .001). However, there was no statistically significant difference (P = .083) in the control group during the study. Serum protein C levels on days 5 and 10 showed a significant difference between the 2 groups (P = .01 and P = .00).

During the study, the reduction of SAPS II level was statistically noteworthy in the intervention group (P = .001). Nevertheless, no statistically dramatic difference was found in the control group (P = .41). SAPS II levels on day 10th showed a significant difference between the 2 groups (P = .03) (Figure 5).

Discussion

Sepsis was defined previously as a SIRS in patients with infection, but now it reveals a greater degree of illness, characterized by OD, de-emphasizing intervention at earlier stages when it is most treatable.³⁷

In a study on the plasma of rats with myocardial ischemia and human plasma conducted by Manikandan et al, they reported the anticoagulant effects of curcumin and showed that curcumin prolongs blood clotting time as determined by PTT, PT, and APTT.¹³ In this study, we showed that oral supplementation with nanocurcumin significantly improves coagulation factors and SAPS II score in patients with sepsis. In sepsis, endothelial damage and subsequent tissue injury cause multi-organ failure and disseminated intravascular coagulation. These disorders result in hypoperfusion and are thromboinflammatory responses that affect patient outcomes.³⁸ Infection and inflammation activate coagulation in septic patients by expression of tissue factor on endothelial cells. Findings from a multinational study by Dhainaut et al showed that coagulation disorders occurred in patients with sepsis before dysfunction of several organs. Thus, continued coagulation disorders during the first day of severe sepsis can increase the risk of new OD, which can eventually lead to death.⁷ In our study, nanocurcumin prolonged PTT and increased protein C levels.

Another study by Iba et al concerning OD status in 78 patients with sepsis admitted to the ICU found that protein C and antithrombin levels were lower in the OD group than in the non-OD group.⁸ Our findings are inconsistent with the results of the Fung et al study. They performed an intervention study in 3 phases and each phase for 3 weeks as herbal compounds containing curcumin, aspirin, herbal compounds containing curcumin, and aspirin on 25 healthy individuals. They found that there was no significant difference in the status of platelet aggregation and PT and aPTT between different phases.³⁹ Furthermore, some studies have shown the effect of curcumin by inhibiting cyclooxygenase activity and blocking calcium signaling. The sensitivity of platelet agonists to the inhibitory effect of curcumin varies, but the accumulation of platelet activation factor and arachidonic acid is the most sensitive agent and directly affects the stimulation of thromboxane A2.

Thromboxane A2 can affect platelet receptors and activate the Gq protein, resulting in the secretion of calcium ions and ultimately leading to platelet aggregation.⁴⁰

According to most herbalists, the anti-inflammatory and antiplatelet effect of curcumin is due to inhibition of prostaglandin and thromboxane synthesis and stimulation of hydrocortisone secretion.⁴¹

On the other hand, some studies have shown that the anticoagulant effect of curcumin in prolonging is because of the hydrophilic groups in curcumin.¹³

Although our study did not indicate a significant effect on TGF-β1 as an anti-inflammatory factor in septic patients, Khajehdehi et al, in a case-control study of 40 patients with diabetic nephropathy, observed that 500 mg of turmeric (containing 22.1 mg of curcumin) 3 times daily for 2 months significantly decreased serum levels of TGF-β1 and IL-8 and urinary excretion of protein.⁴² TGF-β1 plays an important role in controlling the immune system and exhibits different activities on different cell types or at various stages of cells growth. Most immune cells (or leukocytes) secrete TGF-β1, whose effects on macrophages and monocytes are mainly suppressive. This cytokine can inhibit the proliferation of these cells and prevent the production of reactive oxygen species (such as superoxide [O2−]) and nitrogen (such as nitric oxide [NO]). In addition, the expression of monocyte cytokines such as IL-1α, IL-1β, and TNF-α and phagocytic macrophages can be increased by TGF-β1.⁴³ Some T cells (eg, regulatory T cells) release TGF-β1 to block the function of other T cells. In particular, TGF-β1 prevents IL-1 and IL2-dependent proliferation in activated T cells as well as activation of T-helper cells and cytotoxic T cells.^44-46 Similarly, TGF-β1 can inhibit the secretion and activity of many other cytokines, including interferon-γ, TNF-α, and various interleukins. It can also reduce the expression level of cytokine receptors such as IL-2 receptors to reduce the activity of immune cells. However, TGF-β1 can also increase the expression of specific cytokines in T cells and enhance their proliferation.⁴⁷ In this regard, Esmaeilzadeh et al, in a study of mice with autoimmune encephalomyelitis by injecting 20 mg/kg body weight of curcumin for 21 days, found that TGF-β gene expression was 4.5 times higher in mice receiving curcumin than in other mice. They also found that curcumin modulates inflammation by down-regulating pro-inflammatory cytokines such as TNF-α and IL-6 and up-regulating TGF-β as an anti-inflammatory cytokine.⁴⁸

As we saw in our study, curcumin supplementation caused a significant reduction in SAPS II scores during the intervention. SAPS II questionnaire is used to predict mortality risk in the ICU. To the best of our knowledge, there is no study about the effect of curcumin on SAPS II score. This questionnaire contains some parameters like systolic blood pressure and blood urea nitrogen. Curcumin appears to lower blood pressure by inducing endothelial nitric oxide synthase protein expression, enhancing antioxidant capacity through glutathione recovery, and reducing the overproduction of reactive oxygen species. Curcumin can also improve the relaxation response of endothelial vessels to acetylcholine and increase NO bioavailability, which in turn reduces blood pressure. On the other hand, curcumin can regulate blood pressure by inhibiting the activation of the angiotensin-converting enzyme and thus reducing the production of angiotensin-2 in the brain.⁴⁹ The protective effect of curcumin against renal dysfunction is associated with inhibition of Keap-1 and activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and ultimately increased Nrf2 nuclear translocation. Curcumin significantly stimulates the Nrf2 signaling pathway to reduce epithelial to mesenchymal transmission by reducing the effect of E-cadherin and increasing smooth muscle α-actin expression.⁵⁰

In this study, we had some limitations: we did not include the patients with septic shock in our intervention, so we can’t generalize the results. Due to financial constraints, it was not possible to increase the duration of the intervention. Evaluation of TGF-β1 gene expression could more accurately predict the effect on anti-inflammatory factors. Patients with SIRS receive different medicine in different doses like anticoagulants and antibiotics. Consequently, it may affect the result. Due to being immoral to coming off the medication, it can influence the study outcome.

Conclusions

Overall, this study showed that nanocurcumin supplementation could increase coagulation factors and had beneficial effects on SAPS II score in SIRS.

Footnotes

Acknowledgements

The authors are grateful to all patients who agreed to participate in this study.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Tabriz University of Medical Sciences (grant number 61090).

ORCID iDs

Elham Zarei

Arash Karimi

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