Effects of Curcumin Intake on CVD Risk Factors and Exercise-Induced Oxidative Stress in Healthy Volunteers—An Exploratory Study

: Background: Evidence suggests that turmeric or curcumin intake can improve antioxidant defense, blood pressure, ageing and gut microbiota. The effects of turmeric concentrate (curcumin) intake on cardiovascular risk factors and exercise-induced oxidative stress were investigated. Methods: A randomized placebo-controlled study was performed to assess the effects of turmeric extract in healthy volunteers before and after a 30-minute exercise bout. Participants ( n = 22) were given either 500 mg turmeric concentrate (Curcumin C3, Jarrow Formulas, Los Angeles, CA, USA) or placebo supplements. Anthropometry, systolic and diastolic blood pressure (SBP and DBP), pulse wave velocity (PWV), biomarkers of oxidative stress, perceived exertion and lipid peroxidation were assessed. Results: There were no signiﬁcant differences in all baseline parameters between the placebo and the curcumin groups ( p > 0.05). In the curcumin group, blood pressure response to exercise following curcumin intake was blunted, and the increase was not signiﬁcant compared to basal values. In the last run, there was a signiﬁcant difference (before–after) between curcumin and placebo groups ( ∆ in SBP: 7.3 ± 6.8 vs. 13.8 ± 6.3 mmHg, p = 0.007, and ∆ in DBP: 2.3 ± 6.9 V 8.0 ± 6.8 mmHg, p = 0.012). Final PWV scores were reduced signiﬁcantly in the curcumin group (7.2 ± 0.97 to 6.7 ± 0.77 m/s, p = 0.033), and this reduction was signiﬁcant compared to the control ( ∆ of 0.56 vs. 0.21 m/s, p = 0.04). A signiﬁcant increase was observed in urinary antioxidant power ( p = 0.031) and total polyphenol levels ( p = 0.022) post curcumin intervention, and those in the placebo did not show signiﬁcant changes. The increase in exercise-induced MDA levels was blunted only in the curcumin group, and the before–after difference was signiﬁcant compared to the control ( ∆ of − 0.81 vs. +0.205 µ mole/day, p = 0.032). The distance ran by the participants taking curcumin was signiﬁcantly longer ( p = 0.005), and compared to the placebo, the before–after difference was signiﬁcant ( ∆ of − 0.69 vs. +0.28 km, p = 0.014). Conclusion: Our study suggests that turmeric concentrate intake can reduce blood pressure and improve antioxidant, anti-inﬂammatory status and arterial compliance. Curcumin may improve exercise performance and ameliorate oxidative stress. Larger studies are warranted to validate these ﬁndings and test other cardiovascular risk factors.


Introduction
Regular physical exercise is known to convey several health benefits and is regarded to be a good practice to combat many metabolic diseases including cardiovascular disease (CVD), cancer, obesity, and diabetes [1][2][3]. However, strenuous, and prolonged exercise generates inflammatory cytokines and reactive oxygen species (ROS) [4,5]. It has been reported that the negative effects associated with eccentric exercise such as inflammation and DOMS are caused by a large increase in inflammatory cytokines in the working muscle, plasma and brain generated because of oxidative stress which stimulates the production of free radicals [5,6]. Retamoso et al. [7] found that eccentric exercise may cause delayed onset muscle soreness (DOMS), causing discomfort of skeletal muscles. MDA is the most used biomarker of oxidative stress in several conditions such as cancer, chronic obstructive pulmonary disease, and cardiovascular diseases [8]. It is vital to monitor both SBP and DBP throughout exercise. In addition, pulse wave velocity (PWV) is regarded the gold standard measurement of arterial stiffness and it is generally assessed by using carotidfemoral or brachial-ankle approaches [9]. PWV rises with stiffening of the aorta and consequently causes an earlier return of reflected pressure waves from the periphery to the aorta which enhances aortic SBP and reduces DBP [10]. In CVD and hypertensive patients, the incidence of oxidative stress can be determined in biological fluids by the thiobarbitoric acid (TBARS) assay [8,11]. These patients also display impaired antioxidant defense, and in the heart, the production of ROS exceeds the capacity of the antioxidant defense mechanism to buffering the ROS, resulting in cardiac dysfunction, ischemia-reperfusion injury, hypertrophy, cell death and heart failure [11].
Curcumin is a natural polyphenol derived from the rhizome of Curcuma longa [12,13] that has antioxidative, anti-inflammatory, cardiovascular, mental wellbeing and ageing protective effects and interacts with gut microbiota and several other actions [14][15][16]. Curcumin and turmeric extract have been shown to improve oxidative stress markers [17] by acting on cytokine/ROS-mediated inflammatory pathways to reduce the expression of NFkB/cyclooxygenase-2, enhancing antioxidant activity [18] and inhibiting the production of prostaglandin and NF-kB signaling [19]. In addition, curcumin may have musculoprotective effects against exercise-induced muscle damage (EIMD) by inhibiting free radical formation in injured skeletal muscles [18,20]. The aim of this short preliminary study was to investigate the effects of turmeric extract (rich in curcumin) intake on exercise-induced oxidative stress, blood pressure, PWV and lipid peroxidation in human volunteers.

Methods and Results
Study Design: We used a randomized placebo-controlled parallel study to investigate the efficacy of curcumin supplementation on exercise-induced oxidative stress and blood pressure over a period of 11 days ( Figure 1). The study was granted ethical approval by the Ethics Committee of Queen Margaret University (QMU); code, 11010149-Honors/Curcumin/DNBS/QMU Ethical Committee. Supplement: Each participant in both groups was supplied with eight capsules, either turmeric concentrate (curcumin C3 complex (500 mg; Jarrow Formulas, Los Angeles, CA, USA) or placebo capsules made by filling empty gelatin capsules with corn flour.
Anthropometry and Physiological Measurements: Measurements of Body Mass Index (BMI) were facilitated by recording the weight and height of each subject on day 1 of the study, allowing us to calculate their BMI using the equation: [BMI = weight (kg)/height (m) 2 ]. Arterial compliance measured by pulse wave velocity (PWV) was performed between the carotid and femoral artery (PWVcf) by means of a validated Vicorder™ device (Skidmore Medical Limited, Bristol, UK). Blood pressure (BP) was measured, and the average of three SBP and DBP readings were calculated. A Borg rating of perceived exertion scale (1-10) was used to measure each subject's level of exertion and intensity during each of the 30-minute runs [21].
Urinary Biomarkers assays: Urinary Polyphenols Levels, Urinary FRAP excretion and MDA concentration were measured.

Discussion
This short study has highlighted some of the beneficial effects of curcumin supplements in healthy volunteers. The present study confirms the antioxidant and antiinflammatory properties of curcumin as evidenced in the significant increase in antioxidant concentrations (FRAP) and total polyphenol levels in the urine samples of the curcumin group [16,22] (Table 1). Studies have confirmed that polyphenols possess antioxidant and free radical scavenging properties, which reduce low-density lipoprotein (LDL) oxidation [23]. We believe that the increase in antioxidant and polyphenol concentrations might have provided a protective mechanism against vascular dysfunction by neutralizing free radicals and reducing BP during exercise [24] (Tables 2 and 3).
This supports the data of published studies that showed curcumin intake was able to reduce BP [25]. Other CVD parameters that may be of relevance: Arterial stiffness compliance as measured by PWV cf was significantly reduced after curcumin intake, indicating its cardiovascular beneficial effects [26]. Turmeric extract intake attenuated the exercise-induced increase in lipid peroxidation (Table 4). In addition, the Borg score of perceived exertion was lowered, and thus the curcumin group felt they were able to run at a greater intensity during the last run compared to their first run [27] (Table 5). The limitations in this present study were that of short duration with a low number of participants, and the study implemented a parallel design due to the notion that both crossover and parallel designs offer advantages and disadvantages (Table 6). Finally, the influence of oral bioavailability of turmeric and curcumin should be considered in relation to gut microbiota of individuals [28].   Table 4. TBARS as a determinant of lipid peroxidation was assessed by the estimation of MDA levels (µmole/day). Data are presented as the mean ± SD. Significant differences were measured against the basal concentration of each group.

Conclusions
Our study has demonstrated that curcumin possesses antioxidant and anti-inflammatory properties which have proven to lower blood pressure and improve CVD risk factors, exercise performance and ameliorate oxidative stress. Larger studies investigating the effects of turmeric extract or curcumin on oxidative stress, exercise performance and other cardiovascular parameters are warranted.  Data Availability Statement: Study data are available from the authors upon request.

Acknowledgments:
The authors would like to thank Anum Mizher of the Queen Margaret University for her technical support and the University of Edinburgh for the estimation of steroid hormones. We are also grateful for all the volunteers who participated in this research study.

Conflicts of Interest:
The authors declare no conflict of interest.