Citrus aurantium for cardiovascular health -
In detail, the plant composition of the capsule consisted of mg Cistus creticus , mg Citrus aurantium and Olea europaea blend, at an approximate ratio of 1.
The composition and content in the bioactive ingredients of the Citrus aurantium and Olea europaea blend have also been previously described in the study by Merola et al All participants were instructed to receive the capsules for 12 weeks and were reassessed after this period, without any instructions for alterations in diet or exercise patterns.
Blood samples 5 ml were drawn at the initial patient visit at the outpatient hypertension clinic and following the end of treatment week 12, re-evaluation visit. Statistical analyses were conducted using IBM SPSS software version 29; IBM Corp. The Kolmogorov-Smirnov test was used to assess the normality of the data.
The parametric two-sided paired sample t-test was used to compare the blood results before and after supplement administration. The mean TC levels at the initial visit were measured at The average reduction in TC levels was 5.
Statistical analysis using the paired t-test indicated that the average TC levels before the administration of the supplement differed from the respective values following treatment.
Boxplots of total cholesterol levels, before blue box and after orange box the administration of the supplement. The average measured LDL levels at the initial visit were The mean reduction in LDL levels was 4.
Variations in average values after 12 weeks of the daily intake of capsules of the supplement. Statistical analysis using the paired t-test indicated that the mean LDL-C levels prior to the administration of the test capsule differed from the levels after the administration of the capsule.
However, the reduction in LDL cholesterol was not statistically significant p. Boxplots of low-density lipoprotein levels, before blue box and after orange box the administration of the supplement. The average values of HDL at the initial medical examination were The average increase in the HDL levels reached 5.
Statistical analysis using the paired t-test indicated that the average HDL levels prior to the intake of the supplement differed from the final test results values. The HDL values increased; however, this increase was not statistically significant p. Boxplots of high-density lipoprotein levels, before blue box and after orange box the administration of the supplement.
The average values of the TG levels at the initial examination were Following 12 weeks of the daily consumption of two capsules of the test supplement, the TG values were The average decrease was After performing statistical analysis paired t-test , the results revealed a statistically significant decrease following the administration of the capsules for a week period p.
Boxplots of triglyceride levels, before blue box and after orange box the administration of the supplement. A summary of the final results of the study regarding the efficacy of the nutritional supplement on the lipid profiles of the study participants is presented in Table II and Fig.
Following 3 months of receiving the supplement, the TC levels were reduced by 5. Overall, although the changes in the LDL levels are not deemed statistically significant, a tendency towards an improvement was observed in the results for TC, HDL and TG levels.
Median levels of TC, LDL, HDL and TGs at the beginning of the study and after 12 weeks of consumption of the supplement. TC, total cholesterol; LDL, low-density lipoprotein; HDL, high-density lipoprotein; TGs, triglycerides. The present open observational prospective study in individuals with mild hyperlipidemia, demonstrated that the nutritional supplement combining plant extracts from Citrus aurantium, Olea europaea leaf and Cistus creticus , administered for a period of 12 weeks, significantly reduced TG levels by The results are consistent with those of previous publications , in which the herbal extracts of the study supplement were studied separately.
In both studies, the doses of the extracts used were higher than those used in the present study. Since in the present study, the decrease in TG levels was considerably higher, yet with smaller doses, it can be assumed that this decrease may be attributed to the synergistic effect of the plant extracts.
High TG levels are considered a marker of high cholesterol levels in TG-rich lipoproteins, which are associated with low-grade inflammation Hypertriglyceridemia and high levels of TG-rich lipoproteins are considered an independent risk factor for atherosclerotic cardiovascular disease; therefore, any decrease in TG levels may have a beneficial effect on risk reduction.
In another study, fasting TG levels were shown to be associated with short- and long-term cardiovascular risk, even in individuals who were treated effectively with statins Additionally, from a multiple single nucleotide polymorphism Mendelian randomization analysis, the genetic findings support a casual effect of TGs on coronary heart disease events Increased levels of TGs are associated with increased levels of remnant cholesterol and with reduced levels of HDL-C On the other hand, HDL-C is important for the lipid transportation and metabolism, due to the removal of the excess cholesterol from peripheral tissues, but also for its anti-inflammatory and antioxidant properties 27 , 28 , attributed to the associated enzyme paraoxonase 1 PON1 PON1 binds to HDL-C and increases its antioxidant anti-atherogenic effects In the present study, a marked increase of 3.
Since it is widely accepted that HDL-C is critical due to its anti-atherogenic properties in mediating cholesterol transport from peripheral tissues to the liver 31 , an increase in HDL-C alongside with a significant decrease in TG levels appears to be beneficial for individuals with mild cardiovascular risk factors.
The blend of ingredients which was used in the present study, has been previously suggested to improve PON1 activity in parallel with an increase in HDL-C levels and a decrease in TG levels Moreover, supplementation with a water infusion of Cistus incanus also known as Cistus criticus 32 , has been demonstrated to exert antioxidant effects by significantly decreasing the malondialdehyde and advanced oxidative protein product concentrations in healthy volunteers Recently, Cistus incanus extract, through its potent antioxidant activity due to its high content of flavonoids, was proven to attenuate the negative effects of high fat-carbohydrates on erythrocytes in animal models It has also been demonstrated in vitro to have the ability to decrease the overproduction of reactive carbonyl species, particularly advanced glycation end products, which function as a prooxidant and pro-inflammatory agent in the organism Cistus creticus is considered to be an excellent source of natural antioxidants and the European Food Safety Authority included it in its scientific opinion In previous research, the administration of polyphenol-rich olive leaf extracts was found to significantly lower the serum levels of TC, TGs and LDL-C, and to increase the serum level of HDL-C.
These extracts were found to increase the serum antioxidant potential and the hepatic catalase and superoxide dismutase activities Additionally, there are studies that recommend supplementing with vitamin B3 niacin or a fibrate as suggested options for the correction of atherogenic dyslipidemia 13 , Extracts from fruits of the Citrus family, have been mentioned as lipid-lowering components, with statin-like effects More specifically, the use of hesperidin, a flavonoid compound abundantly occurring in Citrus family fruit peel, has been found to lower serum TG levels in hypertriglyceridemic subjects, possibly by reducing very low-density lipoprotein metabolic abnormalities In another study, conducted with the use of Citrus extracts and olive polyphenols, in relation to the lipid profile, there was a significant improvement in the serum levels of TC and LDL Due to the key antioxidant and anti-inflammatory effects of the plant extracts used in the composition of the nutritional supplement used herein along with vitamins B and chromium, a significant decrease in the TG levels was achieved.
The main limitation of the present study was that the findings were obtained from a small group of individuals, as well as in its short duration. The results attained in the present study, even if these are derived from a small sample size, establish a tendency. Although the findings, particularly the suppressive effect on TG levels, appear promising, further larger studies for this nutritional supplement are required.
Additionally, possible genetic profiling studies, related to the metabolism of TGs are required to further elucidate the regulatory mechanisms and the individual response after the use of a personalized intervention. Funding: The present study was funded by the National and Kapodistrian University of Athens research grands research grant no.
ND and SB conceived the study. DK and CPT performed the patient medical examinations. EK, AT, SB and ND were involved in the acquisition of data, in the design of the study, and in the writing of the manuscript.
VE performed the statistical analyses. All authors have read and approved the final manuscript. AT and VE confirm the authenticity of all the raw data.
The other authors declare that they have no competing interests. Rader DJ, Hoeg JM and Brewer HB Jr: Quantitation of plasma apolipoproteins in the primary and secondary prevention of coronary artery disease.
Ann Intern Med. Kopin L and Lowenstein CJ: Dyslipidemia. Berberich AJ and Hegele RA: A modern approach to dyslipidemia. According to that, since the inflammatory process and antioxidant system involves MI induced by ISO, we hypothesized that this plant extract may have cardio protective effects.
The purpose of this study was to explore the possible antioxidant effect of c itrus aurantium flower extract and cardio protection against MI induced by ISO through electrocardiographic, myocardial marker injury, lipid profile changes as well as peroxidation of lipids, changes in antioxidant system and histopathological parameters.
Isoproterenol hydrochloride was purchased from Sigma Aldrich Chemical Company, St. Louis, MO, USA. Lipid peroxidation product MDA and antioxidant assay kits SOD, GSH, CAT, GP X were bought from Zell Bio Company, Germany.
Other biochemical substances were of analytical grade and purchased from Pars-Azmoon Company, Iran. All experiment and procedures defined in this study were approved by the local ethics committee of Zahedan University of Medical Sciences. Animals were fed with standard pellet diet and water ad libitum.
at 24 h interval for 2 days to experimental myocardial infarction induction [16]. After acclimatization, the animals were allocated randomly into 4 groups 6 in each group. The volume of solution injected was same in all groups. Total duration of experiment was two weeks and all experiments started at 9 am every day.
ECG recordings obtained through computerized Power Lab system AD Instruments, Australia and analyzed with chart7 software. After recording the ECG, the animals were sacrificed and blood samples were taken.
Samples were centrifuged at rpm for ten minutes. Serum was taken and kept at 0C, and then CK-MB, LDH, ALP, AST, ALT, and lipid profile were measured using routine laboratory kits Pars Azmoon, Tehran.
Serum LDL-cholesterol was calculated by the Friedewald formula. MDA, SOD, GP X , GSH, and CAT were measured using Zell Bio kit Zell Bio GmbH, Deutschland and ELISA method. The fixed tissues were inserted in paraffin, sectioned at 5 µm and stained with hematoxylin and eosin [17]. The samples were observed under light microscope, and then photomicrographs were taken.
It should also be mentioned that grading of histopathological changes was classified by a blind pathologist as: low, mild focal myocytes injury or multifocal deterioration with a mild degree of inflammation , moderate myofibrillar degeneration or moderate inflammatory process and severe necrosis with extensive inflammatory process.
Citrus aurantium flowers were taken from Shiraz, Iran, in The plant was recognized and authenticated by the botany department of Sistan and Baluchistan University.
During the time of experiments, the extract was dissolved in saline and animals were forced-fed with above-mentioned doses [14]. Data is expressed as mean ± SE. Statistical analysis was done by SPSS software version The effects of ISO and citrus aurantium extract treatment on pattern of ECG are depicted in Figure 1 and Table 1.
Control and citrus aurantium treated rats showed normal pattern of ECG, whereas rats treated with ISO showed a significant increase in S-T voltage, decrease in R amplitude as compared to control rats, suggestive of myocardial infarction.
ISO treated rats likewise displayed the pathological Q wave, demonstrating transmural myocardial infarction induction. Also, a significant decrease in QRS and R-R interval and a significant increase in heart rate were detected in rats treated with ISO.
Figure 1: Electrocardiographic patterns in control A , ISO B , pretreated with citrus aurantium extract then treated with ISO C and citrus aurantium alone D groups. Table 1: Effect of citrus aurantium pretreatment on electrocardiographic parameters in ISO induced myocardial infarction in rats.
Table 2 represents the effects of ISO and citrus aurantium extract treatment on cardiac marker enzymes such as CK-MB, LDH, ALP, AST and ALT. ISO treated rats showed an increased significantly in activities of these enzymes as compared to the control group. ISO treated animals that pre-treated with citrus aurantium extract exhibited significantly decrease the CK-MB, LDH, ALP, AST and ALT activities.
No significant difference was detected in rats treated with the extract alone when compared to control rats. Table 2: Effect of citrus aurantium pretreatment on cardiac marker enzymes in ISO induced myocardial infarction in rats.
The levels of MDA and GSH along with the activities of the enzymes GP X , SOD, and catalase in normal and experimental rats are listed in Table 3.
The value of MDA, end product of lipid peroxidation and marker for oxidative stress, showed significantly increase in ISO treated rats, as compared to the control group. ISO treatment also caused in the significant decrease in the level of GSH, an endogenous antioxidant in comparison with normal control rats.
Activities of glutathione-dependent antioxidant enzyme and antiperoxidative enzymes were significantly lowered in ISO treated rats as compared to the control group. Pre and co-treatment with citrus aurantium in MI induced by ISO rats significantly decreased the level of MDA as compared to rats treated with ISO alone.
The pre-treatment of citrus aurantium for 14 days resulted in a significant rise in the level of GSH and activities of GP X , SOD and catalase.
Normal rats that receive citrus aurantium alone did not display any substantial alteration when compared with other normal rats, indicating that it does not per se have any adverse effects. Table 3: Effect of citrus aurantium pretreatment on lipid peroxidation, endogenous antioxidant and antioxidant enzymes in ISO induced myocardial infarction in rats.
Table 4 lists the levels of total cholesterol, HDL, LDL and triglycerides in the serum of all groups of animals. Rats treated with ISO only exhibited a significant rise in these parameters with the levels of HDL-cholesterol being an exception where there was a significant decrease. Pre-treatment of citrus aurantium for 14 days beside with ISO administration on 13 th and 14 th days considerably reduced the levels of LDL and triglycerides with a following noteworthy increase in the levels of HDL-cholesterol as compared to ISO alone treated rats.
No significant change in total cholesterol was observed when compared to ISO treated group. In the citrus aurantium alone group, there was no substantial alteration detected in serum lipoproteins and triglycerides levels in comparison to those of the control rats.
Figure 2 illustrates the histological photographs of heart tissues of all studied groups. Histopathological analysis of myocardial tissue achieved from normal control animals displayed clear integrity of membrane of myocardial cells.
Normal untreated rats indicated typical cardiac tissues without any infarction and infiltration of inflammatory cells was not seen in this group. Histopathological results revealed that the ISO caused induction of MI in cardiac muscle.
Tissues sample from myocardial infarction induced by ISO, exhibited extensive myocardial structure abnormality and subendocardial necrosis with capillary dilatation and leukocyte infiltration as compared to the control group. Prior administration of citrus aurantium showed reduced grade of infiltration of inflammatory cells and the appearance of myocardial cells was comparatively well conserved with no evidence of focal necrosis.
Extract treated group rats displayed no change in morphology of heart tissue as compared to the normal control group. The pathophysiology mechanism of MI has not been fully revealed.
Although catecholamines have regulatory effect on contraction and metabolism of myocardial muscle, these substances may be responsible for cell damages in the long term.
The same situation can be observed in clinical situations such as angina, temporary myocardial hypoxia, acute inadequacy in coronary blood flow and subendocardial infarction. Isoproterenol, a potent synthetic catecholamine, can improve injuries like myocardial infarction when injected in animals.
These lesions are apparently same to those of coagulative myocytolysis or myofibrillar deterioration. This is one of the findings during acute MI and unexpected death in man [18,19]. Different mechanisms have been reported as responsible for induction of myocardial infarction by ISO.
Previous reports recommended that coronary inadequacy, sarcoplasmic calcium excess, changed metabolic and electrolyte balancing system and oxidative stress are the main causative factors in catecholamine induced cardiac insufficiency [20].
Imbalance between oxygen delivery and request of myocytes after coronary hypotension and cardiac muscle hyperactivity due to augmented heart rate and contractility could cause myocardial damage [21]. Interaction of ISO with β1 and β2 adrenoceptors, activation of which causes to positive inotropic and chronotropic effects on heart, which produce relative ischemia due to myocardial hyperactivity and coronary hypotension [22].
ECG deliberated the single most important primary clinical exam for diagnosis of infarction and ischemia in cardiac muscle and. In our study, ISO administration causes pathological Q wave in rats, the most characteristic finding of transmural MI of the left ventricle.
Administration of ISO also showed a decline in R-R interval, and increase in QRS time and heart rate. These changes could be due to the damage of cell membrane in injured cardiac muscle [23].
It has been exposed that a rise in heart rate is responsible for augmented oxygen consumption causing to enhanced necrosis of myocardial tissue [24]. ISO also increased ST-segment voltage and decreased R- wave voltage.
This is favorable with the comments of earlier reports. ST-segment elevation reproduces the potential difference in the border between ischemic and non-ischemic regions and consequences in loss of cell membrane function whereas decrease in R-wave voltage might be due to the start of myocardial edema subsequent ISO treatment [25].
Citrus aurantium pre-treatment in ISO treated rats prohibited the pathological changes in the ECG, which suggest s protective effect for its cell membrane. Cardiac muscle contains different diagnostic markers of MI and when heart metabolism injured, it discharges its contents into the extracellular fluid [26].
Cytotoxic enzymes such as CK-MB, LDH, AST, ALT and ALP, which serve as diagnostic markers, could be released from tissues damaged in the circulation due to permeable or disagreement of cell membrane and reflect the changes in plasma membrane integrity [27].
Our data confirmed significant increase in the levels of these enzymatic biomarkers of serum in ISO treated rats, which were in same direction with previous reports. Citrus aurantium pre-co-treatment caused in the dropped activity of the marker enzyme in serum. It validated that citrus aurantium could sustain cell membrane integrity, thereby limiting the leakage of these enzymes.
Free radical scavenging enzymes for example SOD, catalase and GP X are the first line of cellular protective system against oxidative stress, excluding reactive oxygen spices ROS such as superoxide and hydrogen peroxide.
These enzymes inhibit the formation of more worsening hydroxyl radical. P-synephrine is also found in other citrus fruits and their juices, such as mandarins and clementines 4 , 7. Like other citrus fruits, bitter orange provides limonene — a compound shown to have anti-inflammatory and antiviral properties 10 , 11 , Population studies suggest that limonene may prevent certain cancers, namely colon cancer.
However, more rigorous human research is needed An ongoing study is also exploring the use of limonene as a treatment for COVID However, the results are not yet known.
Bear in mind that limonene cannot prevent or cure COVID Another protoalkaloid found in bitter orange is p-octopamine. However, little to no p-octopamine exists in bitter orange extracts. The leaves of the bitter orange plant are rich in vitamin C , which acts as an antioxidant. Antioxidants are substances that may protect your body from disease by preventing cell damage.
They work by deactivating free radicals, which are unstable compounds that damage your cells, increasing inflammation and your disease risk 15 , Protoalkaloids are plant compounds found in bitter orange that have anti-inflammatory and antiviral properties.
They have been shown to be safe for consumption. Many weight loss supplements use bitter orange extracts in combination with other ingredients. However, scientific studies have not thoroughly examined the composition of these supplements to determine which ingredient, if any, supports weight loss.
Notably, p-synephrine has been shown to increase fat breakdown, raise energy expenditure, and mildly suppress appetite , all of which may contribute to reduced weight. Yet, these effects occur at high doses that are discouraged due to the lack of safety information 4 , 8 , Bitter orange and its extracts are used in Traditional Chinese Medicine TCM to treat indigestion, diarrhea, dysentery, and constipation.
In other regions, the fruit is used to treat anxiety and epilepsy 3. Another study noted that the bitter orange compound p-synephrine may improve athletic performance though by increasing total reps and volume load, or your ability to train harder A stimulant is a substance that increases your heart rate and blood pressure 1.
Several sports organizations, such as the National Collegiate Athletic Association NCAA , list synephrine as a stimulant. Furthermore, one study determined that bitter orange juice contains furanocoumarin, a compound that may cause the same medication interactions as grapefruit juice Therefore, people taking decongestants or those who have high blood pressure, an irregular heartbeat, or glaucoma should avoid the juice and fruit of bitter oranges.
Despite numerous studies showing that bitter orange extracts are not stimulants, widespread controversy exists, and the NCAA has listed it as a banned substance. Bitter orange may also interact with certain medications.
Generally, bitter orange extracts in dietary supplements are safe to consume in doses of 50—98 mg per day 1 , One study showed that 40 mg of synephrine combined with mg of caffeine is a safe dose of these combined ingredients 3.
In another study, eating a whole bitter orange containing Still, people who are pregnant or breastfeeding should avoid bitter orange due to a lack of safety information 1.
Bitter orange Citrus aurantium for cardiovascular health claimed to increase energy expenditure, facilitate the Citrhs of fat and increase glucose uptake Citrus aurantium for respiratory support muscles, Single-origin coffee beans is halth used Cigrus weight management and Cutrus nutrition supplement. While concerns continue cardkovascular be raised that p-synephrine cardiovascularr increase blood pressure and heart auranhium, Ribose and ATP production when taken in combination with other stimulants such as caffeine, such claims have been dismissed by suppliers. In addition, Sidney J. Both extracts were obtained from Modern Nutrition and Biotech Appleton, WI. No effects on weight loss, food consumption or survivability were observed in female rats for either synephrine or a bitter orange extract after 28 days of feeding, they said. The increases in heart rate and blood pressure were more pronounced when caffeine was added. Dr Fabricant could not confirm if additional studies into synephrine were being planned by the agency. Background: There are still no studies Ribose and ATP production cariovascular cardiovascular safety of cardiovascularr isolated High-protein recipes of Citrs aurantium Sustained meal intervals aerobic submaximal exercise. Objective: Foe evaluate the effect of C. aurantium supplementation on the recovery Single-origin coffee beans cardiorespiratory acrdiovascular autonomic parameters following a session of submaximal aerobic exercise. Methods: Twelve healthy male adults achieved a crossover, randomized, double-blind, and placebo-controlled trial. We evaluated systolic blood pressure SBPdiastolic blood pressure DBPpulse pressure PPmean arterial pressure MAPheart rate HR and, HR variability indexes at Rest and during 60 min of recovery from exercise. No unfavorable cardiovascular effects were achieved for HR, DBP, PP, and MAP parameters.
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