Citrus aurantium for respiratory health -
Digitonin is used to permeabilize the cell membranes while leaving the mitochondrial membranes intact because of its specificity for solubilizing cholesterol, which exists in much higher concentrations in the plasma membrane. The study was carried out with two groups of independent substrates in each chamber: chamber A, in mM glutamate 10, pyruvate 5, malate 2, ADP 1 and succinate 10, for the analysis of carbohydrate-related oxidation with electron entry through complexes I and II of the respiratory chain and chamber B, in mM palmitoyl-carnitine 0.
The addition of cytochrome c 10 μM allowed for the evaluation of the integrity of the mitochondrial membrane because an increase in respiration with the addition of cytochrome c indicates a defect in the outer mitochondrial membrane Statistical analyses were performed using GraphPad Prism software version 6.
The body weights of normal litters NL and small litters SL during lactation PND21 are shown in Figure 2. The small litter group SL had a higher body weight than the normal litter group NL on PND4 until weaning PND21, SL: 3. NL: 2. Figure 2. Evolution of body weight during the lactation period 21 days of mice raised in normal NL and small SL litters.
The SL group had a higher body weight NL: SL: SL: 3. aurantium and synephrine did not show significant differences in fat mass with the NL groups Figure 3D.
Figure 3. Effect of treatments with C. aurantium and synephrine on body weight A,C , body composition by Nuclear Magnetic Resonance B,D and tissue weight of visceral WAT E and BAT F of mice raised in normal and small litters in the pre-treatment A,B and post-treatment C—F period.
NL A,B. NL-Syn C,D. SL-Syn E,F. The accumulated body weight from PND30 to PND49 is depicted in Figure 4. The SL groups treated with C.
Figure 4. Accumulated weight gain of mice raised in normal and small litters submitted to treatment with C. There was no significant difference in heart rate Supplementary Figure 1A , systolic blood pressure Supplementary Figure 1B , and diastolic blood pressure Supplementary Figure 1C in the normal and small litter groups treated with C.
aurantium and synephrine or vehicle. There was no significant difference in the OGTT Supplementary Figure 2A or the area under the curve AUC of the OGTT Supplementary Figure 2B in the normal and small litter groups treated with C.
The plasma concentration of leptin in the SL groups treated with C. aurantium and synephrine was not different from that in the NL groups or SL vehicle group Figure 5A. Figure 5.
Effect of treatment with C. aurantium and synephrine in hormonal dosages. Plasma leptin A , Total T3 B and Free T4 C. There was no significant difference in the absolute catecholamine content in the adrenal gland Figure 6A. There was no significant difference in plasma corticosterone Figure 6C.
Figure 6. aurantium and synephrine on the medulla adrenal and plasma corticosterone. aurantium and synephrine 2-fold-increase vs.
NL -Syn; 2-fold-increase vs. Treatment with C. aurantium and synephrine was able to restore the lipid droplet size and quantity of nuclei in the small litter groups. Figure 7. BAT histology by Hematoxylin—Eosin HE staining with 40× magnification.
Quantitative analysis of lipid droplets and nucleus number of the BAT. Figure 8 shows biomarkers related to thermogenesis in BAT.
The NL groups did not show differences in gene expression in BAT. aurantium and synephrine showed increased gene expression of UCP-1, PRDM16, PGC-1α, and PPARγ. Treatment of the SL group with C. SL groups treated with C. The SL-Syn group showed higher relative mRNA expression of PRDM than the SL and NL groups 2.
No significant difference was observed in the gene expression of CPT Figure 8D , ADRβ-3 Figure 8E , or BMP7 Figure 8G. However, treatment with C. Figure 8. aurantium and synephrine on thermogenic factors in BAT. Also, SL-Syn group presented no changes in all parameters of BAT mitochondrial function evaluated.
Figure 9. High resolution respirometry of brown adipose tissue from overfeed mice. Flux per mass with substrates pyruvate, glutamate, malate, and succinate A. Flux per mass with substrates palmitoyl-L-carnitine, malate, and ADP B. It is well known that overfeeding early in life causes metabolic effects in the short- and long-term, but such effects are poorly investigated in adolescence.
The reduction in litter size is an effective and reproducible model of obesity 12 , 15 , Our results demonstrated that both overweight and metabolic changes typical of obesity persist from lactation to adolescence. Moreover, the administration of Citrus aurantium or its active compound, synephrine, proved efficacious in ameliorating certain metabolic dysfunctions induced by postnatal overfeeding, employing distinct mechanisms.
Conceicao et al. We find at PND30, overweight and high body fat in SL group by body composition NMR analyses. Furthermore, we showed that the SL group showed higher body weight from PND4 until adolescence. Studies were carried out upon utilization of products derived from medicinal plants and nutraceuticals for the management of obesity and metabolic disorders Until this moment, no studies have demonstrated the effects of C.
aurantium and synephrine at the same doses and period adolescence used in the current investigation. Here, we used a smaller dose than the one usually used in other studies because it would not be interesting to use elevate adrenergic agonist dose in adolescent animals.
Hansen and collaborators 30 demonstrated, in adult female rats, that the administration of C. In agreement, we also observed that the SL group treated with C.
aurantium or synephrine did not show significant differences in body weight and body fat on PND Synephrine, due to it is an adrenergic agonist effect and its similarity to ephedrine, has potential adverse effects upon the cardiovascular system However, we did not show changes in heart rate or systolic or diastolic blood pressure in the treatments with C.
aurantium extracts and synephrine. Citrus aurantium has been associated with improvement in hyperglycemia Although obese, the SL group had no changes in glucose homeostasis, with no significantly different in TOTG compared to the NL group.
Litter size reduction programming impairs leptin signaling and causes leptin resistance at PND 37 , Corroborating these findings, the SL group showed hyperleptinemia, indicating leptin resistance in these animals as early as 50 days old. However, C. aurantium and synephrine slightly reduced this hyperleptinemia induced by overfeeding.
In the literature, no studies were found about the effect of C. aurantium and synephrine on leptin secretion and signaling. Thus, precocious treatment with C. aurantium may prevent those animals from developing future glucose intolerance since leptin resistance can be one contributor factor to insulin resistance.
Rodrigues and collaborators 37 showed that, in PND21, the SL group had high TSH and serum thyroid hormone concentrations. However, on PND, this group showed normal TSH and lower T3 and T4 in serum. Here, treatment with C. aurantium increased total T3 and free T4 compared to all NL groups in this study, and synephrine SL-Syn increased even more because it was higher than in the SL group.
As there are no studies focusing the interplay between thyroid function and C. aurantium or synephrine , more studies are needed to better understand the mechanisms involved.
aurantium , other than synephrine, can increase adrenal catecholamines, which can occur either by greater synthesis or by accumulation due to deficient secretion. We measured only tissue catecholamines, and this increase was not enough to alter cardiovascular parameters.
However, this change may have resulted in a slight increase in circulating adrenaline, inducing lipolysis in white and brown adipocytes, through their interaction with β-3 adrenergic receptors Only one in vitro study has reported the influence of C.
aurantium on the differentiation and activation of brown adipocytes through anti-adipogenic and thermogenic mechanisms In the current study, we explored the in vivo anti-obesity potential of C.
aurantium extracts and its main active component, synephrine, in brown adipose tissue dysfunction of adolescent mice programmed by early postnatal overfeeding. The whitening of BAT occurs in obesity. In this process, BAT has increased tissue mass with large lipid droplets, low vascularization, high pro-inflammatory cytokine expression, and low UCP-1 and other thermogenesis marker expression 13 , 48 , causing dysfunction.
In the qualitative and quantitative analyses of BAT, we demonstrated a reduction in its mass and in the content of lipid vesicles and an increase in the number of nuclei in the SL groups treated with C. aurantium and synephrine, showing that the treatments normalized the BAT structure and recovered its original phenotype.
We investigated some important markers of thermogenesis and activity in BAT, such as UCP-1, PRDM16, PCG-1α, CPT-1, beta-3AR, PPARγ, and BMP-7 Furthermore, we found, in general, higher gene expression of UCP1, PRDM 16, PGC-1α, and PPARγ, demonstrating the thermogenic action of both C.
aurantium and its active compound, synephrine. β-3 adrenergic receptor expression in BAT was unchanged, but we cannot ignore the effect of synephrine β-3 adrenergic ligand on adrenergic receptors.
PPARγ is responsible for positively regulating genes involved in lipid oxidation CPT-1 and thermogenesis, such as UCP-1 and PGC-1α responsible for mitochondrial biogenesis and stimulation of UCP-1 gene expression In addition, PPARγ participates in several physiological functions, such as glucose metabolism control, adipocyte differentiation regulation, and inflammatory response regulation.
This receptor is considered a primary regulator of adipogenesis, controlling cell differentiation of preadipocytes into mature adipocytes 51 and acting in the direction of white and brown adipocyte differentiation UCP-1 is a key marker of thermogenesis in BAT. In experimental models, the absence of UCP-1 is associated with increased body weight and decreased thermogenesis in BAT In our model of obesity induced by litter size reduction, we observed BAT dysfunction and UCP-1 gene expression reduction.
aurantium on BAT was better than synephrine alone that only caused a higher gene expression for PRDM16, a known transcriptional co-regulator capable to directing brown adipogenesis. Mitochondria primarily produce ATP for cellular energy by directing proton flow to ATP synthase.
This occurs when protons, temporarily stored in the intermembrane space, are released into the mitochondrial matrix by uncoupling proteins, reducing the membrane potential, and producing heat rather than ATP Thus, the induced decrease in proton flux is mediated by an increase in UCP1 in adipose tissue, increasing heat production and potentiating weight loss.
This mechanism is important as a therapeutic target in the regulation of body weight. Considering the higher expression of UCP1 in BAT, this could be one of the mechanisms of action of C.
UCP-1 activity is mainly regulated by fatty acids that represent the main energy substrates for oxidation during thermogenesis, providing NADH and FADH2 to supply the respiratory chain and ensure the proton gradient Isolated synephrine, in turn, did not change oxygen consumption in relation to the energy substrates studied.
In general, C. aurantium and synephrine increased thermogenic marker expression in BAT without modifying the cardiovascular system.
The modern obesogenic environment can significantly increase obesity worldwide, especially in adolescence This period is a crucial stage of human development when several psychological and social changes occur in addition to the acquisition of new life habits that are the foundation for health and wellbeing in adulthood Our results indicate that obesity treatment in the critical period of adolescence, when the neurological system is particularly sensitive to interventions, can be a good therapeutic strategy.
Even when using C. aurantium or synephrine at a low dose, both showed beneficial effects, reducing adipose tissue mass, and improving BAT functionality without impacting blood pressure and glucose homeostasis.
With due care in extrapolating therapy from animals to humans, the set of our findings suggest that therapeutic use of these compounds can improve the metabolic profile of obese adolescents without adverse cardiovascular side effects.
Further studies are necessary to better evaluate the safety of using both C. The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
The animal study was approved by the Animal Care and Use Committee of the Biology Institute of the State University of Rio de Janeiro. The study was conducted in accordance with the local legislation and institutional requirements. AG: Conceptualization, Formal analysis, Investigation, Writing — original draft.
This work was supported by the Carlos Chagas Filho Foundation for Research Support of the State of Rio de Janeiro FAPERJ , grant numbers: We thank the Postgraduate Program in Clinical and Experimental Pathophysiology for administrative and financial support.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
The tree is a member of the Rutaceae family and is native to Southeast Asia. The oil has a fresh, floral, and slightly woody aroma. Notes: Top Common Uses: Petitgrain EcoTrade essential oil is known for its calming and balancing properties. It is often used in aromatherapy to reduce feelings of stress and anxiety, promote relaxation, and improve sleep quality.
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A pilot study conducted with six participants performed the sample size calculation. We applied the root mean square of successive differences between RR intervals in the online software at www. br , which provided the magnitude of the difference.
We measured a standard deviation of The Shapiro-Wilk statistical test was enforced to assess data normality. For the cardiovascular recovery and autonomic reactivity analysis during the experimental protocols Rest vs.
recovery , One-way analysis of variance ANOVA1 for repeated measures and the Bonferroni post-test was enforced when the assumption of data normality was attained. Friedman's test followed by Dunn's post-test was required for data that did not acquire a normal distribution.
Cohen's d calculated effect sizes to measure the magnitude of changes for significant differences. Assessments were achieved using Statistical Package for the Social Sciences SPSS IBM ® SPSS Statistics v.
The descriptive data of twelve healthy males that met the study criteria are included in Table 1. These datasets strengthen the homogeneity of our sample. The HR recovery analysis revealed no significant differences between the protocols.
In the placebo protocol, the comparison of resting and after exercise established an increase in HR from 0 to 5th min of recovery Rest vs. In the C. aurantium protocol, the same results were attained, and HR values remained significantly enlarged from 0 to 5th min of recovery Rest vs.
Table 2. No significant changes were identified in the C. aurantium intervention during the recovery analysis rest vs. recovery for DBP, MAP, and PP.
Only SBP demonstrated significant changes in 1 min following exercise Rest vs. aurantium protocol. During the placebo protocol, SBP remained significantly higher during 3 min of recovery compared to rest Rest vs.
Table 3. Time and frequency domain indices in addition to non-linear analyzes revealed that autonomic heart rate recovery occurred more quickly in the C. aurantium protocol compared to the placebo protocol. In the placebo protocol, the investigation of recovery rest vs.
recovery of the HF index revealed that its values remain depressed throughout 10 min of recording after exercise Rest: Figure 3. In the placebo protocol, pNN50 index values continued to be significantly decreased throughout 20 min of recovery related to resting values Rest: Our findings demonstrate that the ingestion of C.
aurantium p-synephrine mg prior to exercise fast-tracks the fall in SBP after physical exertion. Earlier studies propose that one of the benefits of using C. aurantium equated to other adrenergic substances e. Activation of β-3 adrenergic receptors triggers reverse inotropic effects, antagonizing the activation of further classes of adrenoreceptors β-1 and β-2 in cardiac tissue and, thus, decreasing sympathetic modulation to the heart.
This clarifies why overall, the binding of p-synephrine with β-3 adrenergic receptors does not increase BP or HR, displaying cardioprotective effects In this study, in the placebo intervention, for the spectral analysis, the HF index, representative of parasympathetic modulation, needed 10 min after termination of exercise to recover.
aurantium protocol, we did not find substantial changes in the HF index in exercise recovery vs. Analogous deviations occurred in the pNN50 index and were reduced 20 min after cessation of exercise in the placebo protocol.
While in the protocol with C. aurantium , this index continued to be reduced for only 10 min after exercise. aurantium protocol, transformations were only following 5 min of recovery.
However, in the C. aurantium protocol, the values were only meaningfully reduced for 5 min after the cessation of exercise. These observations make C.
aurantium a safe nutritional compound to be applied during exercise, which supports the recovery of autonomic parameters following exercise. Since a slow post-exercise autonomic recovery is linked with an increased cardiovascular risk 25 , the results of our study indicate that C.
aurantium compounds have a potential preventive role on the onset of cardiovascular complications in physical exercise.
As caffeine and C. aurantium are frequently sold as complementary formulas for use in humans, preceding studies have assessed the effects of using these substances alone and in combination. Through a randomized clinical trial, Guitiérrez-Hellín et al. aurantium alone or in combination with caffeine would have different results for fat utilization during aerobic physical exercise.
No superiority was found between C. aurantium alone and combined with caffeine on the total values of fat consumption during the physical exercise session, while both interventions were superior to the placebo treatment. This supports the isolated use of C. aurantium an alternate way to be applied as an adjunct in cutting body fat without inducing cardiac risk.
In the study by Guitiérrez-Hellín et al. aurantium isolated supplement. In contrast, the HR and SBP were significantly higher when caffeine was included in the formulation. Our study achieved no changes for HR, and SBP was lessened more quickly following exercise.
The identification of β-3 adrenoreceptors in cardiovascular tissues posed challenges to the paradigm of sympathetic regulation by β-1 and β-2 adrenoceptors. The binding response of p-synephrine to the β-3 receptor may elucidate why no increase in HR or BP is detected when C.
aurantium is enforced alone. In contrast, when C. aurantium is combined with caffeine in dietary supplements, it is capable of affecting these parameters, particularly in caffeine-sensitive individuals It has been revealed that the combination of these substances promotes a significant increase in the concentration of plasma catecholamines e.
The study by Kliszczewicz et al. aurantium upsurges sympathetic modulation to the heart throughout rest and corroborates the increases in HR and SBP achieved in the study by Guitiérrez-Hellín et al.
It is assumed that caffeine alone can increase HR during physical exercise Despite that, a recent meta-analysis demonstrated that caffeine could not delay vagal return to the heart after exercise, evaluated by the HF and root mean square of successive differences between RR intervals RMSSD indices Equally, Kliszczewicz et al.
aurantium combined. Caffeine and C. aurantium combination have no extra effects on exercise fat utilization 5. These substances appear to exhibit the opposite cardiovascular effects and, thus, caffeine seems to overlap the beneficial effects of the isolated use of C.
aurantium on cardiovascular health. In this study, C. aurantium supplementation alone optimized the recovery of SBP and HRV indices after exercise. The nutritional characteristics demonstrated in the flavonoids e. aurantium perform antioxidant and anti-inflammatory activities, which are partly answerable for accelerating the return of parasympathetic control of heart rate seen by vagal indices of HRV.
Such properties can hasten the removal of metabolites produced by physical exercise, restoring baroreflex sensitivity and decreasing metaboreflex activation more quickly at the end of physical exercise While C. aurantium exhibited cardioprotective effects, it is essential to be careful with its usage.
Bui et al. Yet, in other studies that enforced doses beneath mg in an acute 5 , 30 , 31 and chronic for 15 days 32 form, no changes were achieved for the HR, SBP, and DBP values, nor electrocardiographic disturbances.
Likewise, our results do not support the findings of Bui et al. The results from the study of Ratamess et al. In your results, the p-synephrine supplementation mg did not evoke changes in HR before, during, and following resistance exercise unless mg of caffeine was added to the formulation.
The same occur in the rest situation, in another study by Ratamess et al. The study of Bui et al. Although it is a randomized and crossover study, there is a lack of information about allocation order in the study. aurantium, and provoked adjustments in blood pressure, because of higher sweet and fat content e.
Furthermore, the authors did not report guarantees that snack was equal on the others evaluation days. Bitter orange caused cardiovascular effect was only observed based on statistical adjustments. A difference was seen compared to placebo but not when compared to baseline.
All these factors raise questions about the validity of their conclusions. The results recognized in our analyses will advance health professionals' conduct who work with the prescription of nutritional supplements.
Consequently, it may be an alternative way to replace other compounds that demonstrate similar contributions regarding fat utilization during exercise but that promote unwanted cardiovascular effects e.
Our study highlights important points about the study population, given that it is restricted to healthy and physically active males. Notwithstanding the number of participants having exceeded the sample size calculation, the final sample is considered small. With the desire to improve body composition.
In spite of this, these facts do not allow these results to be extrapolated to other populations and, therefore, further research with obese individuals is needed to confirm the safety of using C.
aurantium in combination with exercise. For the time being, we prefer to use a healthy population free from metabolic disorders to prevent possible adverse events from C.
aurantium supplementation.
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