Clinical & Experimental Cardiology
Open Access
ISSN: 2155-9880
ISSN: 2155-9880
Mini Review - (2025)Volume 16, Issue 4
Cardiovascular diseases is a leading cause of death worldwide and the process of cardiac remodeling lies at the core of most of these diseases. The sustained cardiac remodeling almost unavoidably ends in progressive muscle dysfunction, heart failure and ultimately death. Therefore, in order to attenuate cardiac remodeling and reduce mortality, different therapies have been used, but it is important to identify adjuvant factors that can help to modulate this process. One of these factors is inclusion of affordable foods in the diet having potential cardio protective properties. Study carried out by Fujimori, et al. showed that ingestion of pera and moro orange juice induces changes in plasma metabolites related to the regulation of extracellular matrix, inflammation, oxidative stress, and membrane integrity in healthy rats. Additionally, the review of the metabolic pathways related to these compounds showed that they are mainly associated with phospholipid metabolism, cannabinoid system and microbiota metabolism. Therefore, ingestion of pera orange and moro orange juice induces changes in plasma metabolites that may be important for modulating cardiac remodeling induced by cardiovascular diseases.
Citrus sinensis L. Osbeck; Pera orange; Moro orange; Cardiac remodeling; Cardiovascular diseases
Cardiovascular Diseases (CVD) is the leading cause of mortality accounting for 17.9 million deaths in 2019, 32% of all global deaths. Most CVD can be prevented by addressing behavioral risk factors, such as diet. The process of muscle remodeling lies at the core of most cardiovascular diseases. Cardiac adaptation to pressure or volume overload, which typically occurs in CVD, is associated with a complex cellular and molecular alterations in cardiomyocytes and interstice which leads to anatomic remodeling of the heart muscle. These alterations include increased oxidative stress and inflammation, changes in energy metabolism, and induction of apoptosis. Although adaptive at its beginnings, the sustained cardiac hypertrophic remodeling almost unavoidably ends in progressive muscle dysfunction, heart failure and ultimately death [1].
In order to attenuate cardiac remodeling and reduce mortality, different therapies have been used. However, because of the high mortality and disability rates, despite treatment, it is important to identify adjuvant factors that can modulate the cardiac remodeling process. One of these factors is inclusion of affordable foods in the diet having potential cardioprotective properties, as shown by Fujimori, et al. [2]. The authors showed that the ingestion of pera and moro orange juice induces changes in plasma metabolites related to the regulation of extracellular matrix, inflammation, oxidative stress, and membrane integrity in healthy rats that may have beneficial effects on pathological cardiac remodeling.
Fujimori, et al. identified that ingestion of pera orange juice is associated with serum changes in the metabolites Ndocosahexaenoyl- phenylalanine (m/z 476.3168), diglyceride (DG; 20:4/24:1) (m/z 709.6141), and phosphatidylethanolamine (PE; O-20:0/16:0) (m/z 734.6044)4. The review of the metabolic pathways related to these compounds showed that they participate in the phospholipid metabolism and the cannabinoid system.
N-docosahexaenoyl phenylalanine belongs to the class of compounds known as N-acylamides. N-acyl amides are one of the main groups of simple lipids with structures consisting of a fatty acid (acyl group) attached to a simple amine by an amide link. These compounds fall into several categories e.g. those acyl amides conjugated with amino acids, such as N-docosahexaenoyl phenylalanine. N-acyl amides can be synthesized both endogenously and by gut microbiota of humans and both can activate host receptors [3].
N-acyl amides have a variety of signaling functions in physiology, including in cardiovascular activity. N-acyl amides are considered “orphan lipids”, since no specific receptor for these molecules has been discovered. However, there is evidence of their ability to bind to different endocannabinoid receptors including CB1 and CB2, to G-Protein-Coupled Receptors (GPCRs) and to some members of the transient receptor potential channels, exerting a cannabimimetic effect. The activation of these receptors plays a central physiological role in the regulation of cardiac function in both health and disease [4].
Endocannabinoids are fatty acid derivatives that act as lipid messengers in intercellular communication. Endocannabinoid receptors and their endogenous ligands exhibit distributions in the cardiovascular system and they exert their effects on the heart by modulating the inflammatory process, endothelial function and atherogenesis [5]. The N-acyl amides are similar to endocannabinoids in structure and metabolism and may present function and regulation of cannabinoid physiology or operate in parallel via overlapping signaling pathways.
The two other compounds altered in plasma by ingestion of pera orange juice were diglyceride (DG; 20:4/24:1) (m/z 709.6141), and phosphatidylethanolamine (PE; O-20:0/16:0) (m/z 734.6044)4. Both of which are part of the synthesis pathways of the main phospholipids and triacylglycerols in eukaryotes.
PE is a glycerophospholipid present in most cell membranes, but in variable proportions and found almost exclusively on the internal (cytoplasmic) surface. One of the synthesis pathways for glycerophospholipids, including phosphatidylethanolamine, is the phosphorylation of a diacylglycerol, such as diglyceride (DG; 20:4/24:1), which was altered after ingestion of pera orange juice. A Cytidine Diphosphate (CDP) is coupled to diacylglycerol, forming the activated phosphatidic, acid CDP-diacylglycerol, and then condensation of an ethanolamine occurs to form phosphatidylethanolamine [6].
PE (20:0/16:0), in particular, consists of one chain of arachidic acid at the C-1 position and one chain of palmitic acid at the C-2 position. The synthesis of ethanolamine from CDPdiacylglycerol is a major PE producing pathway in eukaryotes. In cardiomyocytes, PE is the second most abundant phospholipids representing 37% of total phospholipids.
PE has many biological roles, some of which are associated with cardiovascular health. It is part of the respiratory complex IV and helps to stabilize the sarcolemmal membranes of cardiac tissues when there is an inadequate supply of oxygen, such as what happens during fact, ischemia [7]. In phosphatidylethanolamine deficiency in mammalian mitochondria impairs oxidative phosphorylation and alters mitochondrial morphology.
Additionally, PE is increased in cardiomyocytes from ischemic and reperfused hearts and this is an early apoptotic signal for these cells that is subsequently recognized by macrophages to facilitate the removal of damaged cardiomyocytes.
On the other hand, some studies have shown that PE is associated with risk of vascular manifestations development in macro and micro-circulation, maladaptive cardiac remodeling in CVDs patients and total and cardiovascular mortality [8,9]. However, it appears that different PE species have different effects on cardiac risk and the species shown by the authors cited above is not the same shown by Fujimori, et al.
In addition to the effects mentioned above, phosphoethanolamine also participates in endocannabinoid signaling. Therefore, ingestion of pera orange juice could influence the cardiac remodeling process by alterations in phospholipid metabolism and endocannabinoid system. However, more studies are needed to evaluate this effect in different cardiac pathological conditions.
Regarding the ingestion of moro orange juice, 3 compounds found altered by Fujimori, et al. are not intermediate metabolites of mammalian metabolic pathways, but possibly compounds derived from orange. They are casegravol isovalerate (m/z 361.1639), abscisic alcohol 11-glucoside (m/z 435.1981) and torvoside C (m/z 779.3994).
Casegravol isovalerate belongs to the class of organic compounds known as coumarins and derivatives. These are polycyclic aromatic compounds containing a 1-benzopyran moiety with a ketone group at the C2 carbon atom (1-benzopyran-2-one). Casegravol isovalerate has been detected in Citrus plants, including in some orange species [10]. Based on a literature review very few articles have been published on casegravol isovalerate and there are no studies showing the association of this compound with cardiovascular pathophysiology. However, Detsi, et al. showed that coumarin naturally plant-derived or synthetically obtained substances, presenting a wide variety of biological activities, offering an extensive therapeutic profile. In fact, coumarin derivatives are referred to as receptor modulators, as possible treatment for cardiovascular disease.
The Abscisic alcohol 11-glucoside belongs to the class of organic compounds known as terpene glycosides. These are prenol lipids containing a carbohydrate moiety glycosidically bound to a terpene backbone. It is present in some plants and orange species [11]. As casegravol isovalerate, very few articles have been published on this compound and there are no studies showing its association with cardiovascular pathophysiology. However, some studies have shown that other glycosidic terpenes have antiatherosclerotic effect. Additionally, glycosidic terpenes protect against isoproterenol-induced myocardial ischemic disease potentially by improving cardiac energy metabolism and inhibiting cardiomyocyte apoptosis [12].
The other compound is torvoide C which belongs to the class of organic compounds known as steroidal saponins. These are saponins in which the aglycone moiety is a steroid. In an earlier report by Yahara, et al. torvoside C has been reported from aerial parts of Solanum torvum. There are no studies showing the presence of this compound in oranges, nor the association of this compound with cardiovascular pathophysiology. However, the fruits of Solanum torvum are commonly used in traditional medicine as antihypertensive, antioxidante and anti-platelet aggregation activities [13].
Therefore, these compounds have the potential to modulate cardiac remodeling, but further studies are needed.
Ingestion of Moro orange juice also appears to be associated with changes in microbiota metabolism. The compounds Nformylmaleamic acid (m/z 181.9853) and N2-acetyl-L-ornithine (m/z 197.0893) are metabolites of oral and intestinal microflora.
N-formylmaleamic acid is a metabolite of catabolism of Nicotinamide (Nam) in several bacteria and some yeast [14]. Nam degradation in these organisms is initiated by deamination to form Nicotinic Acid (NA) catalyzed by the nicotinamidase. Nam, as well as NA, are two forms of vitamin B3. They are precursors of the coenzyme Nicotinamide Adenine Dinucleotide (NAD), compound that is required for cellular bioenergetics and metabolism. Additionally, Nam catabolism is a carbon, nitrogen source and energy for these organisms.
The species presents considerable differences in the catabolism of Nam or NA [15]. In mammals, such as rats and humans, for example, the degradation pathway of Nam does not form formylmaleamic acid, the metabolites formed are others such as nicotinamide methochloride, nicotinamide riboside, nicotinamide mononucleotide and N-methylnicotinamide. Therefore, the Nformylmaleamic acid present in the serum of animals that ingested moro orange juice should not be a compound of Nam metabolism in the rat tissues. There are studies in the literature that suggest that the presence of N-formylmaleamic acid may be due to the metabolism of vitamin B3 (which is present in Citrus sinensis L. Osbeck), by the microbiota [16].
In fact, mammals have little or no enzyme for converting Nam into NA. Therefore, for them to use NA as a precursor in the synthesis of the coenzyme NAD, Nam deamination by oral and intestinal microflora first occurs [17]. Elinger, et al. showed that the elimination of metabolites Nam and NA in men, after oral than after parenteral administration is lower, indicating utilization by the intestinal flora. A study carried out in mice showed that Nam and NA are absorbed in the proximal part of the gastrointestinal tract and not available to microbes in the distal gut. Instead, circulating host Nam enters the gut lumen and supports gut microbiome NAD synthesis or is converted into NA, which is taken up and used by the host tissues for NAD synthesis. Furthermore, the main route from oral nicotinamide riboside, a widely used nutraceutical, to host NAD is via conversion into nicotinic acid by the gut microbiome. Thus, we can predict that moro orange influences the microbiota metabolism, and may have effects on different physiological and pathological conditions.
N2-acetyl-L-ornithine is a metabolite of the de novo biosynthetic pathway for ornithine (and therefore arginine) in bacteria. The precursor metabolite is the amino acid glutamate. Glutamate is acetylated to form N-acetylglutamate, which is phosphorylated by acetyl glutamate kinase, giving rise to N-acetyl glutamate-5- phosphate. N-acetyl glutamate-5-phosphate is then reduced by NADPH to N-acetyl-5-semialdehyde which is transaminated to form N-acetyl ornithine. Hydrolysis of the acetyl group forms ornithine which, through the urea cycle, is converted into arginine.
In mammals, the pathways for producing ornithine and arginine are somewhat different. In principle, ornithine can also be synthesized from glutamate by transamination, but the spontaneous cyclization of glutamate semialdehyde, which is directed to the proline synthesis pathway, prevents a sufficient supply of this intermediate for ornithine synthesis. In bacteria there are two additional steps, which avoid the problem of spontaneous cyclization of semialdehyde from glutamate. Therefore, the synthesis of arginine in mammals does not occur through the de novo biosynthetic pathway for ornithine and the metabolite N2-acetyl-L-ornithine is not formed. Arginine is synthesized through reactions in the urea cycle.
Although N2-acetyl-L-ornithine is not a compound of mammalian metabolism, studies investigating changes in plasma metabolomics of rats have shown the presence of this compound [18]. Some authors consider that the changes in ornithine/arginine metabolism observed in humans, rats and mice may be associated with the gut microflora metabolism [19]. Therefore, once again the ingestion of moro orange juice caused changes in the concentration of metabolites related to the gut microflora, which strongly indicated that there were variations in gut microflora in response to Moro orange administration.
The last compound associated with the ingestion of moro orange juice was Cyclic Phosphatidic Acid (CPA; 18:2) (m/z 455.1968). CPA is a glycerophospholipid in which there is a cyclic phosphate at the sn-2 and sn-3 positions of the glycerol carbons, and this structure is absolutely necessary for their activities. CPAs can have different combinations of fatty acids of varying lengths and saturation attached at the C-1 (sn-1). Fatty acids containing 16 and 18 carbons are the most common. CPAs have been detected in a wide range of organisms including humans, especially in the brain but also in serum.
This compound is a naturally occurring analog of the growth factor-like phospholipid mediator, lysophosphatidic acid. CPA affects numerous cellular functions, including anti-mitogenic regulation of the cell cycle, induction of stress fiber formation, inhibition of tumor cell invasion and metastasis, and regulation of differentiation and survival of neuronal cells [20].
Additionally, studies have shown that CPA has an important role in cardiovascular pathophysiology. CPA inhibits arterial wall remodeling and secretion of inflammatory mediators, in addition to suppressing VEGF-stimulated growth and migration, preventing atherosclerosis.
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Citation: Fujimori ASS, Polegato BF, dos Santos PP (2025) Therapeutic Potential of Pera Orange and Moro Orange in Cardiac Remodeling by Cardiovascular Diseases: A Metabolomics Approach. J Clin Exp Cardiolog. 16:946.
Received: 14-Sep-2023, Manuscript No. JCEC-23-26908; Editor assigned: 16-Sep-2023, Pre QC No. JCEC-23-26908 (PQ); Reviewed: 30-Sep-2023, QC No. JCEC-23-26908; Revised: 19-Apr-2025, Manuscript No. JCEC-23-26908 (R); Published: 25-Apr-2025 , DOI: 10.35248/2155-9880.25.16.946
Copyright: © 2025 Fujimori ASS, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.