Inflammation and Oxidative Stress Induced by Obesity, Gestational Diabetes, and Preeclampsia in Pregnancy: Role of High-Density Lipoproteins as Vectors for Bioactive Compounds

Inflammation and oxidative stress are essential components in a myriad of pathogenic entities that lead to metabolic and chronic diseases. Moreover, inflammation in its different phases is necessary for the initiation and maintenance of a healthy pregnancy. Therefore, an equilibrium between a necessary/pathologic level of inflammation and oxidative stress during pregnancy is needed to avoid disease development. High-density lipoproteins (HDL) are important for a healthy pregnancy and a good neonatal outcome. Their role in fetal development during challenging situations is vital for maintaining the equilibrium. However, in certain conditions, such as obesity, diabetes, and other cardiovascular diseases, it has been observed that HDL loses its protective properties, becoming dysfunctional. Bioactive compounds have been widely studied as mediators of inflammation and oxidative stress in different diseases, but their mechanisms of action are still unknown. Nonetheless, these agents, which are obtained from functional foods, increase the concentration of HDL, TRC, and antioxidant activity. Therefore, this review first summarizes several mechanisms of HDL participation in the equilibrium between inflammation and oxidative stress. Second, it gives an insight into how HDL may act as a vector for bioactive compounds. Third, it describes the relationships between the inflammation process in pregnancy and HDL activity. Consequently, different databases were used, including MEDLINE, PubMed, and Scopus, where scientific articles published in the English language up to 2023 were identified.


Introduction
Pregnancy is a physiological process that extends the development phase of the fetus in the uterus.In this period, women experience a series of adjustments to satisfy the metabolic, biochemical, endocrine, and cellular changes that fetuses demand [1].Nevertheless, depending on the woman's wellness, these adaptations may be tolerated or be a hypolipidemic [25] properties.Some of these bioactive compounds include phytochemicals, phenolic compounds, polysaccharides, and unsaturated fatty acids.During pregnancy, the consumption and functionality of these compounds have been established [26], especially in the prevention of diseases and health promotion for both mother and fetus in the different phases of the gestational period [27][28][29].
The consumption of certain polyphenolic compounds in pregnancy improved levels of blood glucose in women with gestational diabetes [30], as well as insulin secretion in the fetus and in the mother [31].Furthermore, it has been reported that some polyphenolic compounds regulate cell apoptosis, the secretion of adipokines, placentation, and arterial pressure.Such regulation occurs mainly through the activity of the matrix metalloproteinases (MMPs) [32,33] and some glucose transporter (GLUT) family members (GLUT1, GLUT4, and GLUT 9) [34].
A wide variety of secondary metabolites including flavonoids, quinones, flavones, tannins, and aromatic compounds are consumed in high frequency and quantity.Nonetheless, they could present a toxic effect mainly on the fetus because some of those metabolites are widely consumed during the first trimester.In fact, some of them are well known to be potentially dangerous because of the vulnerability of the fetus, for example, Japanese mint (Mentha arvensis), linden herb (Justicia pectoralis), verbena (Verbena officinalis), aloe (Aloe vera), chamomile (Matricaria recutita), oregano (Plecthranthus amboinicus), basil (Ocicum basilicum), caña santa (Cymbopoggon citratus), and wormwood (Artemisia abssinthium).Furthermore, some of these compounds could increase estrogenic activity by stimulating uterine contractility, increasing blood pressure, and having a hepatotoxic, mutagenic, or fetal malformation effect.Most of these agents may also have an effect on OS and inflammatory processes present in gestational diabetes mellitus (GDM), preeclampsia, or obesity during pregnancy because they contain phenolic compounds, flavonoids, tannins, omega-3, quercetin, kaempferol, tocopherols, and vitamin C [35][36][37][38][39][40].

Pregnancy-Oxidative Stress-Inflammation Association
A significant increase in inflammatory processes and OS markers during pregnancy happens because of biological actions that are carried out to maintain body homeostasis.The first reports showed an elevation in OS and inflammatory markers in plasma and urine during the physiological course of pregnancy [41,42].The significant increase in inflammatory and pro-oxidant molecules can trigger negative conditions such as preeclampsia, endothelial dysfunction, pre-diabetes, poor fetal development, or premature birth [43,44].
One of the reasons for the increase in OS is the development of the placenta, which contains high quantities of mitochondria, leading to an increase in the concentration of ROS, such as superoxide dismutase (SOD), xanthine oxidase (XO), or NADPH oxidase (NOX).The high activity of these prooxidant enzymes is associated with the onset of preeclampsia, which is one of the most common negative conditions during pregnancy, as well as an increase in cholesterol, triglycerides, and c-LDL levels [45,46].Nevertheless, a number of external factors are related to OS augmentation during pregnancy, such as smoking, consumption of foods rich in saturated fatty acids, carbohydrates, alcohol consumption, ultraviolet radiation, obesity, and consumption of non-steroidal anti-inflammatory drugs like paracetamol, ibuprofen, or diclofenac [47,48].
ROS play a crucial role throughout the entire process of pregnancy.It starts with the generation of steroid hormones in the ovary, oocyte maturation, ovulation, luteolysis, implantation, follicular growth, and maintenance of pregnancy until childbirth [49].Elevated ROS production leads to a decreased ovarian blood flow and tissue damage, polycystic ovarian syndrome, or endometriosis.In addition, inflammatory processes are important and play an important role in both the positive and negative aspects, alongside important functions of the adaptive immune system; during the first and third trimester, there is a presence of pro-inflammatory processes, triggered by implantation and placentation, as well as labor and delivery, whereas, in the second trimester, anti-inflammatory processes proliferate [50,51], ensuring proper fetal growth at this stage.
During gestation, women's bodies possess diverse hormones, cytokines, nutrients, and enzymes that help maintain the balance of antioxidant and inflammatory processes (Figure 1) [52].Advanced oxidation protein products (AOPPs) and C-reactive protein (CRP) levels in the maternal serum of pregnant women were significantly higher in the first and second trimesters compared to non-pregnant women.However, higher levels of AOPP were found in control men than in control non-pregnant women and were similar to pregnant women.Moreover, the CRP concentrations increased gradually from the first to the second trimester [38].In contrast, an increase in OS was observed in the second trimester.The activity of the antioxidant enzyme glutathione peroxidase (GPx) was lower in pregnant women than non-pregnant women and postpartum women.Also, the oxidative damage marker to DNA, 8-hydroxy-2 -deoxyguanosine (8-OHdG), was higher in pregnant women compared to non-pregnant women [53].
ROS production leads to a decreased ovarian blood flow and tissue damage, polycystic ovarian syndrome, or endometriosis.In addition, inflammatory processes are important and play an important role in both the positive and negative aspects, alongside important functions of the adaptive immune system; during the first and third trimester, there is a presence of pro-inflammatory processes, triggered by implantation and placentation, as well as labor and delivery, whereas, in the second trimester, anti-inflammatory processes proliferate [50,51], ensuring proper fetal growth at this stage.
During gestation, women s bodies possess diverse hormones, cytokines, nutrients, and enzymes that help maintain the balance of antioxidant and inflammatory processes (Figure 1) [52].Advanced oxidation protein products (AOPPs) and C-reactive protein (CRP) levels in the maternal serum of pregnant women were significantly higher in the first and second trimesters compared to non-pregnant women.However, higher levels of AOPP were found in control men than in control non-pregnant women and were similar to pregnant women.Moreover, the CRP concentrations increased gradually from the first to the second trimester [38].In contrast, an increase in OS was observed in the second trimester.The activity of the antioxidant enzyme glutathione peroxidase (GPx) was lower in pregnant women than non-pregnant women and postpartum women.Also, the oxidative damage marker to DNA, 8-hydroxy-2′ -deoxyguanosine (8-OHdG), was higher in pregnant women compared to non-pregnant women [53].During the third gestational stage, healthy pregnant women showed higher lipid peroxidation markers, such as malondialdehyde (MDA) in plasma and erythrocytes, than non-pregnant women, as well as lower levels of erythrocyte glutathione (GSH) levels than non-pregnant women [41].Furthermore, a longitudinal study consisting of pregnant women at 30 weeks of gestational age showed that, after delivery, their products decreased levels of Ne-carboxymethyl lysine.Also, a soluble receptor for advanced glycation end products (sRAGE) was observed without changes in tumor necrosis factor alpha (TNF-α), CRP, and MDA in blood samples.Their newborns were healthy, but the newborns levels of sRAGE, TNF-α, and MDA were higher than their mothers at delivery [54].Additionally, factors such as age and race influence OS and inflammation.Older pregnant During the third gestational stage, healthy pregnant women showed higher lipid peroxidation markers, such as malondialdehyde (MDA) in plasma and erythrocytes, than non-pregnant women, as well as lower levels of erythrocyte glutathione (GSH) levels than non-pregnant women [41].Furthermore, a longitudinal study consisting of pregnant women at 30 weeks of gestational age showed that, after delivery, their products decreased levels of Ne-carboxymethyl lysine.Also, a soluble receptor for advanced glycation end products (sRAGE) was observed without changes in tumor necrosis factor alpha (TNF-α), CRP, and MDA in blood samples.Their newborns were healthy, but the newborns' levels of sRAGE, TNF-α, and MDA were higher than their mothers at delivery [54].Additionally, factors such as age and race influence OS and inflammation.Older pregnant women (age > 40 years) with uncomplicated pregnancies had lower anti-inflammatory markers, such as interleukin-10 (IL-10) and interleukin-1 receptor antagonist (IL-RA), and an increase in total antioxidant capacity (TAC) than younger pregnant women [55].In Nigerian pregnant women, levels of vitamin E, an endogenous antioxidant, were observed to be lower than in pregnant women from the USA.However, levels of vitamin E depend on the isoform.Thus, in the US population, higher maternal α-tocopherol levels were associated with birth length (>10th percentile), while higher cord levels of α-tocopherol were associated with birth length (<10th percentile); these results were not observed in the Nigerian population, although the levels of delta-tocopherol were higher than maternal samples from the USA [56].
Undoubtedly, OS and inflammation are major factors in the development of diseases that are considered the first cause of death and morbidity in women during pregnancy since they can exacerbate negative conditions for the development of cardiovascular diseases and diabetes [3,57,58].
The inflammatory response during pregnancy is caused by toll-like receptor (TLR) activation, while inducing the activation of the inflammasome complex, to perpetuate the production of cytokines and chemokines in placenta and endometrium, such as monocyte chemotactic protein 1 (MCP-1), IL-8, IL1-β, and IL-6.This TLR activation triggers immune cell recruitment and the production of prostaglandins and MMPs, which leads to cervical cell activation and uterine contractions [59].According to the stage of pregnancy, in vaginal epithelium, exocervix, endocervix, endometrium, and fallopian tubes, TLRs 1-5 induce the release of cytokines, chemokines, and antimicrobial peptides that modulate both proinflammatory and anti-inflammatory responses.Hence, it can promote or attenuate the onset of chronic diseases or adverse clinical conditions (Table 1) [60].
The mechanisms of inflammation suggested at this stage of life involve the role of type 1 and 2 T Helper (Th) cells, where Th1 cells are responsible for increased levels of interferon gamma (IFN-γ), interleukin 2 (IL-2), and tumor necrosis factor beta (TNF-β), which are responsible for phagocyte-dependent inflammation, as well as protection against intracellular pathogens.On the other hand, Th2 cells produce IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13 and induce an antibody response by downregulating B cells and activating eosinophils, thus inhibiting phagocytic cell activity [51].

OS and Inflammation during Pregnancy, Metabolic Changes in Chronic Diseases
Currently, gestational obesity and diabetes are associated with fetal disorders affecting the proteomic profile.An increase in markers of inflammation and OS is observed, as well as a decrease in the antioxidant system or impairment of vasorelaxation [68].All of these characteristics could be linked to the appearance of neonatal hypoglycemia, respiratory distress syndrome, fetal macrosomia, platelet hyperaggregability, or the development of cardiovascular disease early in life [69,70].Also, obesity is associated with a 1.3-to 3.8-fold increase in the incidence of preeclampsia or GDM [59], short-term hemorrhage, low APGAR score, congenital birth defects, and admission to neonatal intensive care [51].Meanwhile, in the long term, an increased risk of cardiovascular disease and diabetes mellitus type 2 (DM2) in children [51,63,71,72].

Preeclampsia
Among the prominent hypertensive disorders in pregnancy is preeclampsia.It is a multifactorial disorder, one of the most common conditions during pregnancy on which hypertension (≥140/90 mmHg) and proteinuria (≥300 mg of protein in 24 h) are predominant, leading to dysfunction in several organs, poor placental development, and even maternal or fetal death [73,74].Preeclampsia regularly develops from the placenta, and its early stages are known as placental syndrome.This syndrome is characterized by endothelial damage and dysfunction in different tissues accompanied by excessive free radical formation [75][76][77].Hence, some potential OS markers such as ischemia-modified albumin (IMA), uric acid (UA), MDA, and metals like zinc (Zn), copper (Cu), and selenium (Se) have been used as diagnostic biomarkers for preeclampsia [10].Inflammatory processes exacerbate the effects of preeclampsia, being IL-1α and IL-1β mainly secreted and expressed in the placenta.However, the involvement of other members of the interleukin family such as IL-18, IL-33, IL-37, and IL-38 has also been described [78].Leakage of trophoblasts into the uterine wall accentuates inflammation and OS, leading to the presence of hypoxia and an increased placental ROS concentration [79] Obesity, preeclampsia, and GDM pregnancy have an altered lipid metabolism, specifically related to low concentrations of lipoproteins and their lipid composition (free and esterified cholesterol, phospholipids, and triglycerides).Therefore, women with these conditions become susceptible to OS, and this results in an inhibition in the production of nitric oxide (NO).NO is an important vasodilator at the endothelial level, and it can lead to hypertensive disorders, ischemia, or stroke [80].

Obesity
A common condition observed is the accumulation of lipids during the first trimester that decreases towards the end of the third trimester.Conversely, lipolysis decreases in the first trimester and increases by the third trimester.Similarly, glucose tolerance and insulin resistance behave in the same way, respectively [105].Moreover, there is a high variability in lipid, protein, and carbohydrate metabolism, which are regulated by immunometabolic and immunoinflammatory processes, including proinflammatory cytokines and ROS production [106,107].Nevertheless, when antioxidant-ROS balance is disturbed, extreme OS occurs, leading to abnormal placentation with increased vascular resistance inside the placenta, thereby allowing OS to overwhelm antioxidants, to shorten telomeres, and, ultimately, to lead to cellular senescence [108].Also, when pregnant women develop preeclampsia, the processes of apoptosis, autophagy, and cellular senescence, which play a critical role in placental and fetal homeostasis and growth, appear disrupted, increasing susceptibility to negative conditions in the fetus and the mother [109].Among the conditions that present an alteration in metabolic and inflammatory processes is obesity, which is a chronic disease considered a risk factor for the development of preeclampsia, GDM, anemia, complications or death in childbirth in women, increased cardiovascular risk, insulin resistance, hyperinsulinemia, and prevalence of inflammatory processes in the neonate [110][111][112].Usually, pregnant women with obesity at pre-pregnancy or becoming obese have a lipotoxic placental environment leading to increased OS and elevated concentrations of TNF-α, IL-1, IL-1β, IL-3, IL-4 and IL-6, and IFN-γ.These cytokines also regulate the activity and expression of placental fatty acid transporters, and, during the second or third trimester, they downregulate some metabolic pathways then increase the levels of total cholesterol, triglycerides, and very low-density lipoproteins (VLDL) [112][113][114].
Clinical studies show increased lipid peroxidation (MDA, LOOH) [115][116][117][118][119] and significant changes in antioxidant status (total antioxidant capacity and antioxidant enzyme activity) in pregnant women with obesity [119][120][121][122][123] during the third trimester of pregnancy (Table 3).Another study has shown an increase in lipid peroxidation and protein carbonylation (PC) in pregnant women with obesity versus controls, only in the third trimester, but not in the first and second trimesters of pregnancy.However, an increase in TNF-α was observed at 12-13 weeks of gestation, also in women with obesity who developed GDM.The ratio of reduced oxidized glutathione (GSH/GSSG) is an indirect marker of redox status [115].In addition, increased antioxidant activity of SOD and CAT was observed in the placenta [122] and umbilical cord [119] of obese women compared to non-obese women, and compared to plasma activities during the third trimester of pregnancy.These results reveal necessary changes to maintain the homeostatic redox state in the placenta and the umbilical cord at the expense of maternal plasma redox.Inflammatory conditions have also been associated with reduced adiponectin levels in the third trimester [117][118][119][120][121][122][123][124].Maternal BMI has been shown to have a significant positive correlation with increased levels of CRP, PC, GSSG/GSH, IL-6 ratio, and salivary CT [117,120,121].These associations could be affected by hyperglycemia [113,116,119] and maternal age [115].The association of mother and newborn in inflammatory and oxidative statuses revealed a positive correlation in the cord SOD activity of newborns with an increased SOD activity of normoglycemic ones.MDA levels in newborns were lower in term neonates and those with mothers who consumed vitamin supplements [119].[121] Additional abbreviations.CP, carbonylated proteins; EWG, excessive weight gain; LOOH, lipohydroperoxides; PWOb, pregnant women with obesity; PWOw, pregnant women with overweight; red NBT, reduced nitroblue tetrazolium.

Gestational Diabetes Mellitus
The most frequent endocrinological complication in pregnancy, worldwide, is obesity, and it plays an important role in the development of GDM.Also, it is related to negative neonatal and obstetric conditions in the mother and infant at both cardiovascular and neurological levels [125,126].Commonly, GDM is defined as an abnormal glucose tolerance that results in the development of hyperglycemia during pregnancy, and it can be triggered by obesity, a variation in adipokine production, and other external conditions, including maternal age, a diet rich in saturated fatty acids, family history of diabetes, and hypertensive processes during pregnancy [127].The molecular pathophysiology of GDM has been extensively investigated.Proteomic studies in plasma from women with GDM have revealed changes in inflammation and OS markers, insulin resistance, blood coagulation, and lipid homeostasis during the second trimester of pregnancy, as well as elevated CRP in the first trimester of women who developed GDM [128] (Table 4).
Inflammatory processes are a key factor in the development of GDM, as increased activity or expression of inflammatory markers negatively alters insulin receptors, resulting in insulin resistance [129].In addition to TNF-α, IL-6, adiponectin, resistin, or leptin that are involved in obesity, other biomarkers are included, such as the retinol-binding protein-4 (RBP-4), visfatin, adipocyte fatty acid-binding protein (AFAABP), and some novel proteins like visceral adipose tissue-derived serpin A12 (vaspin) [130], apelin [131], and omentin, which may be involved in the development of GDM and in the progression of obesity [132].
During the second trimester of pregnancy, OS and inflammation are established in GDM by an increase in F2 isoprostanes [133,134], ROS in lymphocytes [135], total OS, and OS index in serum [134], as well as an increase in the acute phase reactants, which are independent determinants of GDM after adjustment for BMI [135,136] (Table 4).At the end of pregnancy, there is an increase in antioxidant enzymes, like CAT and GSR in placenta [137].In contrast, other studies did not show an increase in protein carbonylation [138] or TBARS [139].However, in studies with a bigger sample size, an increase in MDA, hsCRP, and IL-6 in the plasma of pregnant women with GDM was observed to be associated with stress and postnatal depression [140].
Both GDM and obesity complications constitute independent risk factors that increase problems during delivery and that are associated with an increase in monocyte count in cord blood and with the expression of several genes like the silent information regulator sirtuin 1 (SIRT1) and uncoupling protein 1 (UCP1) in obese pregnant women [139], while growth/differentiation factor 15 (GDF-15) is increased in GDM [141].Also, an increase in mitochondrial DNA levels, but dysfunctional syncytiotrophoblast mitochondria with morphological abnormalities [142], has been observed in the placenta of obese pregnant women who developed GDM.These physical abnormalities could lead to impaired pregnancy outcomes and future hypertensive [143,144] and neurological disorders [145].Additional abbreviations: GDF, growth differentiation factor-15; GSR, glutathione reductase; IGFBP2, insulin-like growth factor-binding protein 2; MGO, methylglyoxal; MVP, mean platelet volume; NLR, neutrophil to lymphocyte ratio; PAF, platelet-activating factor; PCT, procalcitonin; PLR, platelet to lymphocyte ratio; PON, paraoxonase; PPARα, peroxisome proliferator-activated receptors; SIRT1, silent mating type information regulation 2 homolog; UCP2, uncoupling protein 2; VAP-1, vascular adhesion protein-1.

Risk of Preterm Delivery
OS and inflammation induce impairment of placental permeability, producing a hypoxic placenta, which usually leads to activation of the maternal systemic inflammatory response [148].As a consequence, it affects both maternal and placental functions, thereby causing intrauterine growth restriction (IUGR), preterm delivery, gestational diabetes, preeclampsia, and aortic dissection during pregnancy [61,149].Likewise, there is dysregulation in lipid profiles such as sphingomyelin and phosphatidylcholine, which have been associated with inflammatory biomarkers such as TNF-α, IL-6, and CRP [150].

Non-Alcoholic Fatty Liver Disease (NAFLD)
NAFLD is regarded as a hepatic manifestation of metabolic syndrome (MS), which is characterized by elevated levels of saturated fatty acids, polyunsaturated fatty acids, and reduced levels of phospholipids in both the serum and HDL, specifically according to their PUFA fraction.
In both animals and humans, studies have established a relationship between adaption to maternal malnutrition (over or undernutrition), environmental factors, maternal stress, pathology genetics, and epigenetic modifications and early-life and later development of components of MS in offspring, including obesity, insulin resistance, impaired glucose tolerance, dyslipidemia, low HDL-C, increased VLDL-TG, and abnormal liver function such as NAFLD [151,152].Moreover, recent studies on young adults revealed that being born to an obese mother induced perturbations in adipose tissue function and lipid homeostasis, increasing the risk for developing NAFLD in adulthood three-fold [153].
Declining adipose tissue function is a key characteristic in the transition to metabolically unhealthy, hypertrophic obesity.Dysfunctional adipose tissue is characterized by chronic inflammation that may promote injury, increasing oxidative stress, insulin resistance, dysregulated lipolysis, and eventually lipotoxicity combined with ectopic deposition in peripheral organs such as the liver.Therefore, adiposopathy is a key trigger for the onset of obesity-associated hepatic steatosis [154,155].
In this context, exposure to an abnormal intrauterine milieu may be an important risk factor for the development of cardiometabolic diseases in childhood and adulthood.This adaptation to the intrauterine environment has been explained with Barker's theory, also known as the intrauterine programming effect, where the intrauterine environment alters the metabolism of the fetus, redistributes its blood flows to protect important organs such as the brain, and even adapts to slower growth to decrease its substrate demands.On the other hand, those changes can be permanent in the structure and function of the offspring.According to this theory, the growth and development of the fetus are determined by three factors: first, the mother's nutritional status; second, placental function; and third, the ability of the fetus to utilize nutrients [156].

Lipids and Lipoproteins in Pregnancy
Lipid metabolism during pregnancy becomes relevant since lipid concentrations change according to maternal requirements and fetal growth; subsequently, dysregulation of lipid metabolism is associated with endothelial dysfunction or immunological changes [150], while major alterations are found in the concentration of triglycerides and cholesterol and in the number of LDL and HDL particles [157], hyperlipidemia being a common condition even in normal pregnancy that allows glucose and calories to be utilized by the fetus.Nevertheless, it has been reported that maternal lipid levels during pregnancy are significantly correlated with the lipid profile of children during the first years of life [158].Additionally, it is well known that lipid dysregulation is an important risk factor associated with the development of preeclampsia and cardiovascular disease in pregnancy.

Lipoproteins
Lipoproteins are macromolecular complexes composed of hydrophobic lipids such as triglycerides and cholesterol esters on the inside, whereas their surface is formed by amphipathic lipids like phospholipids and free cholesterol.Moreover, there are proteins, known as the apolipoproteins (Apo), providing stability to the surface and conferring part of their own properties [5] (Figure 2).In recent decades, the role that certain lipoproteins play in different chronic-degenerative diseases has sparked interest, especially high-density lipoproteins (HDL).

HDL
High-density lipoproteins (HDL) are complex and heterogeneous structures constituting a lipid transport mechanism.Different components (lipids and proteins) of HDL are continuously being exchanged.As a result, they modify the composition, charge, and size of these particles.Currently, it has been described that HDL particles can similarly transport other compounds (about 250), such as sphingosine-1-phosphate, paraoxonase-1 (PON1), acute phase proteins (SAA) [159], platelet-activating factor acetylhydrolase (PFA-AH) enzymes and proteins, such as cholesterol ester transporter protein (CETP) and phospholipid transporter protein (PLTP), among many other components [160,161].
In this context, HDL has been attributed to exert some cardioprotective properties, including reverse cholesterol transport and antioxidant, anti-inflammatory, and antiatherogenic activities (Table 5) [162][163][164][165].Many of these functions are important for a healthy pregnancy and good neonatal outcomes [166,167].

Proteins and Lipids Associated with HDL Function
Ref.

Reverse cholesterol transport
HDL promotes cholesterol efflux from various cell types.ABCAI, ABCG1, SR-BI, cubilin, ApoE receptor [168,169] Removing excess cholesterol from lipid-laden macrophages is a crucial process in HDL-mediated vascular protection.

HDL
High-density lipoproteins (HDL) are complex and heterogeneous structures constituting a lipid transport mechanism.Different components (lipids and proteins) of HDL are continuously being exchanged.As a result, they modify the composition, charge, and size of these particles.Currently, it has been described that HDL particles can similarly transport other compounds (about 250), such as sphingosine-1-phosphate, paraoxonase-1 (PON1), acute phase proteins (SAA) [159], platelet-activating factor acetylhydrolase (PFA-AH) enzymes and proteins, such as cholesterol ester transporter protein (CETP) and phospholipid transporter protein (PLTP), among many other components [160,161].
In this context, HDL has been attributed to exert some cardioprotective properties, including reverse cholesterol transport and antioxidant, anti-inflammatory, and antiatherogenic activities (Table 5) [162][163][164][165].Many of these functions are important for a healthy pregnancy and good neonatal outcomes [166,167].These positive effects are explained by the structure and chemical composition of these particles.However, it has been shown that these lipoproteins can lose or reduce their cardioprotective capacity, giving rise to prooxidant, proinflammatory, and proatherogenic lipoproteins, contributing to the process of atherosclerosis; this phenomena has been termed "dysfunctional HDL" [173,174].
Some study groups proposed the hypothesis that HDL delivers lipids to cells.For instance, Pérez-Mendez et al. demonstrated that HDL delivers cholesterol and sphingomyelin to endothelial cells in vitro [175].Therefore, the possibility of the regulation of these lipoproteins on cell function after internalization and the delivery of their content is extremely high.Hence, the lipid delivery of HDL to cells becomes of particular importance when cell membranes should be intensively synthesized or re-structured, i.e., during fetal growth.HDL-C plasma levels and composition may change drastically during inflammatory processes.
It has been described that HDL can inhibit the oxidation of other molecules, such as LDL through free radical damage, which results in the generation of oxidized lipids with pro-inflammatory activity [176].Nonetheless, in certain conditions such as obesity, diabetes, and other cardiovascular diseases, it has been observed that HDL loses its protective properties, becoming dysfunctional HDL [168][169][170], and leads to an increase in inflammatory processes and OS in several conditions, including pregnancy (Figure 3) [166,167].
the oxidation of the LDL Vascular function Modulation of endothelial nitric oxide synthase (eNOS) expression, leading to increased nitric oxide (NO) production and vasodilation ABCA1, SR-BI, S1PR, S1P, Apo M [170][171][172] These positive effects are explained by the structure and chemical composition of these particles.However, it has been shown that these lipoproteins can lose or reduce their cardioprotective capacity, giving rise to prooxidant, proinflammatory, and proatherogenic lipoproteins, contributing to the process of atherosclerosis; this phenomena has been termed "dysfunctional HDL" [173,174].
Some study groups proposed the hypothesis that HDL delivers lipids to cells.For instance, Pérez-Mendez et al. demonstrated that HDL delivers cholesterol and sphingomyelin to endothelial cells in vitro [175].Therefore, the possibility of the regulation of these lipoproteins on cell function after internalization and the delivery of their content is extremely high.Hence, the lipid delivery of HDL to cells becomes of particular importance when cell membranes should be intensively synthesized or re-structured, i.e., during fetal growth.HDL-C plasma levels and composition may change drastically during inflammatory processes.
It has been described that HDL can inhibit the oxidation of other molecules, such as LDL through free radical damage, which results in the generation of oxidized lipids with pro-inflammatory activity [176].Nonetheless, in certain conditions such as obesity, diabetes, and other cardiovascular diseases, it has been observed that HDL loses its protective properties, becoming dysfunctional HDL [168][169][170], and leads to an increase in inflammatory processes and OS in several conditions, including pregnancy (Figure 3) [166,167].Given that this is of great relevance in chronic degenerative diseases, the use of bioactive compounds from fruits, vegetables, foods of animal origin, and plants has become an alternative for improving the functionality and chemical composition of HDL.Thus, they are able to regulate the negative effects caused by OS and inflammatory processes.

HDL Role and Upregulation Contribution in Inflammatory Processes and OS
Pregnant women normally experience physiological changes, involving carbohydrate and lipid metabolism, insulin resistance, inflammation, coagulation, and OS, all of them causing endothelial damage [170].Despite this unfavorable environment, pregnant women have better vascular function.Likewise, during embryogenesis and fetal development, the levels of apolipoproteins, lipoproteins, and lipids increase significantly.HDL-C levels change during pregnancy: in the first trimester, changes are insignificant, but, in the second trimester, these changes increase and then slightly decrease in the third trimester.In chronic inflammatory processes, the functional activities of HDL are reduced, the formation of new particles decreases, and catabolism increases.Also, structural changes occur at the protein level, such as the replacement of PON1 or Apo A1 molecules by proinflammatory proteins, including ceruloplasmin and SAA [177,178] that converts HDL to HDL-proinflammatory and results in increased chemoattractant activity, oxidation of LDL, and the release of additional proinflammatory molecules [179,180].In this chronic inflammation, HDL-proinflammatory may accelerate immune responses toward pathogens, due to HDL remodeling.It is well known that immunological changes occurring in pregnancy for improved fetal tolerance lead to an increased susceptibility to infections.In the acute phase response, HDL levels decrease constantly, with an increase in SAA and ceruloplasmin concentration and a respective decrease in PON1 and Apo A1.Consequently, this could be one of the major risk factors during pregnancy (in trimesters of increased inflammatory processes) for the development of diseases or negative conditions.
Furthermore, an important role of HDL in pregnancy has been reported in the reducing of OS levels, both at placental level and in umbilical cord blood, which are mainly associated with PON1 activity [181].An important factor in pregnancy is the higher activity of lipoprotein-associated phospholipase A2 (LpPla2) (mainly LDL and HDL), which is an enzyme synthesized predominantly by macrophages and associated with inflammatory processes and higher triglyceride levels, as well as in conditions of elevated OS such as GDM concentration of LpPla2, which is highly elevated compared to healthy women.However, this enzyme can be associated with HDL because it improves the antioxidant and anti-inflammatory functions of HDL, thereby reducing OS levels in plasma [182].
Another important complication of pregnancy caused by the increase in OS is preeclampsia, which affects both pregnant women and newborns and presents oxidative alterations in both LDL and HDL, caused by lipoperoxidation and inactivation of PON1, potentially leading to improper placentation [183].
It has been shown that a maternal diet rich in saturated and trans fatty acids causes harmful changes in the bacteria that colonize the intestine of the offspring, and these in turn produce metabolites that can subsequently affect different organs.Organic acids produced by intestinal bacteria may be involved in inflammatory mechanisms and play a key role in changes in the metabolism and develop neonatally or in adulthood.A high-fat diet during perinatal life predisposes greater expression of the NF-κB gene, which is a transcription factor of multiple biological processes, including immune and inflammatory responses and cell growth and survival [184,185].
Several studies have suggested that HDL dysfunction is a common pathological factor that connects the metabolic syndrome to NAFLD and cardiovascular disease development.The composition and structure of HDL particles seem to be characterized by the depletion of polyunsaturated fatty acid phospholipids and enrichment of saturated fatty acid ceramides [151,186].In this context, preclinical studies have provided mechanistic insights as to how PUFA (especially essential fatty acids, EFA) deficiency promotes hepatic steatosis.EFA can negatively modulate the hepatic de novo lipogenesis machinery toward the negative modulation of the liver X receptor (LXR) of SREBP-1 and/or of the carbohydrate response element binding protein (ChREBP).Also, PUFA can activate the peroxisome proliferator, activated receptor-alpha (PPARα), and may promote fatty acid oxidation [186].This is strong evidence for the role of PUFAs in modulating hepatic lipid metabolism [151].

Bioactive Compounds and HDL Functionality
Bioactive compounds have been widely studied as mediators of inflammation and OS in several conditions and diseases.Nevertheless, their mechanism of action remains unclear.Some studies describe that they are an important part of the secretion of inflammatory molecules (cytokines, adipokines, etc.), of the mediation of metabolic pathways, or of the regulation of gene expression at the muscle or adipose tissue level [187].Currently, the most commonly studied bioactive compounds are folates [188], polyphenolic compounds [189], polyunsaturated fatty acids [190], prebiotics [191], and probiotics [192], along with their derivatives.
Studies have described that part of the functionality of HDL is linked to its chemical composition.This, in turn, depends on the appearance of some diseases causing HDL dysfunction [193], especially chronic degenerative diseases, which may also change HDL size as well as the number of circulating particles.In DM and coronary heart disease patients, it has been reported that, in addition to Apo A concentration modifications, the presence of OX increases glycoxidation and peroxidation of protein and lipid fractions of HDL, respectively [194][195][196][197].
An alternative way to reverse the mentioned effects is via bioactive compounds from functional foods.It is well documented that foods, for example, fruits and vegetables, fish, legumes, cereals, red wine, and elements of the Mediterranean diet, increase the concentration of HDL, TRC, and antioxidant activity at the same time, increasing the activity and/or expression of paraoxonase-1 (PON1), an atheroprotective enzyme that is bound to HDL [198][199][200].Likewise, it has been reported that foods rich in polyphenols, hydrolysable tannins, and polyunsaturated fatty acids (PUFAs) modify the protein [201] c-HDL, Tg-HDL, and Phos-HDL content of HDL [197,198].
Alternative dietary modifications such as Mediterranean diet [202] seek to enhance HDL functionality via regulation of RCT.On the other hand, olive oil consumption [203] seems to have a similar effect but is attributable to its effect on the size and stability of HDL.For instance, a study based on red yeast rice extract and additional compounds shown to reduce cardiovascular risk in humans, a significant decrease in the lipid profile associated with cardiovascular risk, mainly c-LDL, and an increase in Apo A1 were found in 102 participants.However, there was no significant difference in the levels of c-HDL [204].In contrast, a pilot study of 167 patients with metabolic syndrome features, bioactive compounds such as docosahexaenoic acid, β-glucans, and anthocyanins were proved as components of fortified functional foods, and a significant decrease in triglycerides and an increase in LDL-C were observed [205].Moreover, in a study that evaluated the structure and function of HDL in adults with overweight, obesity, and cardiovascular risk, it was observed that there is a relationship between the decrease in inflammation markers such as IL-6 with sphingosine 1 phosphate (SP1) of HDL under a diet based on a Mediterranean diet [206].
Studies by our research group have demonstrated this: in an animal model as well as in women with acute coronary ischemic syndrome (ACS), by using a microencapsulated product enriched in antioxidants and PUFAs, mainly punicic acid, it was observed that this treatment improved the lipid profile, PON1 activity, and endothelial function mediated by HDL.In ACS women, the dysfunctionality of HDL was reverted by regulating the protein and lipid composition of the smallest subclasses (HDL3) [201,207].Two possible explanations for these results suggest that bioactive compounds present in this microencapsulated product could remodel alterations in HDL under conditions of dyslipidemia, OS, and inflammation.Also, another possible explanation is that HDL acts as a vector for bioactive compounds, enhancing its bioavailability and potentially increasing its health benefits.

Conclusions
Health in pregnant women is of great relevance in preventing cardiometabolic diseases in offspring.In this context, the properties of HDL, like removing oxidized lipids, carrying bioactive compounds, inhibiting expression and activity of pro-inflammatory molecules, lipid transport or regulation of lipid metabolism, are important during pregnancy to progress to childbirth without complications, in addition to promoting placentation and healthy development of the fetus.Moreover, processes of lipoperoxidation, glycoxidation, and the release of pro-inflammatory molecules, which may possibly be reverted by the interaction and transport of bioactive compounds that are present in foods, characterize diseases such as preeclampsia, diabetes, and gestational obesity during pregnancy.However, more studies are needed in order to find therapies that regulate metabolic processes to prevent diseases and to ensure a healthy pregnancy.

Figure 1 .
Figure 1.Inflammation and OS processes during and after pregnancy.

Figure 1 .
Figure 1.Inflammation and OS processes during and after pregnancy.

Figure 3 .
Figure 3. Functional and dysfunctional HDL during pregnancy.Figure 3. Functional and dysfunctional HDL during pregnancy.

Figure 3 .
Figure 3. Functional and dysfunctional HDL during pregnancy.Figure 3. Functional and dysfunctional HDL during pregnancy.

Table 1 .
Pregnancy phases and inflammation.

Table 2 .
Markers of OS and inflammation in pregnant women with preeclampsia.

Table 2 .
CRP of PE is similar to non-PE at the end of pregnancy ↑ TNF-α in PE across pregnancy and ↑ 8-isoprostane in PE in early gestation.No changes in IL-1, IL-6, IL-10 and 8-OHdG Cont.Plasmatic and urinary 8-iso-prostane in PE and Ctrl vs. non-PW but not in PE vs. Ctrl ↓ α-tocopherol in PE and Ctrl vs. Non PW γ-tocopherol decreased in PE vs. Ctrl and vs.

Table 3 .
Markers of OS and inflammation in pregnant women with obesity.

Table 4 .
Inflammation and OS markers in pregnant women with GDM.