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Melatonin is a hormone that regulates sleep–wake cycles and is mainly synthesized in the pineal gland from tryptophan after its conversion into serotonin. Under normal conditions, less than 5% of tryptophan is reserved for the synthesis of serotonin and melatonin. The remaining 95% is metabolized in the liver through the kynurenine pathway. Increased levels of proinflammatory cytokines and cortisol increase the metabolism of tryptophan through the kynurenine pathway and reduce its availability for the synthesis of melatonin and serotonin, which may cause alterations in mood and sleep. The standardized saffron extract (affron®) has shown beneficial effects on mood and sleep disorders in humans, but the underlying mechanisms are not well understood. Thus, the aim of this work was to study the effects of affron® supplementation on the kynurenine pathway and the synthesis of melatonin in rats. For this purpose, adult male Wistar rats were supplemented for 7 days with 150 mg/kg of affron® or vehicle (2 mL/kg water) administered by gavage one hour before sleep. Affron® supplementation reduced body weight gain and increased the circulating levels of melatonin, testosterone, and c-HDL. Moreover, animals supplemented with affron® showed decreased serum levels of kynurenine, ET-1, and c-LDL. In the pineal gland, affron® reduced Il-6 expression and increased the expression of Aanat, the key enzyme for melatonin synthesis. In the liver, affron® administration decreased the mRNA levels of the enzymes of the kynurenine pathway Ido-2, Tod-2, and Aadat, as well as the gene expression of Il-1β and Tnf-α. Finally, rats treated with affron® showed increased mRNA levels of the antioxidant enzymes Ho-1, Sod-1, Gsr, and Gpx-3, both in the liver and in the pineal gland. In conclusion, affron® supplementation reduces kynurenine levels and promotes melatonin synthesis in rats, possibly through its antioxidant and anti-inflammatory effects, making this extract a possible alternative for the treatment and/or prevention of mood and sleep disorders.

Abstract Olive leaves are rich in bioactive substances which exert anti-inflammatory, antioxidant, insulin-sensitizing and antihypertensive effects. The aim of this study was to analyze the possible beneficial effects of an olive leaf extract (OLE) rich in secoiridoids and phenolic compounds on the aging-induced metabolic and vascular alterations. Three experimental groups of rats were used: 3-month-old rats, 24-month-old rats and 24-month-old rats supplemented 21 days with OLE (100 mg/kg). Administration of OLE to aged rats decreased the weight of adrenal glands and prevented the aging-induced loss of body weight and muscle mass. In the serum, OLE reduced the circulating levels of LDL-cholesterol and IL-6 and increased the concentrations of leptin and adiponectin. In the liver OLE attenuated the decreased gene expression of SOD-1, GSR, GCK and GSK-3β and reduced the aging-induced overexpression of NOX-4, Alox-5, iNOS and TNF-α. In aorta segments, OLE prevented endothelial dysfunction and vascular insulin resistance and improved vasoconstriction in response to KCl and NA. Improvement in vascular function was associated with the attenuation of the alterations in the gene expression of COX-2, IL-6, GPx, NOX-1 and IL-10. In conclusion, OLE exerts anti-inflammatory and antioxidant effects in aged rats and attenuates the alterations in vascular function associated with aging.

Nutraceuticals are products of natural origin widely used for the treatment and/or prevention of some chronic diseases that are highly prevalent in Western countries, such as obesity or type II diabetes, among others. However, its possible use in the prevention of acute diseases that can put life at risk has been poorly studied. Sepsis is an acute condition that causes cardiovascular and skeletal muscle damage due to a systemic inflammatory state. The aim of this work was to evaluate the possible beneficial effect of a new nutraceutical based on a mixture of algae oil (AO) and extra virgin olive oil (EVOO) supplemented with an olive leaf extract (OLE) in the prevention of cardiovascular alterations and skeletal muscle disorders induced by sepsis in rats. For this purpose, male Wistar rats were treated with the nutraceutical or with water p.o. for 3 weeks and after the treatment they were injected with 1mg/kg LPS twice (12 and 4 h before sacrifice). Pretreatment with the nutraceutical prevented the LPS-induced decrease in cardiac contractility before and after the hearts were subjected to ischemia-reperfusion. At the vascular level, supplementation with the nutraceutical did not prevent hypotension in septic animals, but it attenuated endothelial dysfunction and the increased response of aortic rings to the vasoconstrictors norepinephrine and angiotensin-II induced by LPS. The beneficial effects on cardiovascular function were associated with an increased expression of the antioxidant enzymes SOD-1 and GSR in cardiac tissue and SOD-1 and Alox-5 in arterial tissue. In skeletal muscle, nutraceutical pretreatment prevented LPS-induced muscle proteolysis and autophagy and significantly increased protein synthesis as demonstrated by decreased expression of MURF-1, atrogin-1, LC3b and increased MCH-I and MCH -IIa in gastrocnemius muscle. These effects were associated with a decrease in the expression of TNFα, HDAC4 and myogenin. In conclusion, treatment with a new nutraceutical based on a mixture of AO and EVOO supplemented with OLE is useful to prevent cardiovascular and muscular changes induced by sepsis in rats. Thus, supplementation with this nutraceutical may constitute an interesting strategy to reduce the severity and mortality risk in septic patients.

The low oxidative stability of polyunsaturated fatty acids (PUFA) in omega-3 supplements may cause the formation of compounds that may have negative healthy effects. Extra virgin olive oil (EVOO) contains high content of monounsaturated fatty acids (MUFA) and polyphenols, which might improve PUFA oxidative stability when combined with vegetable oils enriched in them. In order to prevent the formation of oxidized compounds and improve the shelf-life of PUFA, different proportions of EVOO (enriched in oleic acid and polyphenols) and algae oil (AO) were studied. For this purpose, both pure oils combined in different proportions were stored under accelerated degradation conditions (40 and 55 °C) for 70 days. Correlations and significant changes in levels of fatty acids composition, phenolic components and oxidation rates during storage time were studied. Throughout storage, higher EVOO quantity at the final mixture was related with less PUFA degradation, where a 27.53% decrease in PUFA of AO passed to less than 12% in a resulting oil of at least 75% of EVOO. PUFA concentration correlated with the formation of secondary peroxides, while MUFA content from EVOO produced a reduction in PUFA degradation. In addition, high secoiridoid levels in mixtures decreased the hydrolysis of triglycerides over the time.

Carob, the fruit of Ceratonia siliqua L. exerts antidiabetic, anti-inflammatory, and antioxidant effects and could be a useful strategy for the treatment and/or prevention of metabolic syndrome (MetS). The aim of this study was to analyze whether supplementation with a carob fruit extract (CSAT+®), alone or in combination with aerobic training, accelerates the recovery of cardiometabolic health in mice with MetS subjected to a caloric restriction. For this purpose, mice were fed with a high fat (58% kcal from fat)/high sugar diet for 23 weeks to induce MetS. During the next two weeks, mice with MetS were switched to a diet with a lower caloric content (25% kcal from fat) supplemented or not with CSAT+® (4.8%) and/or subjected to aerobic training. Both caloric reduction and aerobic training improved the lipid profile and attenuated MetS-induced insulin resistance measured as HOMA-IR. However, only supplementation with CSAT+® enhanced body weight loss, increased the circulating levels of adiponectin, and lowered the plasma levels of IL-6. Moreover, CSAT+® supplementation was the only effective strategy to reduce the weight of epidydimal adipose tissue and to improve insulin sensitivity in the liver and in skeletal muscle. Although all interventions improved endothelial function in aorta segments, only supplementation with CSAT+® reduced obesity-induced hypertension, prevented endothelial dysfunction in mesenteric arteries, and decreased the vascular response of aorta segments to the vasoconstrictor AngII. The beneficial cardiometabolic effects of CSAT+® supplementation, alone or in combination with aerobic training, were associated with decreased mRNA levels of pro-inflammatory markers such as MCP-1, TNFα, IL-1β, and IL-6 and with increased gene expression of antioxidant enzymes, such as GSR, GPX-3, and SOD-1 in the liver, gastrocnemius, retroperitoneal adipose tissue, and aorta. In conclusion, supplementation with CSAT+®, alone or in combination with aerobic training, to mice with MetS subjected to caloric restriction for two weeks enhances body weight loss, improves the lipid profile and insulin sensitivity, and exerts antihypertensive effects through its anti-inflammatory and antioxidant properties.

Olive-derived products, such as virgin olive oil (EVOO) and/or olive leaf extracts (OLE), exert anti-inflammatory, insulin-sensitizing and antihypertensive properties and may be useful for stabilizing omega 3 fatty acids (n-3 PUFA) due to their high content in antioxidant compounds. In this study, the addition of OLE 4:0.15 (w/w) to a mixture of algae oil (AO) rich in n-3 PUFA and EVOO (25:75, w/w) prevents peroxides formation after 12 months of storage at 30 °C. Furthermore, the treatment with the oil mixture (2.5 mL/Kg) and OLE (100 mg/Kg) to 24 month old Wistar rats for 21 days improved the lipid profile, increased the HOMA-IR and decreased the serum levels of miRNAs 21 and 146a. Treatment with this new nutraceutical also prevented age-induced insulin resistance in the liver, gastrocnemius and visceral adipose tissue by decreasing the mRNA levels of inflammatory and oxidative stress markers. Oil mixture + OLE also attenuated the age-induced alterations in vascular function and prevented muscle loss by decreasing the expression of sarcopenia-related markers. In conclusion, treatment with a new nutraceutical based on a mixture of EVOO, AO and OLE is a useful strategy for improving the stability of n-3 PUFA in the final product and to attenuate the cardiometabolic and muscular disorders associated with aging.

Aging is associated with increased visceral adiposity and a decrease in the amount of brown adipose tissue and muscle mass, known as sarcopenia, which results in the development of metabolic alterations such as insulin resistance. In this study, we aimed to analyze whether 3-week supplementation with a phenolic-rich olive leaf extract (OLE) to 24 months-old male Wistar rats orally (100 mg/kg) attenuated the aging-induced alterations in body composition and insulin resistance. OLE treatment increased brown adipose tissue and attenuated the aging-induced decrease in protein content and gastrocnemius weight. Treatment with OLE prevented the aging-induced increase in the expression of PPAR-γ in visceral and brown adipose tissues, while it significantly increased the expression of PPAR-α in the gastrocnemius of old rats and reduced various markers related to sarcopenia such as myostatin, HDAC-4, myogenin and MyoD. OLE supplementation increased insulin sensitivity in explants of gastrocnemius and epididymal visceral adipose tissue from aged rats through a greater activation of the PI3K/Akt pathway, probably through the attenuation of inflammation in both tissues. In conclusion, supplementation with OLE prevents the loss of muscle mass associated with aging and exerts anti-inflammatory and insulin-sensitizing effects on adipose tissue and skeletal muscle.

Aging is one of the major risk factors for suffering cardiovascular and metabolic diseases. Due to the increase in life expectancy, there is a strong interest in the search for anti-aging strategies to treat and prevent these aging-induced disorders. Both omega 3 polyunsaturated fatty acids (ω-3 PUFA) and extra virgin olive oil (EVOO) exert numerous metabolic and cardiovascular benefits in the elderly. In addition, EVOO constitutes an interesting ingredient to stabilize ω-3 PUFA and decrease their oxidation process due to its high content in antioxidant compounds. ω-3 PUFA are commonly obtained from fish. However, more ecological and sustainable sources, such as algae oil (AO) can also be used. In this study, we aimed to study the possible beneficial effect of an oil mixture composed by EVOO (75%) and AO (25%) rich in ω-3 PUFA (35% docosahexaenoic acid (DHA) and 20% eicosapentaenoic acid (EPA)) on the cardiometabolic alterations associated with aging. For this purpose; young (three months old) and old (24 months old) male Wistar rats were treated with vehicle or with the oil mixture (2.5 mL/kg) for 21 days. Treatment with the oil mixture prevented the aging-induced increase in the serum levels of saturated fatty acids (SFA) and the aging-induced decrease in the serum concentrations of mono-unsaturated fatty acids (MUFA). Old treated rats showed increased serum concentrations of EPA and DHA and decreased HOMA-IR index and circulating levels of total cholesterol, insulin and IL-6. Treatment with the oil mixture increased the mRNA levels of antioxidant and insulin sensitivity-related enzymes, as well as reduced the gene expression of pro-inflammatory markers in the liver and in cardiac and aortic tissues. In addition, the treatment also prevented the aging-induced endothelial dysfunction and vascular insulin resistance through activation of the PI3K/Akt pathway. Moreover, aortic rings from old rats treated with the oil mixture showed a decreased response to the vasoconstrictor AngII. In conclusion, treatment with a mixture of EVOO and AO improves the lipid profile, insulin sensitivity and vascular function in aged rats and decreases aging-induced inflammation and oxidative stress in the liver, and in the cardiovascular system. Thus, it could be an interesting strategy to deal with cardiometabolic alterations associated with aging.

The incidence of metabolic syndrome (MetS) is increasing worldwide which makes necessary the finding of new strategies to treat and/or prevent it. The aim of this study was to analyze the possible beneficial effects of a carob fruit extract (CSAT+®) on the cardiometabolic alterations associated with MetS in mice. 16-week-old C57BL/6J male mice were fed for 26 weeks either with a standard diet (chow) or with a diet rich in fats and sugars (HFHS), supplemented or not with 4.8% of CSAT+®. CSAT+® supplementation reduced blood glucose, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and circulating levels of total cholesterol, low-density lipoprotein (LDL) cholesterol (LDL-c), insulin, and interleukin-6 (IL-6). In adipose tissue and skeletal muscle, CSAT+® prevented MetS-induced insulin resistance, reduced macrophage infiltration and the expression of pro-inflammatory markers, and up-regulated the mRNA levels of antioxidant markers. Supplementation with CSAT+® prevented MetS-induced hypertension and decreased the vascular response of aortic rings to angiotensin II (AngII). Moreover, treatment with CSAT+® attenuated endothelial dysfunction and increased vascular sensitivity to insulin. In the heart, CSAT+® supplementation reduced cardiomyocyte apoptosis and prevented ischemia-reperfusion-induced decrease in cardiac contractility. The beneficial effects at the cardiovascular level were associated with a lower expression of pro-inflammatory and pro-oxidant markers in aortic and cardiac tissues.