The isoproterenol-induced myocardial fibrosis: A biochemical and histological investigation.

The isoproterenol (ISO)-induced myocardial fibrosis is considered a reliable and repeatable experimental model characterized by a relatively low mortality rate. Although is well-known that ISO stimulates the ß1 adrenergic receptors at the myocardial level, a high degree of heterogeneity emerges around the doses and duration of the treatment generating unclear results. Therefore, we propose to gain insights into the progression of ISO-induced myocardial fibrosis, in order to critically analyze and optimize the experimental model. Male Wistar rats (12-14-week-old) were submitted to subcutaneous injection of ISO, in particular, two doses were selected: the commonly used dose of 5 mg/kg and a lower dose of 1 mg/kg, administered for 3 and 6 days. Biochemical and histological examinations were conducted either immediately after the last administration or after a recovering period of 7 or 14 days from the initial administration. Noteworthy, from our investigation emerged that even the lower dose of ISO was able to induce the maximal biochemical and histological alterations, suggesting that lower doses should be considered to control the progression of the damage more precisely and to identify a prodromic phase in which intervention with pharmacological or nutraceutical tools can be effectively attempted.

Improved Cardiovascular Effects of a Novel Pomegranate Byproduct Extract Obtained through Hydrodynamic Cavitation.

The healthy properties of pomegranate fruit, a highly consumed food, have been known for a long time. However, the pomegranate supply chain is still rather inefficient, with the non-edible fraction, whose weight is roughly half the total and is endowed with plenty of valuable bioactive compounds, either disposed of or underutilized. A novel extract obtained from non-edible byproducts (called PPE), using hydrodynamic cavitation, a green, efficient, and scalable technique, was investigated for its cardiovascular effects in vivo. PPE showed efficacy in an acute phenylephrine (PE)-induced hypertensive rat model, similar to the extract of whole fruit (PFE) obtained using the same extractive technique, along with good intestinal bioaccessibility after oral administration. Finally, when chronically administered for 6 weeks to spontaneously hypertensive rats, PPE was shown to significantly contain the increase in systolic blood pressure, comparable to the reference drug Captopril, and at a dose remarkably lower than the reported effective dose of ellagic acid. The extract from the non-edible fraction of the pomegranate fruit also showed good anti-inflammation and anti-fibrotic effects. The findings of this study, along with the extraction technique, could contribute to enhancing the value of the pomegranate supply chain, relieve the related environmental burden, and potentially improve public health.

Role of hydrogen sulfide in the regulation of lipid metabolism: Implications on cardiovascular health.

The World Health Organization (WHO) defines obesity as an urgency for health and a social emergency. Today around 39 % of people is overweight, of these over 13 % is obese. It is well-consolidated that the adipose cells are deputy to lipid storage under caloric excess; however, despite the classical idea that adipose tissue has exclusively a passive function, now it is known to be deeply involved in the regulation of systemic metabolism in physiological as well as under obesogenic conditions, with consequences on cardiovascular health. Beside two traditional types of adipose cells (white and brown), recently the beige one has been highlighted as the consequence of the healthy remodeling of white adipocytes, confirming their metabolic adaptability. In this direction, pharmacological, nutraceutical and nutrient-based approaches are addressed to positively influence inflammation and metabolism, thus contributing to reduce the obese-associated cardiovascular risk. In this scenario, hydrogen sulfide emerges as a new mediator that may regulate crucial targets involved in the regulation of metabolism. The current evidence demonstrates that hydrogen sulfide may induce peroxisome proliferator activated receptor γ (PPARγ), a crucial mediator of adipogenesis, inhibit the phosphorylation of perlipin-1 (plin-1), a protein implicated in the lipolysis, and finally promote browning process, through the release of irisin from skeletal muscle. The results summarized in this review suggest an important role of hydrogen sulfide in the regulation of metabolism and in the prevention/treatment of obese-associated cardiovascular diseases and propose new insight on the putative mechanisms underlying the release of hydrogen sulfide or its biosynthesis, delineating a further exciting field of application.

Role of mitochondrial potassium channels in ageing.

Ageing is described as an inevitable decline in body functions over time and an increase in susceptibility to age-related diseases. Therefore, the increase of life expectancy is also viewed as a condition in which many elderly will develop age-related diseases and disabilities, such as cardiovascular, metabolic, neurological and oncological ones. Currently, several recognized cellular hallmarks of senescence are taken in consideration to evaluate the level of biological ageing and are the topic to plan preventive/curative anti-ageing interventions, including genomic instability, epigenetic alterations, and mitochondrial dysfunction. In this scenario, alterations in the function/expression of mitochondrial ion channels have been found in ageing and associated to an impairment of calcium cycling and a reduced mitochondrial membrane potential. Although several ion channels have been described at mitochondrial level, undoubtedly the mitochondrial potassium (mitoK) channels are the most investigated. Therefore, this review summarized the evidence that sheds to light a correlation between age-related diseases and alteration of mitoK channels, focusing the attention of the main age-related diseases, i.e. cardiovascular, neurological and oncological ones.

Sirtuin 1-activating derivatives belonging to the anilinopyridine class displaying in vivo cardioprotective activities.

Sirtuin 1 (SIRT1) is an enzyme that relies on NAD+ cofactor and functions as a deacetylase. It has been associated with various biological and pathological processes, including cancer, diabetes, and cardiovascular diseases. Recent studies have shown that compounds that activate SIRT1 exhibit protective effects on the heart. Consequently, targeting SIRT1 has emerged as a viable approach to treat cardiovascular diseases, leading to the identification of several SIRT1 activators derived from natural or synthetic sources. In this study, we developed anilinopyridine-based SIRT1 activators that displayed significantly greater potency in activating SIRT1 compared to the reference compound resveratrol, as demonstrated in enzymatic assays. In particular, compounds 8 and 10, representative 6-aryl-2-anilinopyridine derivatives from this series, were further investigated pharmacologically and found to reduce myocardial damage caused by occlusion and subsequent reperfusion in vivo, confirming their cardioprotective properties. Notably, the cardioprotective effects of 8 and 10 were significantly superior to that of resveratrol. Significantly, compound 10 emerged as the most potent among the tested compounds, demonstrating the ability to substantially decrease the size of the ischemic area at a dosage one hundred times lower (0.1 mg kg-1) than that of resveratrol/compound 1. These promising findings open avenues for expanding and optimizing this chemical class of potent SIRT1 activators as potential agents for cardioprotection.

Erucin Exerts Cardioprotective Effects on Ischemia/Reperfusion Injury through the Modulation of mitoKATP Channels.

Modulation of mitochondrial K channels represents a pharmacological strategy to promote cardioprotective effects. Isothiocyanates emerge as molecules capable of releasing hydrogen sulfide (H2S), an endogenous pleiotropic gasotransmitter responsible for anti-ischemic cardioprotective effects also through the involvement of mitoK channels. Erucin (ERU) is a natural isothiocyanate resulting from the enzymatic hydrolysis of glucosinolates (GSLs) present in Eruca sativa Mill. seeds, an edible plant of the Brassicaceae family. In this experimental work, the specific involvement of mitoKATP channels in the cardioprotective effect induced by ERU was evaluated in detail. An in vivo preclinical model of acute myocardial infarction was reproduced in rats to evaluate the cardioprotective effect of ERU. Diazoxide was used as a reference compound for the modulation of potassium fluxes and 5-hydroxydecanoic acid (5HD) as a selective blocker of KATP channels. Specific investigations on isolated cardiac mitochondria were carried out to evaluate the involvement of mitoKATP channels. The results obtained showed ERU cardioprotective effects against ischemia/reperfusion (I/R) damage through the involvement of mitoKATP channels and the consequent depolarizing effect, which in turn reduced calcium entry and preserved mitochondrial integrity.

Anti-Proliferative Properties of the Novel Hybrid Drug Met-ITC, Composed of the Native Drug Metformin with the Addition of an Isothiocyanate H2S Donor Moiety, in Different Cancer Cell Lines.

Metformin (Met) is the first-line therapy in type 2 diabetes mellitus but, in last few years, it has also been evaluated as anti-cancer agent. Several pathways, such as AMPK or PI3K/Akt/mTOR, are likely to be involved in the anti-cancer Met activity. In addition, hydrogen sulfide (H2S) and H2S donors have been described as anti-cancer agents affecting cell-cycle and inducing apoptosis. Among H2S donors, isothiocyanates are endowed with a further anti-cancer mechanism: the inhibition of the histone deacetylase enzymes. On this basis, a hybrid molecule (Met-ITC) obtained through the addition of an isothiocyanate moiety to the Met molecule was designed and its ability to release Met has been demonstrated. Met-ITC exhibited more efficacy and potency than Met in inhibiting cancer cells (AsPC-1, MIA PaCa-2, MCF-7) viability and it was less effective on non-tumorigenic cells (MCF 10-A). The ability of Met-ITC to release H2S has been recorded both in cell-free and in cancer cells assays. Finally, its ability to affect the cell cycle and to induce both early and late apoptosis has been demonstrated on the most sensitive cell line (MCF-7). These results confirmed that Met-ITC is a new hybrid molecule endowed with potential anti-cancer properties derived both from Met and H2S.

Plants and Mushrooms as Possible New Sources of H2S Releasing Sulfur Compounds.

Hydrogen sulfide (H2S), known for many decades exclusively for its toxicity and the smell of rotten eggs, has been re-discovered for its pleiotropic effects at the cardiovascular and non-cardiovascular level. Therefore, great attention is being paid to the discovery of molecules able to release H2S in a smart manner, i.e., slowly and for a long time, thus ensuring the maintenance of its physiological levels and preventing "H2S-poor" diseases. Despite the development of numerous synthetically derived molecules, the observation that plants containing sulfur compounds share the same pharmacological properties as H2S led to the characterization of naturally derived compounds as H2S donors. In this regard, polysulfuric compounds occurring in plants belonging to the Alliaceae family were the first characterized as H2S donors, followed by isothiocyanates derived from vegetables belonging to the Brassicaceae family, and this led us to consider these plants as nutraceutical tools and their daily consumption has been demonstrated to prevent the onset of several diseases. Interestingly, sulfur compounds are also contained in many fungi. In this review, we speculate about the possibility that they may be novel sources of H2S-donors, furnishing new data on the release of H2S from several selected extracts from fungi.

An Overview of the Health Benefits, Extraction Methods and Improving the Properties of Pomegranate.

Pomegranate (Punica granatum L.) is a polyphenol-rich edible food and medicinal plant of ancient origin, containing flavonols, anthocyanins, and tannins, with ellagitannins as the most abundant polyphenols. In the last decades, its consumption and scientific interest increased, due to its multiple beneficial effects. Pomegranate is a balausta fruit, a large berry surrounded by a thick colored peel composed of exocarp and mesocarp with edible arils inside, from which the pomegranate juice can be produced by pressing. Seeds are used to obtain the seed oil, rich in fatty acids. The non-edible part of the fruit, the peel, although generally disposed as a waste or transformed into compost or biogas, is also used to extract bioactive products. This review summarizes some recent preclinical and clinical studies on pomegranate, which highlight promising beneficial effects in several fields. Although further insight is needed on key aspects, including the limited oral bioavailability and the role of possible active metabolites, the ongoing development of suitable encapsulation and green extraction techniques enabling the valorization of waste pomegranate products point to the great potential of pomegranate and its bioactive constituents as dietary supplements or adjuvants in therapies of cardiovascular and non-cardiovascular diseases.

Flavonoids as new regulators of mitochondrial potassium channels: contribution to cardioprotection.

OBJECTIVES: Acute myocardial ischemia is one of the major causes of illness in western society. Reduced coronary blood supply leads to cell death and loss of cardiomyocyte population, resulting in serious and often irreversible consequences on myocardial function. Mitochondrial potassium (mitoK) channels have been identified as fine regulators of mitochondrial function and, consequently, in the metabolism of the whole cell, and in the mechanisms underlying the cardioprotection. Interestingly, mitoK channels represent a novel putative target for treating cardiovascular diseases, particularly myocardial infarction, and their modulators represent an interesting tool for pharmacological intervention. In this review, we took up the challenge of selecting flavonoids that show cardioprotective properties through the activation of mitoK channels. KEY FINDINGS: A brief overview of the main information on mitoK channels and their participation in the induction of cytoprotective processes was provided. Then, naringenin, quercetin, morin, theaflavin, baicalein, epigallocatechin gallate, genistein, puerarin, luteolin and proanthocyanidins demonstrated to be effective modulators of mitoK channels activity, mediating many beneficial effects. SUMMARY: The pathophysiological role of mitoK channels has been investigated as well as the impact of flavonoids on this target with particular attention to their potential role in the prevention of cardiovascular disorders.

Anti-Inflammatory Effect of the Natural H2S-Donor Erucin in Vascular Endothelium.

Vascular inflammation (VI) represents a pathological condition that progressively affects the integrity and functionality of the vascular wall, thus leading to endothelial dysfunction and the onset of several cardiovascular diseases. Therefore, the research of novel compounds able to prevent VI represents a compelling need. In this study, we tested erucin, the natural isothiocyanate H2S-donor derived from Eruca sativa Mill. (Brassicaceae), in an in vivo mouse model of lipopolysaccharide (LPS)-induced peritonitis, where it significantly reduced the amount of emigrated CD11b positive neutrophils. We then evaluated the anti-inflammatory effects of erucin in LPS-challenged human umbilical vein endothelial cells (HUVECs). The pre-incubation of erucin, before LPS treatment (1, 6, 24 h), significantly preserved cell viability and prevented the increase of reactive oxygen species (ROS) and tumor necrosis factor alpha (TNF-α) levels. Moreover, erucin downregulated endothelial hyperpermeability and reduced the loss of vascular endothelial (VE)-Cadherin levels. In addition, erucin decreased vascular cell adhesion molecule 1 (VCAM-1), cyclooxygenase-2 (COX-2) and microsomal prostaglandin E-synthase 1 (mPGES-1) expression. Of note, erucin induced eNOS phosphorylation and counteracted LPS-mediated NF-κB nuclear translocation, an effect that was partially abolished in the presence of the eNOS inhibitor L-NAME. Therefore, erucin can control endothelial function through biochemical and genomic positive effects against VI.

Luteolin-Induced Activation of Mitochondrial BKCa Channels: Undisclosed Mechanism of Cytoprotection.

Luteolin (LUT) is a well-known flavonoid that exhibits a number of beneficial properties. Among these, it shows cardioprotective effects, as confirmed by numerous studies. However, its effect on mitochondrial potassium channels, the activation of which is related to cytoprotection, as well as on heart ischemia/reperfusion (I/R) damage prevention, has not yet been investigated. The large conductance calcium-regulated potassium channel (mitoBKCa) has been identified in both the mitochondria of the vascular endothelial cells, which plays a significant role in the functioning of the cardiovascular system under oxidative stress-related conditions, and in the mitochondria of cardiomyocytes, where it is deeply involved in cardiac protection against I/R injury. Therefore, the aim of this study was to explore the role of the mitoBKCa channel in luteolin-induced cytoprotection. A number of in vitro, in vivo, ex vivo and in silico studies have confirmed that luteolin activates this channel in the mitochondria of cardiomyocytes and endothelial cells, which in turn leads to the protection of the endothelium and a significant reduction in the extent of damage resulting from myocardial infarction, where this effect was partially abolished by the mitoBKCa channel blocker paxilline. In conclusion, these results suggest that luteolin has cardioprotective effects, at least in part, through the activation of the mitoBKCa channel, shedding light on a new putative mechanism of action.

Sirtuin 1-Activating Compounds: Discovery of a Class of Thiazole-Based Derivatives.

Sirtuin 1 (SIRT1) is a NAD+-dependent deacetylase implicated in various biological and pathological processes, including cancer, diabetes, and cardiovascular diseases. In recent years, SIRT1-activating compounds have been demonstrated to exert cardioprotective effects. Therefore, this enzyme has become a feasible target to treat cardiovascular diseases, and many SIRT1 activators, of a natural or synthetic origin, have been identified. In the present work, we developed thiazole-based SIRT1 activators, which showed remarkably higher SIRT1 activation potencies compared with those of the reference compound resveratrol when tested in enzymatic assays. Thiazole 8, a representative compound of this series, was also subjected to further pharmacological investigations, where it was proven to reduce myocardial damage induced by an in vivo occlusion/reperfusion event, thus confirming its cardioprotective properties. In addition, the cardioprotective effect of compound 8 was significantly higher than that of resveratrol. Molecular modeling studies suggest the binding mode of these derivatives within SIRT1 in the presence of the p53-AMC peptide. These promising results could pave the way to further expand and optimize this chemical class of new and potent SIRT1 activators as potential cardioprotective agents.

Cardioprotective Effects of Grapefruit IntegroPectin Extracted via Hydrodynamic Cavitation from By-Products of Citrus Fruits Industry: Role of Mitochondrial Potassium Channels.

Citrus flavonoids are well-known for their beneficial effects at the cardiovascular and cardio-metabolic level, but often the encouraging in vitro results are not confirmed by in vivo approaches; in addition, the clinical trials are also inconsistent. Their limited bioavailability can be, at least in part, the reason for these discrepancies. Therefore, many efforts have been made towards the improvement of their bioavailability. Hydrodynamic cavitation methods were successfully applied to the extraction of byproducts of the Citrus fruits industry, showing high process yields and affording stable phytocomplexes, known as IntegroPectin, endowed with great amounts of bioactive compounds and high water solubility. The cardioprotective effects of grapefruit IntegroPectin were evaluated by an ex vivo ischemia/reperfusion protocol. Further pharmacological characterization was carried out to assess the involvement of mitochondrial potassium channels. Grapefruit IntegroPectin, where naringin represented 98% of the flavonoids, showed anti-ischemic cardioprotective activity, which was better than pure naringenin (the bioactive aglycone of naringin). On cardiac-isolated mitochondria, this extract confirmed that naringenin/naringin were involved in the activation of mitochondrial potassium channels. The hydrodynamic cavitation-based extraction confirmed a valuable opportunity for the exploitation of Citrus fruits waste, with the end product presenting high levels of Citrus flavonoids and improved bioaccessibility that enhances its nutraceutical and economic value.

The Efficacy of Camelina sativa Defatted Seed Meal against Colitis-Induced Persistent Visceral Hypersensitivity: The Relevance of PPAR α Receptor Activation in Pain Relief.

Brassicaceae are natural sources of bioactive compounds able to promote gut health. Belonging to this plant family, Camelina sativa is an ancient oil crop rich in glucosinolates, polyunsaturated fatty acids, and antioxidants that is attracting renewed attention for its nutraceutical potential. This work aimed at investigating the therapeutic effects of a defatted seed meal (DSM) of Camelina sativa on the colon damage and the persistent visceral hypersensitivity associated with colitis in rats. Inflammation was induced by the intrarectal injection of 2,4-dinitrobenzenesulfonic acid (DNBS). The acute administration of Camelina sativa DSM (0.1-1 g kg-1) showed a dose-dependent pain-relieving effect in DNBS-treated rats. The efficacy of the meal was slightly enhanced after bioactivation with myrosinase, which increased isothiocyanate availability, and drastically decreased by pre-treating the animals with the selective peroxisome proliferator-activated receptor alpha (PPAR α) receptor antagonist GW6471. Repeated treatments with Camelina sativa DSM (1 g kg-1) meal counteracted the development, as well as the persistence, of visceral hyperalgesia in DNBS-treated animals by reducing the intestinal inflammatory damage and preventing enteric neuron damage. In conclusion, Camelina sativa meal might be employed as a nutraceutical tool to manage persistent abdominal pain in patients and to promote gut healing.

Inhibitors of Mitochondrial Human Carbonic Anhydrases VA and VB as a Therapeutic Strategy against Paclitaxel-Induced Neuropathic Pain in Mice.

Neuropathy development is a major dose-limiting side effect of anticancer treatments that significantly reduces patient's quality of life. The inadequate pharmacological approaches for neuropathic pain management warrant the identification of novel therapeutic targets. Mitochondrial dysfunctions that lead to reactive oxygen species (ROS) increase, cytosolic Ca2+ imbalance, and lactate acidosis are implicated in neuropathic pain pathogenesis. It has been observed that in these deregulations, a pivotal role is played by the mitochondrial carbonic anhydrases (CA) VA and VB isoforms. Hence, preclinical studies should be conducted to assess the efficacy of two novel selenides bearing benzenesulfonamide moieties, named 5b and 5d, and able to inhibit CA VA and VB against paclitaxel-induced neurotoxicity in mice. Acute treatment with 5b and 5d (30-100 mg/kg, per os - p.o.) determined a dose-dependent and long-lasting anti-hyperalgesic effect in the Cold plate test. Further, repeated daily treatment for 15 days with 100 mg/kg of both compounds (starting the first day of paclitaxel injection) significantly prevented neuropathic pain development without the onset of tolerance to the anti-hyperalgesic effect. In both experiments, acetazolamide (AAZ, 100 mg/kg, p.o.) used as the reference drug was partially active. Moreover, ex vivo analysis demonstrated the efficacy of 5b and 5d repeated treatments in reducing the maladaptive plasticity that occurs to glia cells in the lumbar portion of the spinal cord and in improving mitochondrial functions in the brain and spinal cord that were strongly impaired by paclitaxel-repeated treatment. In this regard, 5b and 5d ameliorated the metabolic activity, as observed by the increase in citrate synthase activity, and preserved an optimal mitochondrial membrane potential (ΔΨ) value, which appeared depolarized in brains from paclitaxel-treated animals. In conclusion, 5b and 5d have therapeutic and protective effects against paclitaxel-induced neuropathy without tolerance development. Moreover, 5b and 5d reduced glial cell activation and mitochondrial dysfunction in the central nervous system, being a promising candidate for the management of neuropathic pain and neurotoxicity evoked by chemotherapeutic drugs.

Cardiovascular benefits of Eruca sativa mill. Defatted seed meal extract: Potential role of hydrogen sulfide.

Eruca sativa Mill. is an edible plant belonging to the Brassicaceae botanical family with a long story as a medicinal material, mainly linked to the presence of glucoerucin. One of the main products of this glucosinolate is erucin, a biologicallly active isothiocyanate recently recognized as a hydrogen sulfide (H2 S) donor. In this work, an Eruca sativa extract has been obtained from a defatted seed meal (DSM), achieving a powder rich in thiofunctionalized glucosinolates, glucoerucin, and glucoraphanin, accounting for 95% and 5% of the total glucosinolate content (17% on a dry weight basis), associated with 13 identified phenolic acids and flavonoids accounting for 2.5%. In a cell-free model, Eruca sativa DSM extract slowly released H2 S. Moreover, this extract promoted significant hypotensive effects in hypertensive rats, and evoked dose-dependent cardioprotection in in vivo model of acute myocardial infarct, obtained through a reversible coronary occlusion. This latter effect was sensitive to blockers of mitochondrial KATP and Kv7.4 potassium channels, suggesting a potential role of these mitochondrial channels in the protective effects of Eruca sativa DSM extract. Accordingly, Eruca sativa DSM extract reduced calcium uptake and apoptotic cell death in isolated cardiac mitochondria. Taken together, these results demonstrate that Eruca sativa DSM extract is endowed with an interesting nutraceutical profile on the cardiovascular system due to, at least in part, its H2 S releasing properties. These results pave the way for future investigations on active metabolites.

New Synthetic Analogues of Natural Polyphenols as Sirtuin 1-Activating Compounds.

NAD+-dependent deacetylase SIRT1 regulates many different biological processes, thus being involved in pathogenic conditions such as metabolic diseases, neurogenerative disorders and cancer. Notably, experimental evidence underlined that the activation of SIRT1 had promising cardioprotective effects. Consequently, many efforts have been so far devoted to finding new SIRT1 activators, both derived from natural sources or prepared by synthetic procedures. Herein, we discovered new SIRT1-activating derivatives, characterized by phenolic rings spaced by sulfur, nitrogen or oxygen-based central linkers. The newly synthesized derivatives were analyzed in enzymatic assays to determine their ability to activate SIRT1, as compared with that of resveratrol. Among the tested molecules, bisarylaniline compound 10 proved to be the most efficient SIRT1 activator. An evaluation of the effects caused by focused structural variations revealed that its para-hydroxy-substituted diphenyl moiety of 10 was the fundamental structural requirement for achieving good SIRT1 activation. Compound 10 was further investigated in ex vivo studies in isolated and perfused rat hearts submitted to ischemia/reperfusion (I/R), where it showed significant protection of the myocardium against I/R injury. Molecular modeling studies suggest the binding mode of 10 within SIRT1 in the presence of the p53-AMC peptide. Our findings reveal that this chemical scaffold may be used as the starting point to develop a new class of more potent SIRT1 activators as cardioprotective agents.

Supplementation of Enriched Polyunsaturated Fatty Acids and CLA Cheese on High Fat Diet: Effects on Lipid Metabolism and Fat Profile.

Epidemiological studies have demonstrated a positive relationship between dietary fat intake and the onset of several metabolic diseases. This association is particularly evident in a diet rich in saturated fatty acids, typical of animal foods, such as dairy products. However, these foods are the main source of fatty acids with a proven nutraceutical effect, such as the ω-3 fatty acid α-linolenic acid (ALA) and the conjugated linoleic acid (CLA), which have demonstrated important roles in the prevention of various diseases. In the present study, the effect of a supplementation with cheese enriched with ω-3 fatty acids and CLA on the metabolism and lipid profiles of C57bl/6 mice was evaluated. In particular, the analyses were conducted on different tissues, such as liver, muscle, adipose tissue and brain, known for their susceptibility to the effects of dietary fats. Supplementing cheese enriched in CLA and ω-3 fats reduced the level of saturated fat and increased the content of CLA and ALA in all tissues considered, except for the brain. Furthermore, the consumption of this cheese resulted in a tissue-specific response in the expression levels of genes involved in lipid and mitochondrial metabolism. As regards genes involved in the inflammatory response, the consumption of enriched cheese resulted in a reduction in the expression of inflammatory genes in all tissues analyzed. Considering the effects that chronic inflammation associated with a high-calorie and high-fat diet (meta-inflammation) or aging (inflammaging) has on the onset of chronic degenerative diseases, these data could be of great interest as they indicate the feasibility of modulating inflammation (thus avoiding/delaying these pathologies) with a nutritional and non-pharmacological intervention.

Beneficial Effects of Eruca sativa Defatted Seed Meal on Visceral Pain and Intestinal Damage Resulting from Colitis in Rats.

Most therapies used in patients affected by inflammatory bowel diseases are ineffective in preventing the development of chronic visceral hypersensitivity, mainly due to inflammation-induced enteric neuroplasticity. Glucosinolates, secondary metabolites mainly of Brassicaceae with anti-inflammatory and neuroprotective properties, are effective in treating both neuropathic and arthritis pain through H2S release and Kv7 potassium channel activation. The aim of this work was to investigate the protective and anti-hyperalgesic efficacy of a defatted seed meal from Eruca sativa Mill. (Brassicaceae), rich in glucosinolates, in a rat model of colitis induced by 2,4-dinitrobenzene sulfonic acid (DNBS). The mechanisms of action were also investigated. Visceral pain was assessed by measuring the abdominal response to colorectal distension. Fifteen days after colitis induction, the acute administration of E. sativa defatted seed meal (0.1-1 g kg-1 p.o.) dose-dependently relieved pain. This effect was hampered by co-administering an H2S scavenger or a selective Kv7 blocker. Administering E. sativa (1 g kg-1) for 14 days, starting after DNBS injection, contributed to counteracting visceral pain persistence in the post-inflammatory phase of colitis by promoting colon healing from the damage and reducing enteric gliosis. E. sativa defatted seed meal might be employed as a nutraceutical tool for supporting abdominal pain relief in patients.