Docosahexaenoic acid and etanercept could reduce functional and metabolic alterations during collagen-induced arthritis in rats without any synergistic effect.

AIMS: Rheumatoid arthritis is an autoimmune disease which induces chronic inflammation and increases the risk for sarcopenia and metabolic abnormalities. Nutritional strategies using omega 3 polyunsaturated fatty acids could be proposed to alleviate inflammation and improve the maintenance of lean mass. Independently, pharmacological agents targeting key molecular regulators of the pathology such as TNF alpha could be proposed, but multiple therapies are frequently necessary increasing the risk for toxicity and adverse effects. The aim of the present study was to explore if the combination of an anti-TNF therapy (Etanercept) with dietary supplementation with omega 3 PUFA could prevent pain and metabolic effects of RA. MATERIALS AND METHODS: RA was induced using collagen-induced arthritis (CIA) in rats to explore of supplementation with docosahexaenoic acid, treatment with etanercept or their association could alleviate symptoms of RA (pain, dysmobility), sarcopenia and metabolic alterations. KEY FINDINGS: We observed that Etanercept had major benefits on pain and RA scoring index. However, DHA could reduce the impact on body composition and metabolic alterations. SIGNIFICANCE: This study revealed for the first time that nutritional supplementation with omega 3 fatty acid could reduce some symptoms of rheumatoid arthritis and be an effective preventive treatment in patients who do not need pharmacological therapy, but no sign of synergy with an anti-TNF agent was observed.

Evaluation of bone excision effects on a human skull model - I: Mechanical testing and digital image correlation.

The mechanisms of skull impact loading may change following surgical interventions such as the removal of bone lesions, but little is known about the consequences in the event of subsequent head trauma. We, therefore, prepared acrylonitrile butadiene styrene human skull models based on clinical computed tomography skull data using a three-dimensional printer. Six replicate physical skull models were tested, three with bone excisions and three without. A drop tower was used to simulate the impact sustained by falling backwards onto the occipital lobe region. The impacts were recorded with a high-speed camera, and the occipital strain response was determined by digital image correlation. Although the hole affected neither the magnitude nor the sequence of the fracture pattern, the digital image correlation analysis highlighted an increase in strain around the excised area (0.45%-16.4% of the principal strain). Our approach provides a novel method that could improve the quality of life for patients on many fronts, including protection against trauma, surgical advice, post-operative care, advice in litigation cases, as well as facilitating general biomechanical research in the area of trauma injuries.

A procedure to extract functional isolated mitochondria from small-sized human atrial samples. Application to obesity with a partial characterisation of the organelles.

Evaluating the activity of cardiac mitochondria is probably the best way to estimate early cellular damage in chronic pathology. Early diagnosis allows rapid therapeutic intervention thus increasing patient survival rate in a number of diseases. However, data on human cardiac mitochondria are scarce in the international literature. Here, we describe a method to extract and study functional mitochondria from the small-sized right atrial aliquots (minimum of 400 mg) obtained during extracorporeal circulation and usually considered as surgical waste products. The mitochondria were purified through several mechanical processes (fine myocardial cutting, tissue grinding and potter Elvehjem homogenising), an enzymatic proteolytic action (subtilisin) and differential centrifugations. In chronic pathologies, including obesity, early disturbances of mitochondrial function can occur. The effects of obesity on the rate of mitochondrial oxygen consumption and H2O2 release were thus determined with three different substrates (glutamate/malate, succinate/rotenone and palmitoylcarnitine/malate). The human atrial mitochondria were of high quality from a functional viewpoint, compared to rat ventricle organelles, but the extraction yield of the human mitochondria was twice lower than that of rat mitochondria. Tests showed that glutamate/malate-related ADP-stimulated respiration was strongly increased in obese subjects, although the oxidation of the other two substrates was unaffected. Reactive oxygen species (ROS) production by the isolated mitochondria was low in comparison with that of the lean subjects. These results confirm those found in one of our previous studies in the ventricles of rats fed a high-fat diet. In conclusion, the described method is simple, reliable and sensitive. It allows for the description of the impact of obesity on the function of atrial mitochondria while using only a small patient sampling (n = 5 in both the lean and the obese groups).

EPA is Cardioprotective in Male Rats Subjected to Sepsis, but ALA Is Not Beneficial.

It has been proven that dietary eicosapentaenoic acid (C20:5 n-3 or EPA) protects the heart against the deleterious effects of sepsis in female rats. We do not know if this is the case for male rodents. In this case, the efficiency of other n-3 polyunsaturated fatty acids (PUFAs) remains to be determined in both female and male rats. This study aimed at (i) determining whether dietary EPA is cardioprotective in septic male rats; (ii) evaluating the influence of dietary α-linolenic (C18:3 n-3 or ALA) on cardiac function during this pathology; and (iii) finding out the physiological and molecular mechanisms responsible for the observed effects. Sixty male rats were divided into three dietary groups. The animals were fed a diet deficient in n-3 PUFAs (DEF group), a diet enriched with ALA (ALA group) or a diet fortified with EPA (EPA group) for 6 weeks. Thereafter, each group was subdivided into 2 subgroups, one being subjected to cecal ligation and puncture (CLP) and the other undergoing a fictive surgery. Cardiac function was determined in vivo and ex vivo. Several parameters related to the inflammation process and oxidative stress were determined. Finally, the fatty acid compositions of circulating lipids and cardiac phospholipids were evaluated. The results of the ex vivo situation indicated that sepsis triggered cardiac damage in the DEF group. Conversely, the ex vivo data indicated that dietary ALA and EPA were cardioprotective by resolving the inflammation process and decreasing the oxidative stress. However, the measurements of the cardiac function in the in vivo situation modulated these conclusions. Indeed, in the in vivo situation, sepsis deteriorated cardiac mechanical activity in the ALA group. This was suspected to be due to a restricted coronary flow which was related to a lack of cyclooxygenase substrates in membrane phospholipids. Finally, only EPA proved to be beneficial in sepsis. Its action necessitates both resolution of inflammation and increased coronary perfusion. In that sense, dietary ALA, which does not allow the accumulation of vasodilator precursors in membrane lipids, cannot be protective during the pathology.

About the controversies of the cardioprotective effect of n-3 polyunsaturated fatty acids (PUFAs) between animal studies and clinical meta-analyses: a review with several strategies to enhance the beneficial effects of n-3 PUFAs.

Several meta-analyses describing the effect of n-3 polyunsaturated fatty acids on the survival rate of the victims of an acute coronary event do not clearly support a beneficial impact of these fatty acids. Yet, animal studies consistently show n-3 PUFA-induced protection against ischemia-reperfusion-induced myocardial injuries. The impact on reperfusion arrhythmias of these PUFAs is more controversial. The literature shows the anti-arrhythmic properties of circulating n-3 PUFAs. However, when these fatty acids are incorporated in the cardiac membrane, they protect the myocardial tissue vis a vis cellular damage but they can be either pro- or anti-arrhythmic during reperfusion, depending on the severity of tissue injuries. The latter elements can explain the lack of beneficial effect observed in the meta-analyses, but a proper use of n-3 PUFAs may provide advantages in terms of survival rate. This review discusses the different results obtained in humans and animals and presents several strategies to enhance the beneficial effects of n-3 PUFAs.

Dietary EPA Increases Rat Mortality in Diabetes Mellitus, A Phenomenon Which Is Compensated by Green Tea Extract.

: Diabetes is characterized by a high mortality rate which is often associated with heart failure. Green tea and eicosapentaenoic acid (EPA) are known to lessen some of the harmful impacts of diabetes and to exert cardio-protection. The aim of the study was to determine the effects of EPA, green tea extract (GTE), and a combination of both on the cardiac consequences of diabetes mellitus, induced in Wistar rats by injection of a low dose of streptozotocin (33 mg/kg) combined with a high fat diet. Cardiac mechanical function, coronary reactivity, and parameters of oxidative stress, inflammation, and energy metabolism were evaluated. In the context of diabetes, GTE alone limited several diabetes-related symptoms such as inflammation. It also slightly improved coronary reactivity and considerably enhanced lipid metabolism. EPA alone caused the rapid death of the animals, but this effect was negated by the addition of GTE in the diet. EPA and GTE combined enhanced coronary reactivity considerably more than GTE alone. In a context of significant oxidative stress such as during diabetes mellitus, EPA enrichment constitutes a risk factor for animal survival. It is essential to associate it with the antioxidants contained in GTE in order to decrease mortality rate and preserve cardiac function.

Antioxidant and Cardioprotective Effects of EPA on Early Low-Severity Sepsis through UCP3 and SIRT3 Upholding of the Mitochondrial Redox Potential.

Sepsis still causes death, often through cardiac failure and mitochondrial dysfunction. Dietary ω3 polyunsaturated fatty acids are known to protect against cardiac dysfunction and sepsis lethality. This study set out to determine whether early low-severity sepsis alters the cardiac mitochondrial function in animals fed a Western-type diet and whether dietary eicosapentaenoic acid (EPA) administration protects the myocardium against the deleterious effects of sepsis and if so to seek possible mechanisms for its effects. Rats were divided into two groups fed either an ω3 PUFA-deficient diet ("Western diet," DEF group) or an EPA-enriched diet (EPA group) for 5 weeks. Each group was subdivided into two subgroups: sham-operated rats and rats subjected to cecal ligation and puncture (CLP). In vivo cardiac mechanical function was examined, and mitochondria were harvested to determine their functional activity. Oxidative stress was evaluated together with several factors involved in the regulation of reactive oxygen species metabolism. Sepsis had little effect on cardiac mechanical function but strongly depressed mitochondrial function in the DEF group. Conversely, dietary EPA greatly protected the mitochondria through a decreased oxidative stress of the mitochondrial matrix. The latter was probably due to an increased uncoupling protein-3 expression, already seen in the sham-operated animals. CLP rats in the EPA group also displayed increased mitochondrial sirtuin-3 protein expression that could reinforce the upholding of oxidative phosphorylation. Dietary EPA preconditioned the heart against septic damage through several modifications that protect mitochondrial integrity. This preconditioning can explain the cardioprotective effect of dietary EPA during sepsis.

Dietary canolol protects the heart against the deleterious effects induced by the association of rapeseed oil, vitamin E and coenzyme Q10 in the context of a high-fat diet.

BACKGROUND: Obesity progressively leads to cardiac failure. Omega-3 polyunsaturated fatty acids (PUFA) have been shown to have cardio-protective effects in numerous pathological situations. It is not known whether rapeseed oil, which contains α-linolenic acid (ALA), has a similar protective effect. Omega-3 PUFAs are sensitive to attack by reactive oxygen species (ROS), and lipid peroxidation products could damage cardiac cells. We thus tested whether dietary refined rapeseed oil (RSO) associated with or without different antioxidants (vitamin E, coenzyme Q10 and canolol) is cardio-protective in a situation of abdominal obesity. METHODS: Sixty male Wistar rats were subdivided into 5 groups. Each group was fed a specific diet for 11 weeks: a low-fat diet (3% of lipids, C diet) with compositionally-balanced PUFAs; a high-fat diet rich in palm oil (30% of lipids, PS diet); the PS diet in which 40% of lipids were replaced by RSO (R diet); the R diet supplemented with coenzyme Q10 (CoQ10) and vitamin E (RTC diet); and the RTC diet supplemented with canolol (RTCC diet). At the end of the diet period, the rats were sacrificed and the heart was collected and immediately frozen. Fatty acid composition of cardiac phospholipids was then determined. Several features of cardiac function (fibrosis, inflammation, oxidative stress, apoptosis, metabolism, mitochondrial biogenesis) were also estimated. RESULTS: Abdominal obesity reduced cardiac oxidative stress and apoptosis rate by increasing the proportion of arachidonic acid (AA) in membrane phospholipids. Dietary RSO had the same effect, though it normalized the proportion of AA. Adding vitamin E and CoQ10 in the RSO-rich high fat diet had a deleterious effect, increasing fibrosis by increasing angiotensin-2 receptor-1b (Ag2R-1b) mRNA expression. Overexpression of these receptors triggers coronary vasoconstriction, which probably induced ischemia. Canolol supplementation counteracted this deleterious effect by reducing coronary vasoconstriction. CONCLUSION: Canolol was found to counteract the fibrotic effects of vitamin E + CoQ10 on cardiac fibrosis in the context of a high-fat diet enriched with RSO. This effect occurred through a restoration of cardiac Ag2R-1b mRNA expression and decreased ischemia.

Early sepsis does not stimulate reactive oxygen species production and does not reduce cardiac function despite an increased inflammation status.

If it is sustained for several days, sepsis can trigger severe abnormalities of cardiac function which leads to death in 50% of cases. This probably occurs through activation of toll-like receptor-9 by bacterial lipopolysaccharides and overproduction of proinflammatory cytokines such as TNF-α and IL-1ß In contrast, early sepsis is characterized by the development of tachycardia. This study aimed at determining the early changes in the cardiac function during sepsis and at finding the mechanism responsible for the observed changes. Sixty male Wistar rats were randomly assigned to two groups, the first one being made septic by cecal ligation and puncture (sepsis group) and the second one being subjected to the same surgery without cecal ligation and puncture (sham-operated group). The cardiac function was assessed in vivo and ex vivo in standard conditions. Several parameters involved in the oxidative stress and inflammation were determined in the plasma and heart. As evidenced by the plasma level of TNF-α and gene expression of IL-1ß and TNF-α in the heart, inflammation was developed in the sepsis group. The cardiac function was also slightly stimulated by sepsis in the in vivo and ex vivo situations. This was associated with unchanged levels of oxidative stress, but several parameters indicated a lower cardiac production of reactive oxygen species in the septic group. In conclusion, despite the development of inflammation, early sepsis did not increase reactive oxygen species production and did not reduce myocardial function. The depressant effect of TNF-α and IL-1ß on the cardiac function is known to occur at very high concentrations. The influence of low- to moderate-grade inflammation on the myocardial mechanical behavior must thus be revisited.