Perfluorohexyloctane in dry eye disease: A systematic review of its efficacy and safety as a novel therapeutic agent.

Perfluorohexyloctane (F6H8), a physically and chemically inert synthetic compound, has recently emerged as a promising candidate for the treatment of DED due to its unique properties. A systematic review that only include full-length randomized controlled studies (RCTs), reporting the effects of F6H8 in three databases, PubMed, Scopus and Web of Science, was performed according to the PRISMA statement. The search period was performed between June 1, 2023, and June 21, 2023. The Cochrane risk of bias tool was used to analyze the quality of the studies selected. A total of six RCTs were included in this systematic review. F6H8 tear substitutes treatment achieved a higher improvement than control group interventions in most of the reported variables. The mean differences between both groups were in favor of F6H8 and were as follow: eye dryness score (EDS) base on a visual analogue scale (VAS) of -6.12 ± 4.3 points, ocular surface disease index (OSDI) questionnaire score of -2.8 ± 2.3 points, lipid layer thickness (LLT) of 11.4 ± 10.4 µm, total corneal fluorescein staining (tCFS) of -0.8 ± 0.3 points and ocular treatment-emergent adverse events (TEAEs) of -0.66 ± 1.7. Tear film break-up time (TBUT) was the only variable in favor of control group with a mean of -0.5 ± 0.4 s. Patient satisfaction after F6H8 tear substitutes treatment was high. Therefore, F6H8 tear substitutes improve dry eye symptoms and signs with a satisfactory tolerability and could be recommended in patients with DED.

Effects of Dietary Oleacein Treatment on Endothelial Dysfunction and Lupus Nephritis in Balb/C Pristane-Induced Mice.

Systemic lupus erythematosus (SLE) is a chronic immune-inflammatory disease characterized by multiorgan affectation and lowered self-tolerance. Additionally, epigenetic changes have been described as playing a pivotal role in SLE. This work aims to assess the effects of oleacein (OLA), one of the main extra virgin olive oil secoiridoids, when used to supplement the diet of a murine pristane-induced SLE model. In the study, 12-week-old female BALB/c mice were injected with pristane and fed with an OLA-enriched diet (0.01 % (w/w)) for 24 weeks. The presence of immune complexes was evaluated by immunohistochemistry and immunofluorescence. Endothelial dysfunction was studied in thoracic aortas. Signaling pathways and oxidative-inflammatory-related mediators were evaluated by Western blotting. Moreover, we studied epigenetic changes such as DNA methyltransferase (DNMT-1) and micro(mi)RNAs expression in renal tissue. Nutritional treatment with OLA reduced the deposition of immune complexes, ameliorating kidney damage. These protective effects could be related to the modulation of mitogen-activated protein kinases, the Janus kinase/signal transducer and transcription activator of transcription, nuclear factor kappa, nuclear-factor-erythroid-2-related factor 2, inflammasome signaling pathways, and the regulation of miRNAs (miRNA-126, miRNA-146a, miRNA-24-3p, and miRNA-123) and DNMT-1 expression. Moreover, the OLA-enriched diet normalized endothelial nitric oxide synthase and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-1 overexpression. These preliminary results suggest that an OLA-supplemented diet could constitute a new alternative nutraceutical therapy in the management of SLE, supporting this compound as a novel epigenetic modulator of the immunoinflammatory response.

Oleocanthal supplemented diet improves renal damage and endothelial dysfunction in pristane-induced systemic lupus erythematosus in mice.

Systemic lupus erythematosus (SLE) is a multiorgan disorder with a deregulated immune-inflammatory response. Nutritional therapy has been considered a promising approach to SLE management. Oleocanthal (OLE), the main extra virgin olive oil (EVOO)-derived secoiridoid, has shown to regulate the immune-inflammatory response in various disease contexts; however, its possible beneficial effects on SLE remain unclear. This study sought to evaluate the effects of OLE enriched diet on renal damage and aortic endothelial dysfunction in murine pristane-induced SLE, focusing on the action mechanisms and signaling pathways involved. BALB/c mice were injected with pristane and fed with OLE supplemented diet (0.01 % (w/w)) for six months. Levels of cytokines were measured by ELISA in lipopolysaccharide (LPS)-stimulated peritoneal macrophages and splenocytes. Presence of immunoglobulin G (IgG) and IgM immune complexes were examined by immunofluorescence and immunohistochemistry. Thoracic aortas were used to evaluate endothelial dysfunction. Western blotting was employed to detect signaling pathways and oxidative-inflammatory-related mediators. Dietary OLE supplementation reduced Th1/Th17 pro-inflammatory cytokines production and alleviated renal damage by decreasing immunoglobulin complexes deposition, and inflammation-mediating enzymes expression. The mechanisms underlying these protective effects could be related to the regulation of nuclear factor erythroid 2-related factor 2/Haem oxygenase 1 (Nrf-2/HO-1), mitogen-activated protein kinases (MAPKs), signal transducer and transcription activator of transcription (STAT-3), inflammasome and, nuclear factor kappa B (NF-κB) signaling pathways. Also, dietary OLE improved aortic endothelial dysfunction and vascular reactivity, normalizing endothelial nitric oxide synthase (eNOS) uncoupling, and NADPH oxidase-1 (NOX-1) overexpression. This study shows the immunomodulatory effects of OLE in an in vivo model of SLE by improving renal damage and regulating aortic endothelial dysfunction. These preliminary results provide OLE as a new therapeutic strategy in SLE management.

Pomace Olive Oil Concentrated in Triterpenic Acids Restores Vascular Function, Glucose Tolerance and Obesity Progression in Mice.

Pomace olive oil, an olive oil sub-product, is a promising source of bioactive triterpenoids such as oleanolic acid and maslinic acid. Considering the vascular actions of pomace olive oil and the potential effects of the isolated oleanolic acid on metabolic complications of obesity, this study investigates for the first time the dietary intervention with a pomace olive oil with high concentrations of the triterpenic acids (POCTA), oleanolic and maslinic acid, during diet-induced obesity in mice. The results demonstrate that obese mice, when switched to a POCTA-diet for 10 weeks, show a substantial reduction of body weight, insulin resistance, adipose tissue inflammation, and particularly, improvement of vascular function despite high caloric intake. This study reveals the potential of a functional food based on pomace olive oil and its triterpenic fraction against obesity progression. Our data also contribute to understanding the health-promoting effects attributable to the Mediterranean diet.

Bioavailability of the ferulic acid-derived phenolic compounds of a rice bran enzymatic extract and their activity against superoxide production.

Rice bran is an exceptional source of such antioxidant molecules as γ-oryzanol and ferulic acid, but their bioavailability and metabolism within this matrix remain unknown. The aims of this work were to describe the oral bioavailability and metabolic pathways of the ferulic acid-derived phenolic compounds contained in a rice bran enzymatic extract (RBEE), and to determine its effect on NADPH oxidase activity. Wistar rats were administered with RBEE and sacrificed at different times over a period of 24 h to obtain plasma. An additional group was used for collection of urine and faeces over a period of 48 h. The phenolic metabolites were determined by ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS), and plasma pharmacokinetic parameters were calculated. In parallel, aortic rings were incubated in the plasma of rats sacrificed 30 min after RBEE gavage, or in the presence of RBEE, ferulic acid or γ-oryzanol. Endothelin-1-induced superoxide production was recorded by lucigenin-enhanced luminescence. Twenty-five ferulic acid metabolites showing biphasic behaviour were found in the plasma, most of which were found in the urine as well, while in the faeces, colonic metabolism led to simpler phenolic compounds. Superoxide production was abrogated by phenolic compound-enriched plasma and by RBEE and ferulic acid, thus showing the biological potential of RBEE as a nutraceutical ingredient.

Rice bran enzymatic extract restores endothelial function and vascular contractility in obese rats by reducing vascular inflammation and oxidative stress.

BACKGROUND: Rice bran enzymatic extract (RBEE) used in this study has shown beneficial activities against dyslipidemia, hyperinsulinemia and hypertension. Our aim was to investigate the effects of a diet supplemented with RBEE in vascular impairment developed in obese Zucker rats and to evaluate the main mechanisms mediating this action. METHODS AND RESULTS: Obese Zucker rats were fed a 1% and 5% RBEE-supplemented diet (O1% and O5%). Obese and their lean littermates fed a standard diet were used as controls (OC and LC, respectively). Vascular function was evaluated in aortic rings in organ baths. The role of nitric oxide (NO) was investigated by using NO synthase (NOS) inhibitors. Aortic expression of endothelial NOS (eNOS), inducible NOS (iNOS), tumor necrosis factor (TNF)-α and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits and superoxide production in arterial wall were determined. Endothelial dysfunction and vascular hyperreactivity to phenylephrine in obese rats were ameliorated by RBEE treatment, particularly with 1% RBEE. Up-regulation of eNOS protein expression in RBEE-treated aortas should contribute to this activity. RBEE attenuated vascular inflammation by reducing aortic iNOS and TNF-α expression. Aortas from RBEE-treated groups showed a significant decrease of superoxide production and down-regulation of NADPH oxidase subunits. CONCLUSION: RBEE treatment restored endothelial function and vascular contractility in obese Zucker rats through a reduction of vascular inflammation and oxidative stress. These results show the nutraceutical potential of RBEE to prevent obesity-related vascular complications.

Pharmacological effects and clinical applications of propionyl-L-carnitine.

Propionyl-L-carnitine (PLC) is a naturally occurring derivative of carnitine that plays an important role in the metabolism of both carbohydrates and lipids, leading to an increase of ATP generation. PLC, however, is not only a metabolic drug; it is also a potent antiradical agent and thus may protect tissues from oxidative damage. PLC has been demonstrated to exert a protective effect in different models of both cardiac and endothelial dysfunction, to prevent the progression of atherosclerosis, and, more recently, to improve some of the cardiometabolic alterations that frequently accompany insulin resistance. As a result, most of the clinical trials conducted in humans highlight PLC as a potential treatment option in cardiovascular diseases such as peripheral arterial disease, chronic heart failure, or stable angina, especially when type 2 diabetes mellitus or hyperglycemia (i.e., patients on hemodialysis) are also present. The aim of this review is to summarize the pharmacological effects and possible therapeutic applications of PLC, including the most recent findings to date.

Chronic treatment with the cannabinoid 1 antagonist rimonabant altered vasoactive cyclo-oxygenase-derived products on arteries from obese Zucker rats.

To investigate the effect of chronic cannabinoid 1 antagonism on vascular prostanoid production, obese Zucker rats were treated with rimonabant (10 mg/kg per day) during 20 weeks and then vascular and endothelial reactivity were assessed in aortic rings by analyzing response to phenylephrine and acetylcholine. The presence of cyclo-oxygenase-1 and cyclo-oxygenase-2 selective inhibitors (SC-560 and NS-398, respectively) and the enzyme immunoassay revealed lower PGI2 production by aortic rings from obese rats with rimonabant able to restore such response toward levels found in the lean animals. The treatment also reduced TXB2 but did not alter its participation on acetylcholine-induced relaxation as the TP receptor antagonist ICI-192,605 revealed. Those effects were associated with an enhancement of cyclo-oxygenase-2 expression without affecting p38MAPK phosphorylation. Obese rats also exhibited higher nitric oxide plasma concentrations and greater inducible nitric oxide synthase participation on vascular phenylephrine-induced response without changes in inducible nitric oxide synthase protein expression. Although rimonabant reduced such alteration, the values were still higher than those found in lean rats. Finally, rimonabant was also able to reduce tumor necrosis factor-α produced by adipose tissue of obese Zucker rats. These results highlight a crosstalk among cannabinoids and cyclo-oxygenase-derived products in the vasculature of obese animals.

Effects of pomace olive oil-enriched diets on endothelial function of small mesenteric arteries from spontaneously hypertensive rats.

Pomace olive oil (POM), an olive oil subproduct traditionally used in Spain, is a good source of minor components from the unsaponifiable fraction such as triterpenoids, mainly in the form of oleanolic acid, which induces vascular protection and vasodilatation. Our aim was to evaluate the effects of long-term intake of diets enriched in POM with high concentration in oleanolic acid on endothelial dysfunction associated to hypertension in small mesenteric arteries (SMA) from spontaneously hypertensive rats (SHR). During 12 weeks, rats (six rats per group) were fed either a control 2 % maize oil diet (BD), or high-fat diets containing 15 % refined olive oil (OL), pomace olive oil (POM), or pomace olive oil supplemented in oleanolic acid (POMO; up to 800 parts per million). Endothelial and vascular functions were assessed by relaxing or contracting responses to acetylcholine (ACh) or phenylephrine, respectively. The involvement of endothelium-derived relaxing factors in these responses was evaluated. In contrast to BD, SHR fed high-fat diets showed a biphasic response to ACh related to changes in eicosanoid metabolism. POM enhanced the endothelial function in SMA from SHR by increasing the endothelium-derived hyperpolarising factor (EDHF)-type component, whereas administration of POMO resulted in a similar contribution of NO/EDHF in the endothelial response to ACh. The present study shows that despite the lack of changes in blood pressure, consumption of POM improves endothelial function in SMA from SHR by improving the agonist-mediated EDHF/NO response. Thus, triterpenoids confer a protective role to POM against endothelial dysfunction in hypertension.

Time-dependent protective efficacy of Trolox (vitamin E analog) against microcystin-induced toxicity in tilapia (Oreochromis niloticus).

Microcystins (MCs), hepatotoxins from cyanobacteria, induce oxidative stress and pathological changes in fish that can be ameliorated with chemoprotectants such as vitamin E (vit E). This study investigated the time period after MCs exposure in which Trolox, a vitamin E analog, is effective against oxidative and histological damage in different organs of tilapia (Oreochromis niloticus). Fish were fed Trolox supplement (700 mg/kg diet) for 7 days, or received only commercial fish food, and then were exposed to a single oral dose of 120 microg/fish microcystin-LR, and sacrificed in 24, 48, or 72 h. The Trolox protective efficacy was evaluated based on lipid peroxidation (LPO), protein oxidation, enzymatic and non-enzymatic antioxidants, and a morphologic study. Regarding the oxidative stress biomarkers altered by MCs, the higher protective action of Trolox was observed 24 h post toxin exposure, although it extends also until 48 h in gills (superoxide dismutase (SOD), catalase (CAT)), and liver, where glutathione reductase (GR) backed to control values 48 and 72 h after the toxin application. Glutathione-S- transferase (GST) activity in the liver was ameliorated by the chemoprotectant after 24 and 48 h, although control values were not recovered. Trolox modulation of these biomarkers and its ability to quench free radicals explain the recovery of LPO values in all organs at 24 h and also in gills at 48 h. Histopathologically, Trolox efficacy was more evident after 72 h.

l-carnitine and its propionate: improvement of endothelial function in SHR through superoxide dismutase-dependent mechanisms.

To clarify the mechanism underlying the antioxidant properties of l-carnitine (LC) and propionyl-l-carnitine (PLC) on spontaneously hypertensive (SHR) and normotensive WKY, animals were treated with either PLC or LC (200 mg kg(- 1)). Aorta was dissected and contraction to (R)-( - )-phenylephrine (Phe) and relaxation to carbachol (CCh) were assessed in the presence or not of the NO synthase (NOS) inhibitor, l-NAME. [image omitted] production was evaluated by lucigenin-enhanced chemiluminescence and its participation on relaxation was observed after incubation with superoxide dismutase (SOD) plus catalase. Protein expressions of eNOS, Cu/Zn-SOD and Mn-SOD were studied by western blot. Both LC and PLC treatments improved endothelial function of SHR through increasing NO participation and decreasing [image omitted] probably involving higher Cu/Zn-SOD expression. PLC treatment augmented eNOS expression in SHR. Surprisingly, LC increased [image omitted] produced by aorta from WKY and thus diminished NO and damaged endothelial function. Conversely, PLC did not affect CCh-induced relaxation in WKY. These results demonstrate that LC and PLC prevent endothelial dysfunction in SHR through an antioxidant effect.

Pomace olive oil improves endothelial function in spontaneously hypertensive rats by increasing endothelial nitric oxide synthase expression.

BACKGROUND: The effect of dietary pomace olive oil, which has the same concentration of oleic acid but a higher proportion of oleanolic acid (OA) than olive oil, was examined on animal models of hypertension for the first time. METHODS: During 12 weeks, Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) were fed with either a control 2% corn oil diet (BD), or high-fat diets containing 15% of refined olive oil (OL), pomace olive oil (POM), or pomace olive oil supplemented in OA (up to 800 ppm) (POMO). Then, vascular reactivity and endothelial nitric oxide (NO) synthase (eNOS) expression were studied in aortic rings. Plasma nitrite + nitrate levels were also determined. RESULTS: Diets had no effects on blood pressure (BP). In contrast to the BD and OL dietary groups, POM intake improved relaxation evoked by acetylcholine in SHR aorta. The POMO intake increased vasodilatation to acetylcholine and attenuated phenylephrine-induced contractions in both strains of rats associated with a major NO participation revealed by inhibition of NOS. The enhanced relaxation shown in POM and POMO SHR aorta was attributed to an increased eNOS protein expression. Plasma nitrite levels were also increased in these groups. Although olive and pomace oils used in diets contained similar fatty acid composition, beneficial effects on endothelial function were absent in the OL group. Therefore, these effects must be associated with some minor components from pomace olive oil such as OA. CONCLUSIONS: Chronic intake of diets rich in pomace olive oil improves endothelial dysfunction in SHR aorta by mechanisms associated with enhanced eNOS expression. Important evidence is provided regarding the effects of pomace olive oil and OA on endothelial function in hypertensive animals.

Improvement of age-related endothelial dysfunction by simvastatin: effect on NO and COX pathways.

The effects of oral administration of the HMG-CoA reductase inhibitor, simvastatin (SV), on age-related endothelial dysfunction were investigated in the aorta of male Wistar rats. Adult (12-14 weeks) and old (60-80 weeks) rats were treated daily for 12 weeks with either vehicle or SV (1 mg kg(-1)). In old rats, SV treatment did not significantly affect systolic blood pressure and LDL-cholesterol, but it reduced plasma cholesterol, triglycerides and oxidised LDL though it did not affect total antioxidant status. SV improved endothelium-dependent relaxation to acetylcholine and A-23187 in vessels from aged, but not adult, rats. This effect was linked to a greater NO vasodilatation via an increased expression of endothelial NO-synthase. A mechanism sensitive to superoxide dismutase and catalase also accounts for enhanced endothelial vasodilatation. Finally, SV did not affect the release of prostacyclin, but it inhibited the generation of thromboxane (TX) A2 from COX-2 isoform. The effect of the latter was sensitive to the Tp receptor antagonist, ICI-192,605. The present study provides evidence that oral administration of SV improves endothelial dysfunction in the aorta from aged rats by mechanisms associated with enhanced NO vasodilatation, reduced release of TXA2 from cyclo-oxygenase, and increased antioxidant properties of the vessel wall. These data underscore a new therapeutic perspective for SV in age-related endothelial dysfunction.

Endothelium-dependent vasorelaxation induced by L-carnitine in isolated aorta from normotensive and hypertensive rats.

The aim of this work was to investigate the mechanism of the vasodilatory effect induced by L-carnitine. Relaxation produced by L-carnitine was studied in rat aortic rings with and without functional endothelium, pre-contracted with phenylephrine by adding cumulative doses of L-carnitine (10(-7) to 10(-3) M). The relaxation evoked by L-carnitine reached higher values in aortic rings from spontaneously hypertensive rats than those obtained in arteries from normotensive rats; no relaxation was produced in de-endothelialized arteries. However, in the presence of N(G)-nitro-L-arginine (3 x 10(-5) M, a nitric oxide synthase inhibitor), Ro 68070 (10(-4) M, a thromboxane synthetase inhibitor-thromboxane A2/prostaglandin H2 receptor antagonist) or ICI 192605 (10(-5) M, a thromboxane A2 receptor antagonist) the relaxant response to L-carnitine was significantly inhibited. These results show that L-carnitine induced endothelium-dependent relaxation in the rat aorta and the mechanism of this relaxation appeared to be mostly mediated by endothelial production of nitric oxide but#10; also could involve prevention of the action of cyclooxygenase endothelial products acting on the thromboxane A2/prostaglandin H2 receptor.