Abrupt Photoperiod Changes Differentially Modulate Hepatic Antioxidant Response in Healthy and Obese Rats: Effects of Grape Seed Proanthocyanidin Extract (GSPE).

Disruptions of the light/dark cycle and unhealthy diets can promote misalignment of biological rhythms and metabolic alterations, ultimately leading to an oxidative stress condition. Grape seed proanthocyanidin extract (GSPE), which possesses antioxidant properties, has demonstrated its beneficial effects in metabolic-associated diseases and its potential role in modulating circadian disruptions. Therefore, this study aimed to assess the impact of GSPE administration on the liver oxidant system of healthy and diet-induced obese rats undergoing a sudden photoperiod shift. To this end, forty-eight photoperiod-sensitive Fischer 344/IcoCrl rats were fed either a standard (STD) or a cafeteria diet (CAF) for 6 weeks. A week before euthanizing, rats were abruptly transferred from a standard photoperiod of 12 h of light/day (L12) to either a short (6 h light/day, L6) or a long photoperiod (18 h light/day, L18) while receiving a daily oral dose of vehicle (VH) or GSPE (25 mg/kg). Alterations in body weight gain, serum and liver biochemical parameters, antioxidant gene and protein expression, and antioxidant metabolites were observed. Interestingly, GSPE partially ameliorated these effects by reducing the oxidative stress status in L6 through an increase in GPx1 expression and in hepatic antioxidant metabolites and in L18 by increasing the NRF2/KEAP1/ARE pathway, thereby showing potential in the treatment of circadian-related disorders by increasing the hepatic antioxidant response in a photoperiod-dependent manner.

Anti-Inflammatory and Anticancer Effects of Microalgal Carotenoids.

Acute inflammation is a key component of the immune system's response to pathogens, toxic agents, or tissue injury, involving the stimulation of defense mechanisms aimed to removing pathogenic factors and restoring tissue homeostasis. However, uncontrolled acute inflammatory response may lead to chronic inflammation, which is involved in the development of many diseases, including cancer. Nowadays, the need to find new potential therapeutic compounds has raised the worldwide scientific interest to study the marine environment. Specifically, microalgae are considered rich sources of bioactive molecules, such as carotenoids, which are natural isoprenoid pigments with important beneficial effects for health due to their biological activities. Carotenoids are essential nutrients for mammals, but they are unable to synthesize them; instead, a dietary intake of these compounds is required. Carotenoids are classified as carotenes (hydrocarbon carotenoids), such as α- and ß-carotene, and xanthophylls (oxygenate derivatives) including zeaxanthin, astaxanthin, fucoxanthin, lutein, α- and ß-cryptoxanthin, and canthaxanthin. This review summarizes the present up-to-date knowledge of the anti-inflammatory and anticancer activities of microalgal carotenoids both in vitro and in vivo, as well as the latest status of human studies for their potential use in prevention and treatment of inflammatory diseases and cancer.

Preparation and In Vivo Evaluation of Rosmarinic Acid-Loaded Transethosomes After Percutaneous Application on a Psoriasis Animal Model.

The topical use of rosmarinic acid (RA) in skin inflammatory pathologies is restricted due to its poor water solubility, poor permeability, and chemical instability. In this study, RA-loaded transethosomes-in-Carbopol® formulations have been developed to evaluate its anti-inflammatory activity on imiquimod-induced psoriasis-like skin inflammation in mice. In vitro release profiles demonstrated sustained behavior due to the retentive action of gel and the entrapment of RA into the vesicles. However, the low viscosity of the combined formulation increased the drug release rate. Animal evaluation of anti-inflammatory activity demonstrated that transethosomes-in-gel containing dexamethasone (Dex-TE-Gel), as positive control, showed effect in all the pro-inflammatory parameters evaluated, evidencing that these drug-loaded nanocarriers have been effectively reached the site of action. In addition, transethosomes-in-gel containing RA (RA-TE-Gel) formulations produced a great reduction in the punch edema (P < 0.001) and in TNF-α and IL-6 (P < 0.05). However, non-significant differences were obtained for IL-1ß, IL17, and MPO. Despite the protecting effect of Carbopol® and transethosomes on oxidation index and antioxidant activity of RA over the 7 days of treatment, however, a degradation process of this antioxidant to caffeic acid may be the cause of these in vivo results. We have also checked that the pH existing into the intercellular space of damaged cells (pH 6.8) may be affecting. Therefore, our results suggest that RA-TE-Gel could act as an effective RA formulation for skin delivery; further studies will help to understand the loss of activity at the cellular level.

New Eunicellin-Type Diterpenes from the Panamanian Octocoral Briareum Asbestinum.

Gorgonian octocorals are considered a prolific source of secondary metabolites with a wide range of biological activities, including anti-inflammatory activity. In particular, the genus Briareum is known for producing a wealth of diterpenes with complex chemical structures. The chemical study of the methanolic extract of Briareum asbestinum collected in Bocas del Toro, on the Caribbean side of Panama, led to the isolation of three new eunicellin-type diterpenes: briarellin T (1), asbestinin 27 (2), asbestinin 28 (3) and the previously described asbestinin 17 (4). The structures of the new compounds were determined by extensive NMR analyses and HRMS. Anti-inflammatory activity assays showed a significant reduction of the pro-inflammatory cytokines TNF-α, IL-6, IL-1ß and IL-8 as well as a downregulation of COX-2 expression in LPS-stimulated THP-1 macrophages. These findings support the potential use of these marine compounds as therapeutic agents in the treatment of inflammatory diseases.

Fucoxanthin and Rosmarinic Acid Combination Has Anti-Inflammatory Effects through Regulation of NLRP3 Inflammasome in UVB-Exposed HaCaT Keratinocytes.

Excessive exposure to ultraviolet (UV) radiation is the main risk factor to develop skin pathologies or cancer because it encourages oxidative condition and skin inflammation. In this sense, strategies for its prevention are currently being evaluated. Natural products such as carotenoids or polyphenols, which are abundant in the marine environment, have been used in the prevention of oxidative stress due to their demonstrated antioxidant activities. Nevertheless, the anti-inflammatory activity and its implication in photo-prevention have not been extensively studied. Thus, we aimed to evaluate the combination of fucoxanthin (FX) and rosmarinic acid (RA) on cell viability, apoptosis induction, inflammasome regulation, and anti-oxidative response activation in UVB-irradiated HaCaT keratinocytes. We demonstrated for the first time that the combination of FX and RA (5 µM RA plus 5 µM FX, designated as M2) improved antioxidant and anti-inflammatory profiles in comparison to compounds assayed individually, by reducing UVB-induced apoptosis and the consequent ROS production. Furthermore, the M2 combination modulated the inflammatory response through down-regulation of inflammasome components such as NLRP3, ASC, and Caspase-1, and the interleukin (IL)-1ß production. In addition, Nrf2 and HO-1 antioxidant genes expression increased in UVB-exposed HaCaT cells pre-treated with M2. These results suggest that this combination of natural products exerts photo-protective effects by down-regulating NRLP3-inflammasome and increasing Nrf2 signalling pathway.

Microalgae-derived oxylipins decrease inflammatory mediators by regulating the subcellular location of NFκB and PPAR-γ.

Oxylipins (OXLs) are bioactive molecules generated by the oxidation of fatty acids that promote the resolution of acute inflammation and prevent chronic inflammatory processes through molecular mechanisms that are not well known. We have previously reported the anti-inflammatory activity of microalgae-derived OXLs and OXL-containing biomass in two inflammatory bowel disease (IBD) models: 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced acute colitis and TNBS-induced recurrent colitis. In this study, we examined the in vitro anti-inflammatory mechanism of action of the most abundant OXLs isolated from Chlamydomonas debaryana (13S-HOTE and 13S-HODE) and Nannochloropsis gaditana (15S-HEPE). These OXLs decreased IL-1ß and IL-6 pro-inflammatory cytokines production as well as iNOS and COX-2 expression levels in THP-1 macrophages. In addition, OXLs decreased IL-8 production in HT-29 colon cells, the major chemokine produced by these cells. The interaction of OXLs with NFκB and PPAR-γ signaling pathways was studied by confocal microscopy. In THP-1 macrophages and HT-29 colon cells, stimulated by LPS and TNFα respectively, a pre-treatment with 13S-HOTE, 13S-HODE and 15S-HEPE (100µM) resulted in a lower nuclear presence of NFκB in both cell lines. The study of the subcellular localization of PPAR-γ showed that the treatment of THP-1 and HT-29 cells with these OXLs caused the migration of PPAR-γ into the nucleus. Colocalization analysis of both transcription factors in LPS-stimulated THP-1 macrophages showed that the pre-treatment with 13S-HOTE, 13S-HODE or 15S-HEPE lowered nuclear colocalization similar to control value, and increased cytosolic localization above control level. These results indicate that these OXLs could act as agonist of PPAR-γ and consequently inhibit NFκB signaling pathway activation, thus lowering the production of inflammatory markers, highlighting the therapeutic potential of these OXLs in inflammatory diseases such as IBD.

Fucoxanthin-Containing Cream Prevents Epidermal Hyperplasia and UVB-Induced Skin Erythema in Mice.

Microalgae represent a source of bio-active compounds such as carotenoids with potent anti-inflammatory and antioxidant properties. We aimed to investigate the effects of fucoxanthin (FX) in both in vitro and in vivo skin models. Firstly, its anti-inflammatory activity was evaluated in LPS-stimulated THP-1 macrophages and TNF-α-stimulated HaCaT keratinocytes, and its antioxidant activity in UVB-irradiated HaCaT cells. Next, in vitro and ex vivo permeation studies were developed to determine the most suitable formulation for in vivo FX topical application. Then, we evaluated the effects of a FX-containing cream on TPA-induced epidermal hyperplasia in mice, as well as on UVB-induced acute erythema in hairless mice. Our results confirmed the in vitro reduction of TNF-α, IL-6, ROS and LDH production. Since the permeation results showed that cream was the most favourable vehicle, FX-cream was elaborated. This formulation effectively ameliorated TPA-induced hyperplasia, by reducing skin edema, epidermal thickness, MPO activity and COX-2 expression. Moreover, FX-cream reduced UVB-induced erythema through down-regulation of COX-2 and iNOS as well as up-regulation of HO-1 protein via Nrf-2 pathway. In conclusion, FX, administered in a topical formulation, could be a novel natural adjuvant for preventing exacerbations associated with skin inflammatory pathologies as well as protecting skin against UV radiation.

Topical Application of Glycolipids from Isochrysis galbana Prevents Epidermal Hyperplasia in Mice.

Chronic inflammatory skin diseases such as psoriasis have a significant impact on society. Currently, the major topical treatments have many side effects, making their continued use in patients difficult. Microalgae have emerged as a source of bio-active molecules such as glycolipids with potent anti-inflammatory properties. We aimed to investigate the effects of a glycolipid (MGMG-A) and a glycolipid fraction (MGDG) obtained from the microalga Isochrysis galbana on a TPA-induced epidermal hyperplasia murine model. In a first set of experiments, we examined the preventive effects of MGMG-A and MGDG dissolved in acetone on TPA-induced hyperplasia model in mice. In a second step, we performed an in vivo permeability study by using rhodamine-containing cream, ointment, or gel to determinate the formulation that preserves the skin architecture and reaches deeper. The selected formulation was assayed to ensure the stability and enhanced permeation properties of the samples in an ex vivo experiment. Finally, MGDG-containing cream was assessed in the hyperplasia murine model. The results showed that pre-treatment with acetone-dissolved glycolipids reduced skin edema, epidermal thickness, and pro-inflammatory cytokine production (TNF-α, IL-1ß, IL-6, IL-17) in epidermal tissue. The in vivo and ex vivo permeation studies showed that the cream formulation had the best permeability profile. In the same way, MGDG-cream formulation showed better permeation than acetone-dissolved preparation. MGDG-cream application attenuated TPA-induced skin edema, improved histopathological features, and showed a reduction of the inflammatory cell infiltrate. In addition, this formulation inhibited epidermal expression of COX-2 in a similar way to dexamethasone. Our results suggest that an MGDG-containing cream could be an emerging therapeutic strategy for the treatment of inflammatory skin pathologies such as psoriasis.

Goniothalamin prevents the development of chemically induced and spontaneous colitis in rodents and induces apoptosis in the HT-29 human colon tumor cell line.

Colon cancer is the third most incident type of cancer worldwide. One of the most important risk factors for colon cancer development are inflammatory bowel diseases (IBD), thus therapies focusing on IBD treatment have great potential to be used in cancer prevention. Nature has been a source of new therapeutic and preventive agents and the racemic form of the styryl-lactone goniothalamin (GTN) has been shown to be a promising antiproliferative agent, with gastroprotective, antinociceptive and anti-inflammatory effects. As inflammation is a well-known tumor promoter, the major goal of this study was to evaluate the therapeutic and preventive potentials of GTN on chemically induced and spontaneous colitis, as well as the cytotoxic effects of GTN on a human colon tumor cell line (HT-29). GTN treatments inhibited TNBS-induced acute and chronic colitis development in Wistar rats, reducing myeloperoxidase levels and inflammatory cells infiltration in the mucosa. In spontaneous-colitis using IL-10 deficient mice (C57BL/6 background), GTN prevented colitis development through downregulation of TNF-α, upregulation of SIRT-1 and inhibition of proliferation (PCNA index), without signs of toxicity after three months of treatment. In HT-29 cells, treatment with 10µM of GTN induced apoptosis by increasing BAX/BCL2, p-JNK1/JNK1, p-P38/P38 ratios as well as through ROS generation. Caspase 8, 9 and 3 activation also occurred, suggesting caspase-dependent apoptotic pathway, culminating in PARP-1 cleavage. Together with previous data, these results show the importance of GTN as a pro-apoptotic, preventive and therapeutic agent for IBD and highlight its potential as a chemopreventive agent for colon cancer.

Anti-inflammatory effects of an oxylipin-containing lyophilised biomass from a microalga in a murine recurrent colitis model.

Diet and nutritional factors have emerged as possible interventions for inflammatory bowel diseases (IBD), which are characterised by chronic uncontrolled inflammation of the intestinal mucosa. Microalgal species are a promising source of n-3 PUFA and derived oxylipins, which are lipid mediators with a key role in the resolution of inflammation. The aim of the present study was to investigate the effects of an oxylipin-containing lyophilised biomass from Chlamydomonas debaryana on a recurrent 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis mice model. Moderate chronic inflammation of the colon was induced in BALB/c mice by weekly intracolonic instillations of low dose of TNBS. Administration of the lyophilised microalgal biomass started 2 weeks before colitis induction and was continued throughout colitis development. Mice were killed 48 h after the last TNBS challenge. Oral administration of the microalgal biomass reduced TNBS-induced intestinal inflammation, evidenced by an inhibition of body weight loss, an improvement in colon morphology and a decrease in pro-inflammatory cytokines TNF-α, IL-1ß, IL-6 and IL-17. This product also down-regulated colonic expressions of inducible nitric oxide, cyclo-oxygenase 2 and NF-κB, as well as increased PPAR-γ. In addition, lyophilised microalgal biomass up-regulated the expressions of the antioxidant transcription factor nuclear factor E2-related factor 2 and the target gene heme oxygenase 1. This study describes for the first time the prophylactic effects of an oxylipin-containing lyophilised microalgae biomass from C. debaryana in the acute phase of a recurrent TNBS-induced colitis model in mice. These findings suggest the potential use of this microalga, or derived oxylipins, as a nutraceutical in the treatment of IBD.

Bioactive Compounds Isolated from Microalgae in Chronic Inflammation and Cancer.

The risk of onset of cancer is influenced by poorly controlled chronic inflammatory processes. Inflammatory diseases related to cancer development include inflammatory bowel disease, which can lead to colon cancer, or actinic keratosis, associated with chronic exposure to ultraviolet light, which can progress to squamous cell carcinoma. Chronic inflammatory states expose these patients to a number of signals with tumorigenic effects, including nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPK) activation, pro-inflammatory cytokines and prostaglandins release and ROS production. In addition, the participation of inflammasomes, autophagy and sirtuins has been demonstrated in pathological processes such as inflammation and cancer. Chemoprevention consists in the use of drugs, vitamins, or nutritional supplements to reduce the risk of developing or having a recurrence of cancer. Numerous in vitro and animal studies have established the potential colon and skin cancer chemopreventive properties of substances from marine environment, including microalgae species and their products (carotenoids, fatty acids, glycolipids, polysaccharides and proteins). This review summarizes the main mechanisms of actions of these compounds in the chemoprevention of these cancers. These actions include suppression of cell proliferation, induction of apoptosis, stimulation of antimetastatic and antiangiogenic responses and increased antioxidant and anti-inflammatory activity.

Preventive effect of the microalga Chlamydomonas debaryana on the acute phase of experimental colitis in rats.

Inflammatory bowel diseases (IBD) are characterised by chronic uncontrolled inflammation of intestinal mucosa. Diet and nutritional factors have emerged as possible interventions for IBD. Microalgae are rich sources of n-3 PUFA and derived oxylipins. Oxylipins are lipid mediators involved in the resolution of many inflammatory disorders. The aim of the present study was to investigate the effects of the oxylipin-containing biomass of the microalga Chlamydomonas debaryana and its major oxylipin constituent, (9Z,11E,13S,15Z)-13-hydroxyoctadeca-9,11,15-trienoic acid ((13S)-HOTE), on acute 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats. Lyophilised microalgal biomass and (13S)-HOTE were administered by oral route 48, 24 and 1 h before the induction of colitis and 24 h later, and the rats were killed after 48 h. The treatment with the lyophilised microalga and (13S)-HOTE improved body-weight loss and colon shortening, as well as attenuated the extent of colonic damage and increased mucus production. Cellular neutrophil infiltration, with the subsequent increase in myeloperoxidase levels induced by TNBS, were also reduced after the administration of the lyophilised microalga or (13S)-HOTE. The anti-inflammatory effects of these treatments were confirmed by the inhibition of colonic TNF-α production. Moreover, lyophilised microalga or (13S)-HOTE down-regulated cyclo-oxygenase-2 and inducible nitric oxide synthase expression. The present study was the first to show the prophylactic effects of a lyophilised biomass sample of the microalga C. debaryana and the oxylipin (13S)-HOTE on TNBS-induced acute colitis in rats. Our findings suggest that the microalga C. debaryana or derived oxylipins could be used as nutraceuticals in the treatment of the active phase of IBD.

Pharmacological characterization of Solanum cernuum Vell.: 31-norcycloartanones with analgesic and anti-inflammatory properties.

Cycloeucalenone (1) and 24-oxo-31-norcycloartanone (2) obtained from Solanum cernuum Vell. were assayed to explore their pharmacologic roles. Previous studies showed that (2) has selective activity against lung tumor cell line (NCIH460) which expresses high levels of COX-2, suggesting its role in inflammatory process, and also a link between chronic inflammation and cancer-associated process. Dichloromethane crude extract (DCE) significantly reduced writhing and stretching induced by 0.8 % acetic acid at a dose of 100, 300, and 600 mg/kg, po; oral administration of different doses of (1) and (2) also displayed significant analgesic and anti-inflammatory effects in the writhing acetic acid test (p < 0.0001). Selected oral doses of both compounds (100 and 50 mg/kg) were assayed in the carrageenan-induced paw edema model. Compound (2) showed significant activity during the early phase (1.5-6 h) and also in the late phase (48 h) (p < 0.01). The anti-nociceptive activity observed for the compounds (1) and (2) and DCE was found to be related to the inhibition of different mediators involved in inflammation and nociceptive process. Both compounds decrease COX-2 protein expression, although only compound (2) reached a significant response (p < 0.05 vs control). However, in vitro Sirtuin 1 activity and TNF-α production in THP-1 macrophages were not affected.

Photoprotective Effects of Two New Morin-Schiff Base Derivatives on UVB-Irradiated HaCaT Cells.

Ultraviolet (UV) radiation harms the skin, causing oxidative damage, inflammation, and disruption of the skin's barrier function. There is considerable interest in identifying new natural ingredients with antioxidant and anti-inflammatory properties to serve as adjuvants in sunscreens. The flavonoid morin (1) can undergo structural modifications to enhance its biological properties. The aim of this study was to synthesize two new morin-Schiff base derivatives, morin oxime (2) and morin semicarbazone (3), comparing their photoprotective effects with that of the parent compound on UVB-exposed HaCaT keratinocytes. The chemical structure of the novel compounds was revealed based on spectroscopic data analysis. Our findings demonstrated that derivatives 2 and 3 enhanced the light absorption capability in the UV-visible (vis) range compared to 1. Tested compounds exhibited a higher scavenger capacity than Trolox. Moreover, pre-treatment with all compounds protected HaCaT cells from UVB-induced cell death. Compound 3 demonstrated the strongest antioxidant effect, reducing reactive oxygen species (ROS) generation and, subsequently, malondialdehyde (MDA) levels. Additionally, compounds 2 and 3 exhibited greater anti-inflammatory effects than compound 1, significantly reducing interleukin (IL)-6 production levels at all tested concentrations. These findings have demonstrated, for the first time, a promising photoprotective activity of two new Schiff base derivatives and suggest their use as natural sunscreen ingredients.

Functional features of the exopolysaccharide extracts produced by Lactiplantibacillus strains isolated from table olives.

This study evaluates the functional characteristics of the exopolysaccharide (EPS) extracts produced by various strains of Lactiplantibacillus pentosus (LPG1, 119, 13B4, and Lp13) and Lactiplantibacillus plantarum (Lp15) isolated from table olives. None of the EPS crude extracts showed cytotoxicity when administered to THP-1 human macrophage cells at dosages ranging from 6.25 to 50 µg mL-1. Many exhibited anti-inflammatory properties (reduction of pro-inflammatory cytokines TNF-α and IL-6 production) and antioxidant activity (reduction of ROS%) when macrophages were stimulated with Escherichia coli lipopolysaccharide. Notably, the EPS extract produced by the L. pentosus LPG1 strain had the best results corroborated by western blot immune analysis for differential expression of COX-2, Nrf-2, and HO-1 proteins, with the most significant antioxidant and anti-inflammatory response observed at a dosage of 50 µg mL-1. Chemical analysis revealed that the EPS extract produced by this strain contains a heteropolymer composed of mannose (35.45%), glucose (32.99%), arabinose (17.93%), xylose (7.48%), galactose (4.03%), rhamnose (1.34%), and fucose (0.77%). Finally, we conducted response surface methodology to model the EPS extract production by L. pentosus LPG1 considering pH (3.48-8.52), temperature (16.59-33.41 °C) and salt concentration (0.03-8.77% NaCl) as independent variables. The model identified linear effects of salt and pH and quadratic effects of salt as significant terms. The maximum EPS extract production (566 mg L-1) in a synthetic culture medium (MRS) was achieved at pH 7.5, salt 7.0%, and a temperature of 20 °C. These findings suggest the potential for novel applications for the EPS produced by L. pentosus LPG1 as nutraceutical candidates for use in human diets.

Exploring Metabolic and Gut Microbiome Responses to Paraquat Administration in Male Wistar Rats: Implications for Oxidative Stress.

In this study, we examined the metabolic and gut microbiome responses to paraquat (PQ) in male Wistar rats, focusing on oxidative stress effects. Rats received a single intraperitoneal injection of PQ at 15 and 30 mg/kg, and various oxidative stress parameters (i.e., MDA, SOD, ROS, 8-isoprostanes) were assessed after three days. To explore the omic profile, GC-qTOF and UHPLC-qTOF were performed to assess the plasma metabolome; 1H-NMR was used to assess the urine metabolome; and shotgun metagenomics sequencing was performed to study the gut microbiome. Our results revealed reductions in body weight and tissue changes, particularly in the liver, were observed, suggesting a systemic effect of PQ. Elevated lipid peroxidation and reactive oxygen species levels in the liver and plasma indicated the induction of oxidative stress. Metabolic profiling revealed changes in the tricarboxylic acid cycle, accumulation of ketone body, and altered levels of key metabolites, such as 3-hydroxybutyric acid and serine, suggesting intricate links between energy metabolism and redox reactions. Plasma metabolomic analysis revealed alterations in mitochondrial metabolism, nicotinamide metabolism, and tryptophan degradation. The gut microbiome showed shifts, with higher PQ doses influencing microbial populations (e.g., Escherichia coli and Akkermansia muciniphila) and metagenomic functions (pyruvate metabolism, fermentation, nucleotide and amino acid biosynthesis). Overall, this study provides comprehensive insights into the complex interplay between PQ exposure, metabolic responses, and gut microbiome dynamics. These findings enhance our understanding of the mechanisms behind oxidative stress-induced metabolic alterations and underscore the connections between xenobiotic exposure, gut microbiota, and host metabolism.

Up-Regulation of the Nrf2/HO-1 Antioxidant Pathway in Macrophages by an Extract from a New Halophilic Archaea Isolated in Odiel Saltworks.

The production of reactive oxygen species (ROS) plays an important role in the progression of many inflammatory diseases. The search for antioxidants with the ability for scavenging free radicals from the body cells that reduce oxidative damage is essential to prevent and treat these pathologies. Haloarchaea are extremely halophilic microorganisms that inhabit hypersaline environments, such as saltworks or salt lakes, where they have to tolerate high salinity, and elevated ultraviolet (UV) and infrared radiations. To cope with these extreme conditions, haloarchaea have developed singular mechanisms to maintain an osmotic balance with the medium, and are endowed with unique compounds, not found in other species, with bioactive properties that have not been fully explored. This study aims to assess the potential of haloarchaea as a new source of natural antioxidant and anti-inflammatory agents. A carotenoid-producing haloarchaea was isolated from Odiel Saltworks (OS) and identified on the basis of its 16S rRNA coding gene sequence as a new strain belonging to the genus Haloarcula. The Haloarcula sp. OS acetone extract (HAE) obtained from the biomass contained bacterioruberin and mainly C18 fatty acids, and showed potent antioxidant capacity using ABTS assay. This study further demonstrates, for the first time, that pretreatment with HAE of lipopolysaccharide (LPS)-stimulated macrophages results in a reduction in ROS production, a decrease in the pro-inflammatory cytokines TNF-α and IL-6 levels, and up-regulation of the factor Nrf2 and its target gene heme oxygenase-1 (HO-1), supporting the potential of the HAE as a therapeutic agent in the treatment of oxidative stress-related inflammatory diseases.

Photoperiod Conditions Modulate Serum Oxylipins Levels in Healthy and Obese Rats: Impact of Proanthocyanidins and Gut Microbiota.

Seasonal rhythms are emerging as a key factor influencing gut microbiota and bioactive compounds functionality as well as several physiological processes such as inflammation. In this regard, their impact on the modulation of oxylipins (OXLs), which are important lipid mediators of inflammatory processes, has not been investigated yet. Hence, we aimed to investigate the effects of photoperiods on OXLs metabolites in healthy and obesogenic conditions. Moreover, we evaluated if the impact of proanthocyanidins and gut microbiota on OXLs metabolism is influenced by photoperiod in obesity. To this purpose, Fischer 344 rats were housed under different photoperiod conditions (L6: 6 h light, L12: 12 h light or L18:18 h light) and fed either a standard chow diet (STD) or a cafeteria diet (CAF) for 9 weeks. During the last 4 weeks, obese rats were daily administered with an antibiotic cocktail (ABX), an oral dose of a grape seed proanthocyanidin extract (GSPE), or with their combination. CAF feeding and ABX treatment affected OXLs in a photoperiod dependent-manner. GSPE significantly altered prostaglandin E2 (PGE2) levels, only under L6 and mitigated ABX-mediated effects only under L18. In conclusion, photoperiods affect OXLs levels influenced by gut microbiota. This is the first time that the effects of photoperiod on OXLs metabolites have been demonstrated.

Rhythm and ROS: Hepatic Chronotherapeutic Features of Grape Seed Proanthocyanidin Extract Treatment in Cafeteria Diet-Fed Rats.

Polyphenols play a key role in the modulation of circadian rhythms, while the cafeteria diet (CAF) is able to perturb the hepatic biological rhythm and induce important ROS production. Consequently, we aimed to elucidate whether grape seed proanthocyanidin extract (GSPE) administration recovers the CAF-induced hepatic antioxidant (AOX) misalignment and characterize the chronotherapeutic properties of GSPE. For this purpose, Fischer 344 rats were fed a standard diet (STD) or a CAF and concomitantly treated with GSPE at two time-points (ZT0 vs. ZT12). Animals were euthanized every 6 h and the diurnal rhythms of hepatic ROS-related biomarkers, hepatic metabolites, and AOX gene expression were examined. Interestingly, GSPE treatment was able to recover the diurnal rhythm lost due to the CAF. Moreover, GSPE treatment also increased the acrophase of Sod1, as well as bringing the peak closer to that of the STD group. GSPE also corrected some hepatic metabolites altered by the CAF. Importantly, the differences observed at ZT0 vs. ZT12 due to the time of GSPE administration highlight a chronotherapeutic profile on the proanthocyanin effect. Finally, GSPE could also reduce diet-induced hepatic oxidative stress not only by its ROS-scavenging properties but also by retraining the circadian rhythm of AOX enzymes.

9-PAHPA long term intake in DIO and db/db mice ameliorates insulin sensitivity but has few effects on obesity and associated metabolic disorders.

Branched fatty acid esters of hydroxy fatty acids are endogenous lipids reported to have antidiabetic and anti-inflammatory effects. Recently, we showed that 9-palmitic acid esters of hydroxypalmitic acid (9-PAHPA) and 9-oleic acid esters of hydroxypalmitic acid increased insulin sensitivity in mice when incorporated to a chow diet or to a high fat and high sucrose diet. However, preventive supplementation with 9-PAHPA and 9-oleic acid esters of hydroxypalmitic acid in high fat and high sucrose diet mice did not impair significant weight gain or the development of hyperglycemia. The aim of this work was therefore to study whether in two animal models of obesity, namely the classical diet-induced obesity (DIO) and the db/db mice, 9-PAHPA may have beneficial effects against obesity and liver and skeletal muscle metabolic dysfunction. In DIO mice, we observed that 9-PAHPA increased body weight and fat mass. In line with this observation, we found that 9-PAHPA supplementation decreased energy expenditure. In liver and in skeletal muscle, mitochondrial activities and oxidative stress parameters were not modified by 9-PAHPA supplementation. In db/db mice, 9-PAHPA had no effect on the dramatic weight gain and hyperglycemia. In addition, 9-PAHPA supplementation did not correct either the hepatomegaly and hepatic steatosis or the severe muscle atrophy recorded compared with db/+ animals. Likewise, supplementation with 9-PAHPA did not impact the different metabolic parameters analyzed, either in the liver or in the skeletal muscles. However, it decreased insulin resistance in DIO and db/db mice. In conclusion, our study indicated that a long-term intake of 9-PAHPA in DIO and db/db mice improved insulin sensitivity but had only few effects on obesity and associated metabolic disorders.