A recombinant glucocorticoid-induced leucine zipper protein ameliorates symptoms of dextran sulfate sodium-induced colitis by improving intestinal permeability.

Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders characterized by relapsing intestinal inflammation, but many details of pathogenesis remain to be fully unraveled. Glucocorticoid (GC)-induced leucine zipper (GILZ) is a mediator of the anti-inflammatory effects of GCs, the most powerful drugs for IBD treatment, but they cause several unwanted side effects. The fusion protein TAT-GILZ has been successfully used in some pre-clinical models of inflammatory and autoimmune diseases. To test the efficacy of TAT-GILZ for treating dextran sulfate sodium (DSS)-induced colitis and explore its impact on the gut microbiome, colitis was induced by DSS in C57BL/6J mice and treated with TAT-GILZ or dexamethasone. Various hallmarks of colitis were analyzed, including disease activity index, gut permeability, and expression of pro-inflammatory cytokines and tight junction proteins. TAT-GILZ treatment showed a therapeutic effect when administered after the onset of colitis. Its efficacy was associated with improved gut permeability, as evidenced by zonula occludens-1 and CD74 upregulation in inflamed colonic tissue. TAT-GILZ also ameliorated the changes in the gut microbiota induced by the DSS, thus potentially providing an optimal environment for colonization of the mucosa surface by beneficial bacteria. Overall, our results demonstrated for the first time that TAT-GILZ treatment proved effective after disease onset allowing restoration of gut permeability, a key pathogenic feature of colitis. Additionally, TAT-GILZ restored gut dysbiosis, thereby contributing to healing mechanisms. Interestingly, we found unprecedented effects of exogenous GILZ that did not overlap with those of GCs.

Lactobacillus fermentum CECT5716 ameliorates high fat diet-induced obesity in mice through modulation of gut microbiota dysbiosis.

Obesity is one of the main features of metabolic syndrome, where a low-grade chronic inflammation and gut dysbiosis contribute to the development of the related metabolic dysfunctions. Different probiotics have demonstrated beneficial effects on this condition, increasing the interest in the development of probiotic treatments. Lactobacillus fermentum CECT5716 has shown anti-inflammatory effects and capacity to modulate microbiota composition in different experimental models. In this study, L. fermentum CECT5716 was evaluated in a model of high fat diet-induced obesity in mice. It exerts anti-obesity effects, associated with its anti-inflammatory properties and amelioration of endothelial dysfunction and gut dysbiosis. The probiotic restores Akkermansia sp. abundance and reduced Erysipelotrichi class and Clostridium spp presence as well as increased Bacteroides proportion. In conclusion, this probiotic represents a very interesting approach. Our findings describe, for the first time, the ability of this probiotic to ameliorate experimental obesity through microbiome modulation, affecting different bacteria that have been reported to play a key role in the pathogenesis of obesity. Therefore, this suggests a potential use of L. fermentum CECT5716 in clinical practice, also taking into account that probiotic treatments have demonstrated to be relatively safe and well tolerated.

Intestinal anti-inflammatory effects of probiotics in DNBS-colitis via modulation of gut microbiota and microRNAs.

PURPOSE: Probiotics have been shown to exert beneficial effects in IBD although their exact mechanisms are not completely understood. The aim of the present study was to assess the intestinal anti-inflammatory activity of different probiotics (Lactobacillus fermentum CECT5716, Lactobacillus salivarius CECT5713, Escherichia coli Nissle 1917, Saccharomyces boulardii CNCMI-745 in the dinitrobenzene sulfonic acid (DNBS) model of mouse colitis and correlate it with the modifications of the gut microbiota and the immune response, focusing on miRNA expression. METHODS: The probiotics were daily administered orally for 25 days. On day 19 colitis was induced by rectal installation of DNBS. At the end of the treatment, mice were sacrificed and the colonic damage was assessed biochemically by analysing the expression of different markers involved in the immune response, including miRNAs; and the colonic microbiota by pyrosequencing. Probiotics properties were also evaluated in vitro in different immune cell types (CMT-93 intestinal epithelial cells and bone marrow-derived macrophages), where the expression of different mRNAs and miRNAs was examined. RESULTS: All the probiotics displayed intestinal anti-inflammatory effects but slightly different, especially regarding miRNAs expression. Likewise, the probiotics ameliorated the colitis-associated dysbiosis, although showing differences in the main bacterial groups affected. CONCLUSION: Among the probiotics assayed, Lactobacillus fermentum CECT5716 and Escherichia coli Nissle 1917 appear to present the best intestinal anti-inflammatory effects, being the latter one of the few probiotics with reputed efficacy in human IBD. Therefore, Lactobacillus fermentum CECT5716 could be considered as a complementary nutritional strategy for IBD treatment.

Intestinal anti-inflammatory activity of the total alkaloid fraction from Fumaria capreolata in the DSS model of colitis in mice.

Fumaria genus has been traditionally used for managing inflammatory and gastrointestinal disorders. The study evaluates the immunomodulatory potential of the total alkaloid fraction from Fumaria capreolata L. (AFC) in primary macrophages and the intestinal anti-inflammatory effect in a dextran sodium sulphate-induced colitis in mice. AFC inhibited LPS-stimulated bone marrow-derived macrophages gene expression program dose-dependently. In vivo, AFC markedly reduced macroscopic and microscopic signs of intestinal inflammation. Besides, it restored the colonic expression of pro-inflammatory and anti-inflammatory mediators, as well as enhanced the expression of intestinal barrier markers. These results demonstrate the potential of AFC extract as a therapeutic tool for the management of inflammatory bowel disease.

The metabolic and vascular protective effects of olive (Olea europaea L.) leaf extract in diet-induced obesity in mice are related to the amelioration of gut microbiota dysbiosis and to its immunomodulatory properties.

INTRODUCTION: Many studies have showed the beneficial effects of the olive (Olea europaea) leaf extract (OLE) in experimental models of metabolic syndrome, which have been ascribed to the presence of phenolic compounds, like oleuropeoside. This study evaluated the effects of a chemically characterized OLE in high fat diet (HFD)-induced obesity in mice, describing the underlying mechanisms involved in the beneficial effects, with special attention to vascular dysfunction and gut microbiota composition. METHODS: C57BL/6J mice were distributed in different groups: control, control-treated, obese and obese-treated with OLE (1, 10 and 25 mg/kg/day). Control mice received a standard diet, whereas obese mice were fed HFD. The treatment was followed for 5 weeks, and animal body weight periodically assessed. At the end of the treatment, metabolic plasma analysis (including lipid profile) as well as glucose and insulin levels were performed. The HFD-induced inflammatory status was studied in liver and fat, by determining the RNA expression of different inflammatory mediators by qPCR; also, different markers of intestinal epithelial barrier function were determined in colonic tissue by qPCR. Additionally, flow cytometry of immune cells from adipose tissue, endothelial dysfunction in aortic rings as well as gut microbiota composition were evaluated. Faecal microbiota transplantation (FMT) to antibiotic-treated mice fed with HFD was performed. RESULTS: OLE administration reduced body weight gain, basal glycaemia and insulin resistance, and showed improvement in plasma lipid profile when compared with HFD-fed mice. The extract significantly ameliorated the HFD-induced altered expression of key adipogenic genes, like PPARs, adiponectin and leptin receptor, in adipose tissue. Furthermore, the extract reduced the RNA expression of Tnf-α, Il-1ß, Il-6 in liver and adipose tissue, thus improving the tissue inflammatory status associated to obesity. The flow cytometry analysis in adipose tissue corroborated these observations. Additionally, the characterization of the colonic microbiota by sequencing showed that OLE administration was able to counteract the dysbiosis associated to obesity. The extract reversed the endothelial dysfunction observed in the aortic rings of obese mice. FMT from donors HFD-OLE to recipient mice fed an HFD prevented the development of obesity, glucose intolerance, insulin resistance and endothelial dysfunction. CONCLUSION: OLE exerts beneficial effects in HFD-induced obesity in mice, which was associated to an improvement in plasma and tissue metabolic profile, inflammatory status, gut microbiota composition and vascular dysfunction.

Impact of an Evidence-Based Prioritization System and Electronic Consultation in Early Diagnosis of Colorectal Cancer.

(1) Background: Colorectal cancer (CRC) is one of the most common causes of cancer. Timely diagnosis is critical, with even minor delays impacting prognosis. Primary care providers face obstacles in accessing specialist care. This study investigates the impact of implementing an electronic consultation (eConsult) system combined with a specific prioritization system on CRC diagnosis delay and tumor staging. (2) Methods: The study analyzes 245 CRC patients from November 2019 to February 2022, comparing those referred before and after the eConsult system's implementation during the COVID-19 pandemic. Data on referral reasons, pathways, diagnosis delays, and staging were collected. Multivariate analysis aimed to identify independent risk factors for advanced staging at diagnosis. (3) Results: The eConsult system significantly reduced CRC diagnosis delay from 68 to 26 days. The majority of patients referred via eConsult presented with symptoms. Despite expedited diagnoses, no discernible difference in CRC staging emerged between eConsult and traditional referrals. Notably, patients from screening programs or with a positive fecal immunochemical test (FIT) experienced earlier-stage diagnoses. A positive FIT without symptoms and being a never-smoker emerged as protective factors against advanced-stage CRC. (4) Conclusions: This study highlights eConsult's role in reducing CRC diagnosis delay, improving diagnostic efficiency and prioritizing urgent cases, emphasizing FIT effectiveness.

Mitochondrial Dysfunction and Mitophagy in Type 2 Diabetes: Pathophysiology and Therapeutic Targets.

Significance: Type 2 diabetes mellitus, which is related to oxidative stress and mitochondrial dysfunction, is one of the most prevalent diseases in the world. In the past decade, alterations in autophagy have been shown to play a fundamental role in the development and control of type 2 diabetes. Further, mitophagy has been recognized as a key player in eliminating dysfunctional mitochondria in this disease. Recent Advances: Recently, much progress has been made in understanding the molecular events associated with oxidative stress, mitochondrial dysfunction, and alterations in autophagy and mitophagy in type 2 diabetes. Critical Issues: Despite increasing evidence of a relationship between mitochondrial dysfunction, oxidative stress, and alterations of autophagy and mitophagy and their role in the pathophysiolology of type 2 diabetes, effective therapeutic strategies to combat the disease through targeting mitochondria, autophagy, and mitophagy are yet to be implemented. Future Directions: This review provides a wide perspective of the existing literature concerning the complicated interplay between autophagy, mitophagy, and mitochondrial dysfunction in type 2 diabetes. Further, potential therapeutic targets based on these molecular mechanisms are explored. Antioxid. Redox Signal. 39, 278-320.

Minocycline Prevents the Development of Key Features of Inflammation and Pain in DSS-induced Colitis in Mice.

Abdominal pain is a common feature in inflammatory bowel disease (IBD) patients, and greatly compromises their quality of life. Therefore, the identification of new therapeutic tools to reduce visceral pain is one of the main goals for IBD therapy. Minocycline, a broad-spectrum tetracycline antibiotic, has gained attention in the scientific community because of its immunomodulatory and anti-inflammatory properties. The aim of this study was to evaluate the potential of this antibiotic as a therapy for the management of visceral pain in dextran sodium sulfate (DSS)-induced colitis in mice. Preemptive treatment with minocycline markedly reduced histological features of intestinal inflammation and the expression of inflammatory markers (Tlr4, Tnfα, Il1ß, Ptgs2, Inos, Cxcl2, and Icam1), and attenuated the decrease of markers of epithelial integrity (Tjp1, Ocln, Muc2, and Muc3). In fact, minocycline restored normal epithelial permeability in colitic mice. Treatment with the antibiotic also reversed the changes in the gut microbiota profile induced by colitis. All these ameliorative effects of minocycline on both inflammation and dysbiosis correlated with a decrease in ongoing pain and referred hyperalgesia, and with the improvement of physical activity induced by the antibiotic in colitic mice. Minocycline might constitute a new therapeutic approach for the treatment of IBD-induced pain. PERSPECTIVE: This study found that the intestinal anti-inflammatory effects of minocycline ameliorate DSS-associated pain in mice. Therefore, minocycline might constitute a novel therapeutic strategy for the treatment of IBD-induced pain.

Pectin from sunflower by-products obtained by ultrasound: Chemical characterization and in vivo evaluation of properties in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a public health challenge and the use of pectin for symptom amelioration is a promising option. In this work, sunflower pectin has been extracted without (CHP) and with assistance of ultrasound (USP) using sodium citrate as a food-grade extracting agent. At optimal conditions (64 °C, 23 min) the highest yield was obtained with ultrasound application (15.5 vs. 8.1 %). Both pectins were structurally characterized by 1H NMR, HPSEC-ELSD, FT-IR and GC-FID. Unlike CHP, USP showed a lower molecular weight, higher galacturonic acid, lower degree of methyl-esterification and, overall, higher viscosity. These characteristics could affect the anti-inflammatory activity of pectins, evaluated using DSS-induced IBD model mice. So, USP promoted the defence (ICAM-1) and repair of the gastrointestinal mucosa (TFF3, ZO-1) more effectively than CHP. These results demonstrate the potential amelioration of acute colitis in IBD mice through USP supplementation. Taking into account the biomarkers analysed, these results demonstrate, for the first time, the positive impact of sunflower pectin extracted by ultrasound under very soft conditions on inflammatory bowel disease that might open up new possibilities in the treatment of this serious pathology.

Solanum aethiopicum L. from the Basilicata region as a source of specialized metabolites with promising anti-obesity effects: phytochemical characterization and in vivo investigation in high fat diet-fed mice.

Introduction: Solanum aethiopicum L., commonly known as scarlet eggplant (Solanaceae family) is one of the most traditionally cultivated vegetables in Basilicata, a southern region of Italy. Although multiple uses have been given to this vegetable, data about its anti-obesogenic activity are still limited. Methods: This study focuses on testing two different extracts obtained either from the peel or from the whole fruit of the Lucanian Solanum aethiopicum. Their ability to inhibit certain enzymatic activities was tested in vitro and then, the one that showed the better outcomes was tested on an experimental model of High-Fat Diet (HFD) induced obesity. Results: Spectrophotometric assays demonstrated that the peel extract possessed the highest ability to inhibit the selected enzymatic activities and so, its phytochemical profile was obtained through LC-MS chromatography. The oral administration of this extract (25 mg/kg) to HFD-fed mice reduced body weight gain and improved glucose and lipid metabolism. Similarly, the extract ameliorated the obesity-induced inflammatory status by reducing the expression of pro-inflammatory cytokines in both adipose and hepatic tissues. Interestingly, these effects were associated with the improvement of vascular dysfunction. Discussion: Lucanian Solanum aethiopicum extract may represent a new strategic approach for managing obesity and its associated diseases.

The Antioxidant Properties of Salvia verbenaca Extract Contribute to Its Intestinal Antiinflammatory Effects in Experimental Colitis in Rats.

Inflammatory bowel disease (IBD) is a chronic gastrointestinal inflammation with unpredictable symptom fluctuations. While there is no effective cure for IBD, various treatments aim to manage symptoms and improve the quality of life for affected individuals. In recent years, there has been growing interest in the potential benefits of certain natural plants and herbs in the management of IBD. In this regard, this study aimed to evaluate the immunomodulatory and anti-inflammatory effects of a well-characterized extract of Salvia verbenaca (S. verbenaca) in an experimental model of colitis in rats. Interestingly, the daily administration of S. verbenaca (10 and 25 mg/kg) effectively alleviated colitis symptoms, as evidenced by reduced weight/length ratio and colonic damage. Moreover, it reduced oxidative stress markers (MPO and GSH), decreased pro-inflammatory cytokine expression (Il-6, Il-12a, Il-1ß, Il-23, Icam-1, Mcp-1, Cinc-1), and preserved the integrity of the intestinal barrier (Villin, Muc-2, Muc-3). These effects suggest S. verbenaca extract could represent a potential complementary candidate to treat gastrointestinal disorders. Its beneficial actions can be related to its antioxidant properties as well as the downregulation of the immune response, which can result in the improvement in the intestine epithelial barrier.

The Antioxidant Properties of Lavandula multifida Extract Contribute to Its Beneficial Effects in High-Fat Diet-Induced Obesity in Mice.

Obesity is a worldwide public health problem whose prevalence rate has increased steadily over the last few years. Therefore, it is urgent to improve the management of obesity and its comorbidities, and plant-based treatments are receiving increasing attention worldwide. In this regard, the present study aimed to investigate a well-characterized extract of Lavandula multifida (LME) in an experimental model of obesity in mice and explore the underlying mechanisms. Interestingly, the daily administration of LME reduced weight gain as well as improved insulin sensitivity and glucose tolerance. Additionally, LME ameliorated the inflammatory state in both liver and adipose tissue by decreasing the expression of various proinflammatory mediators (Il-6, Tnf-α, Il-1ß, Jnk-1, Pparα, Pparγ, and Ampk) and prevented increased gut permeability by regulating the expression of mucins (Muc-1, Muc-2, and Muc-3) and proteins implicated in epithelial barrier integrity maintenance (Ocln, Tjp1, and Tff-3). In addition, LME showed the ability to reduce oxidative stress by inhibiting nitrite production on macrophages and lipid peroxidation. These results suggest that LME may represent a promising complementary approach for the management of obesity and its comorbidities.

Tigecycline reduces tumorigenesis in colorectal cancer via inhibition of cell proliferation and modulation of immune response.

BACKGROUND: and Purpose: Colorectal cancer (CRC) is one of the cancers with the highest incidence in which APC gene mutations occur in almost 80% of patients. This mutation leads to ß-catenin aberrant accumulation and an uncontrolled proliferation. Apoptosis evasion, changes in the immune response and microbiota composition are also events that arise in CRC. Tetracyclines are drugs with proven antibiotic and immunomodulatory properties that have shown cytotoxic activity against different tumor cell lines. EXPERIMENTAL APPROACH: The effect of tigecycline was evaluated in vitro in HCT116 cells and in vivo in a colitis-associated colorectal cancer (CAC) murine model. 5-fluorouracil was assayed as positive control in both studies. KEY RESULTS: Tigecycline showed an antiproliferative activity targeting the Wnt/ß-catenin pathway and downregulating STAT3. Moreover, tigecycline induced apoptosis through extrinsic, intrinsic and endoplasmic reticulum pathways converging on an increase of CASP7 levels. Furthermore, tigecycline modulated the immune response in CAC, reducing the cancer-associated inflammation through downregulation of cytokines expression. Additionally, tigecycline favored the cytotoxic activity of cytotoxic T lymphocytes (CTLs), one of the main immune defenses against tumor cells. Lastly, the antibiotic reestablished the gut dysbiosis in CAC mice increasing the abundance of bacterial genera and species, such as Akkermansia and Parabacteroides distasonis, that act as protectors against tumor development. These findings resulted in a reduction of the number of tumors and an amelioration of the tumorigenesis process in CAC. CONCLUSION AND IMPLICATIONS: Tigecycline exerts a beneficial effect against CRC supporting the use of this antibiotic for the treatment of this disease.

Metformin modulates mitochondrial function and mitophagy in peripheral blood mononuclear cells from type 2 diabetic patients.

Type 2 diabetes is a chronic metabolic disease that affects mitochondrial function. In this context, the rescue mechanisms of mitochondrial health, such as mitophagy and mitochondrial biogenesis, are of crucial importance. The gold standard for the treatment of type 2 diabetes is metformin, which has a beneficial impact on the mitochondrial metabolism. In this study, we set out to describe the effect of metformin treatment on mitochondrial function and mitophagy in peripheral blood mononuclear cells (PBMCs) from type 2 diabetic patients. We performed a preliminary cross-sectional observational study complying with CONSORT requirements, for which we recruited 242 subjects, divided into 101 healthy volunteers, 93 metformin-treated type 2 diabetic patients and 48 non-metformin-treated type 2 diabetic patients. Mitochondria from the type 2 diabetic patients not treated with metformin displayed more reactive oxygen species (ROS) than those from healthy or metformin-treated subjects. Protein expression of the electron transport chain (ETC) complexes was lower in PBMCs from type 2 diabetic patients without metformin treatment than in those from the other two groups. Mitophagy was altered in type 2 diabetic patients, evident in a decrease in the protein levels of PINK1 and Parkin in parallel to that of the mitochondrial biogenesis protein PGC1α, both of which effects were reversed by metformin. Analysis of AMPK phosphorylation revealed that its activation was decreased in the PBMCs of type 2 diabetic patients, an effect which was reversed, once again, by metformin. In addition, there was an increase in the serum levels of TNFα and IL-6 in type 2 diabetic patients and this was reversed with metformin treatment. These results demonstrate that metformin improves mitochondrial function, restores the levels of ETC complexes, and enhances AMPK activation and mitophagy, suggesting beneficial clinical implications in the treatment of type 2 diabetes.

Roux-en-Y Gastric Bypass Modulates AMPK, Autophagy and Inflammatory Response in Leukocytes of Obese Patients.

Obesity is characterized by low-grade chronic inflammation, metabolic overload, and impaired endothelial and cardiovascular function. Roux-en-Y gastric bypass (RYGB) results in amelioration of the pro-oxidant status of leukocytes and the metabolic profile. Nevertheless, little is known about the precise mechanism that drives systemic and metabolic improvements following bariatric surgery. In this cohort study, we investigated the effect of RYGB on molecular pathways involving energy homeostasis in leukocytes in 43 obese subjects one year after surgery. In addition to clinical and biochemical parameters, we determined protein expression of systemic proinflammatory cytokines by Luminex®, different markers of inflammation, endoplasmic reticulum (ER) stress, autophagy/mitophagy by western blot, and mitochondrial membrane potential by fluorescence imaging. Bariatric surgery induced an improvement in metabolic outcomes that was accompanied by a systemic drop in hsCRP, IL6, and IL1ß levels, and a slowing down of intracellular inflammatory pathways in leukocytes (NF-κB and MCP-1), an increase in AMPK content, a reduction of ER stress (ATF6 and CHOP), augmented autophagy/mitophagy markers (Beclin 1, ATG5, LC3-I, LC3-II, NBR1, and PINK1), and a decrease of mitochondrial membrane potential. These findings shed light on the specific molecular mechanisms by which RYGB facilitates metabolic improvements, highlighting the relevance of pathways involving energy homeostasis as key mediators of these outcomes. In addition, since leukocytes are particularly exposed to physiological changes, they could be used in routine clinical practice as a good sensor of the whole body's responses.

The Role of Mitochondrial Dynamic Dysfunction in Age-Associated Type 2 Diabetes.

Mitochondrial dynamics, such as fusion and fission, play a critical role in maintaining cellular metabolic homeostasis. The molecular mechanisms underlying these processes include fusion proteins (Mitofusin 1 [MFN1], Mitofusin 2 [MFN2], and optic atrophy 1 [OPA1]) and fission mediators (mitochondrial fission 1 [FIS1] and dynamin-related protein 1 [DRP1]), which interact with each other to ensure mitochondrial quality control. Interestingly, defects in these proteins can lead to the loss of mitochondrial DNA (mtDNA) integrity, impairment of mitochondrial function, a severe alteration of mitochondrial morphology, and eventually cell death. Emerging evidence has revealed a causal relationship between dysregulation of mitochondria dynamics and age-associated type 2 diabetes, a metabolic disease whose rates have reached an alarming epidemic-like level with the majority of cases (59%) recorded in men aged 65 and over. In this sense, fragmentation of mitochondrial networks is often associated with defects in cellular energy production and increased apoptosis, leading, in turn, to excessive reactive oxygen species release, mitochondrial dysfunction, and metabolic alterations, which can ultimately contribute to ß-cell dysfunction and insulin resistance. The present review discusses the processes of mitochondrial fusion and fission and their dysfunction in type 2 diabetes, with special attention given to the therapeutic potential of targeting mitochondrial dynamics in this complex metabolic disorder.

Myrianthus arboreus P. Beauv improves insulin sensitivity in high fat diet-induced obese mice by reducing inflammatory pathways activation.

ETHNOPHARMACOLOGICAL RELEVANCE: Metabolic syndrome is currently recognized as the major cause of morbidity, with dramatic complications on life expectancy and health status. Myrianthus arboreus is a medicinal plant traditionally used in local communities as a safe remedy in treating diabetes and other metabolic diseases. AIM OF THE STUDY: This study aimed to investigate the impact of a methanol extract of Myrianthus arboreus leaf (MAL) in a mice model of metabolic syndrome induced by a high-fat diet (HFD) intake. MATERIALS AND METHODS: Male C57BL/6J mice were assigned to the following groups: control, obese control, and obese treated with MAL extract (10, 25, and 50 mg/kg) for 6 weeks. Control mice received a standard chow diet, while all obese mice were fed with HFD. Animal weight and food consumption were periodically measured. At the end of the treatment, fasting blood glucose and metabolic plasma analysis (insulin level, triglycerides, and total cholesterol (TC)) were performed. The HFD-induced inflammatory status and the expression of several obesity-related markers were evaluated in liver and fat using qPCR and Western blot analysis. In addition, the phytochemical composition of MAL was identified by GC-MS and HPLC-MS. RESULTS: MAL administration significantly reduced body weight gain, basal glycemia, and insulin resistance, and improved plasma lipid profile compared with HFD-fed mice. Similarly, this extract improved the HFD-associated inflammatory status in mice by gene expression modulation of different inflammatory markers involved in this experimentally induced metabolic condition. CONCLUSION: These results demonstrate the novel applicability of MAL, thus suggesting it as a promising therapeutic approach for the management of metabolic disorders.

Impact of Roux-en-Y Gastric Bypass on Mitochondrial Biogenesis and Dynamics in Leukocytes of Obese Women.

The chronic low-grade inflammation widely associated with obesity can lead to a prooxidant status that triggers mitochondrial dysfunction. To date, Roux-en-Y gastric bypass (RYGB) is considered the most effective strategy for obese patients. However, little is known about its molecular mechanisms. This interventional study aimed to investigate whether RYGB modulates oxidative stress, inflammation and mitochondrial dynamics in the leukocytes of 47 obese women at one year follow-up. We evaluated biochemical parameters and serum inflammatory cytokines -TNFα, IL6 and IL1ß- to assess systemic status. Total superoxide production -dHe-, mitochondrial membrane potential -TMRM-, leucocyte protein expression of inflammation mediators -MCP1 and NF-kB-, antioxidant defence -GPX1-, mitochondrial regulation-PGC1α, TFAM, OXPHOS and MIEAP- and dynamics -MFN2, MNF1, OPA1, FIS1 and p-DRP1- were also determined. After RYGB, a significant reduction in superoxide and mitochondrial membrane potential was evident, while GPX1 content was significantly increased. Likewise, a marked upregulation of the transcription factors PGC1α and TFAM, complexes of the oxidative phosphorylation chain (I-V) and MIEAP and MFN1 was observed. We conclude that women undergoing RYGB benefit from an amelioration of their prooxidant and inflammatory status and an improvement in mitochondrial dynamics of their leukocytes, which is likely to have a positive effect on clinical outcome.

Intestinal anti-inflammatory and visceral analgesic effects of a Serpylli herba extract in an experimental model of irritable bowel syndrome in rats.

Ethnopharmacological relevance: Serpylli herba extract (SHE), composed of the aerial parts of wild thyme (Thymus serpyllum L.) (Lamiaceae family), is traditionally used in Europe and North Africa to treat diarrhea, gastric ulcers, intestinal parasites and upper respiratory tract infections. Recently, SHE has generated a great interest for irritable bowel syndrome (IBS) management, probably due to its intestinal anti-inflammatory properties shown in experimental colitis and the fact that its active components could preserve the intestinal barrier integrity, which is altered in patients with IBS. Aim of study: We aimed to test the effects of a SHE in a rat experimental model resembling human IBS. Materials and methods: IBS was provoked by deoxycholic acid (DCA). Rats were then treated with SHE (100 mg/kg) or gabapentin (70 mg/kg) and different inflammatory and gut barrier integrity markers were evaluated. Moreover, several gut hypersensitivity and hyperalgesia determinations were performed. Results: SHE improved referred pain and visceral hypersensitivity. Additionally, SHE enhanced immune status by downregulating of the expression of the pro-inflammatory mediators Il-1ß, Il-6, Ifn-γ, Tlr-4, and the inducible enzyme Cox-2, thus inducing visceral analgesia, and promoting the restore of the gut barrier function by upregulating the mucins Muc-2 and Muc-3. These anti-inflammatory effects could be related to its action on mast cells since it significantly inhibited the ß-Hexosaminidase production in RBL-2H3 cells. Lastly, SHE also seems to modulate the serotonin pathway by restoring the altered expression of the 5-HT receptors Htr-3 and Htr-4. Conclusion: SHE could be considered a potential new treatment for IBS, since it ameliorates hypersensitivity, visceral hyperalgesia, and inflammation. These beneficial effects may be due to the inhibition of mast cells degranulation and serotonin pathway.