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Eosinophils are myeloid effector cells whose main homing is the gastrointestinal tract. There, they take part in type I and type II immune responses. They also contribute to other non-immunological homeostatic functions like mucus production, tissue regeneration, and angiogenesis. In colorectal cancer (CRC), eosinophils locate in the center of the tumor and in the front of invasion and play an anti-tumoral role. They directly kill tumor cells by releasing cytotoxic compounds and eosinophil extracellular traps or indirectly by activating other immune cells via cytokines. As CRC progresses, the number of infiltrating eosinophils decreases. Although this phenomenon is not fully understood, it is known that some changes in the microenvironmental milieu and microbiome can affect eosinophil infiltration. Importantly, a high number of intratumoral eosinophils is a favorable prognostic factor independent from the tumor stage. Moreover, after immunotherapy, responding patients usually display eosinophilia, so eosinophils could be a good biomarker candidate to monitor treatment outcomes. Finally, even though eosinophils seem to play an interesting anti-tumoral role in CRC, much more research is needed to fully understand their interactions in the CRC microenvironment. This review explores the multifaceted roles of eosinophils in colorectal cancer, highlighting their anti-tumoral effects, prognostic significance, and potential as a biomarker for treatment outcomes.
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Neoplasias Colorretais , Eosinófilos , Microambiente Tumoral , Humanos , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Eosinófilos/imunologia , Eosinófilos/metabolismo , Microambiente Tumoral/imunologia , Prognóstico , Animais , Imunoterapia/métodos , Biomarcadores Tumorais/metabolismoRESUMO
(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.
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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.
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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.
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Azathioprine is commonly used as an immunosuppressive antimetabolite in the treatment of acute lymphoblastic leukemia, autoimmune disorders (such as Crohn's disease and rheumatoid arthritis), and in patients receiving organ transplants. Thiopurine-S-methyltransferase (TPMT) is a cytoplasmic trans-methylase catalyzing the S-methylation of thiopurines. The active metabolites obtained from thiopurines are hydrolyzed into inactive forms by the Nudix hydrolase 15 (NUDT15). The TPMT*2 (defined by rs1800462), *3A (defined by rs1800460 and rs1142345), *3B (defined by rs1800460), *3C (defined by rs1142345), *6 (defined by rs75543815), and NUDT15 rs116855232 genetic variant have been associated, with the highest level of evidence, with the response to azathioprine, and, the approved drug label for azathioprine and main pharmacogenetic dosing guidelines recommend starting with reduced initial doses in TPMT intermediate metabolizer (IM) patients and considering an alternative treatment in TPMT poor metabolizer (PM) patients. This study aims to assess the clinical impact of azathioprine dose tailoring based on TPMT genotyping studying the azathioprine toxicity and efficacy, treatment starts, and dose adjustments during follow-up, comparing TPMT IM/PM and normal metabolizer (NM) patients. It also studied the association of NUDT15 rs116855232 with response to azathioprine in patients receiving a tailored treatment based on TPMT and characterized the TMPT and NUDT15 studied variants in our population. Results show that azathioprine dose reduction in TPMT IM patients (TPMT*1/*2, *1/*3A, or *1/*3C genotypes) is related to lower toxicity events compared to TPMT NM (TPMT *1/*1 genotype), and lower azathioprine dose adjustments during follow-up without showing differences in the efficacy. The results support the hypothesis of existing other genetic variants affecting azathioprine toxicity.
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Azatioprina , Doença de Crohn , Humanos , Azatioprina/efeitos adversos , Farmacogenética , Imunossupressores/uso terapêutico , Genótipo , Doença de Crohn/tratamento farmacológico , Metiltransferases/genética , Pirofosfatases/genéticaRESUMO
BACKGROUND: Patients with inflammatory bowel disease (IBD) have a higher risk of developing colitis-associated colorectal cancer (CAC) with poor prognosis. IBD etiology remains undefined but involves environmental factors, genetic predisposition, microbiota imbalance (dysbiosis) and mucosal immune defects. Mesenchymal stromal cell (MSC) injections have shown good efficacy in reducing intestinal inflammation in animal and human studies. However, their effect on tumor growth in CAC and their capacity to restore gut dysbiosis are not clear. METHODS: The outcome of systemic administrations of in vitro expanded human intestinal MSCs (iMSCs) on tumor growth in vivo was evaluated using the AOM/DSS model of CAC in C57BL/6J mice. Innate and adaptive immune responses in blood, mesenteric lymph nodes (MLNs) and colonic tissue were analyzed by flow cytometry. Intestinal microbiota composition was evaluated by 16S rRNA amplicon sequencing. RESULTS: iMSCs significantly inhibited colitis and intestinal tumor development, reducing IL-6 and COX-2 expression, and IL-6/STAT3 and PI3K/Akt signaling. iMSCs decreased colonic immune cell infiltration, and partly restored intestinal monocyte homing and differentiation. iMSC administration increased the numbers of Tregs and IFN-γ+CD8+ T cells in the MLNs while decreasing the IL-4+Th2 response. It also ameliorated intestinal dysbiosis in CAC mice, increasing diversity and Bacillota/Bacteroidota ratio, as well as Akkermansia abundance, while reducing Alistipes and Turicibacter, genera associated with inflammation. CONCLUSION: Administration of iMSCs protects against CAC, ameliorating colitis and partially reverting intestinal dysbiosis, supporting the use of MSCs for the treatment of IBD.
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Neoplasias Associadas a Colite , Colite , Doenças Inflamatórias Intestinais , Células-Tronco Mesenquimais , Humanos , Camundongos , Animais , Neoplasias Associadas a Colite/complicações , Neoplasias Associadas a Colite/patologia , Interleucina-6 , Camundongos Endogâmicos C57BL , Disbiose/complicações , Linfócitos T CD8-Positivos , RNA Ribossômico 16S , Fosfatidilinositol 3-Quinases , Colite/patologia , Inflamação , Colo/patologia , Doenças Inflamatórias Intestinais/patologia , Imunidade , Sulfato de Dextrana , Modelos Animais de DoençasRESUMO
Aging is a biological process with high susceptibility to several infections. This risk increases in older patients in residential care facilities (RCF). Thus, there is a clear demand for developing preventive interventions with new therapeutic compounds that combine efficacy and safety. This could be the case of compounds derived from plants of the genus Allium spp. The purpose of this study was to evaluate the impact of a combination of a garlic and onion extract concentrate standardized in organosulfur compounds derived from propiin on the incidence of respiratory tract infections in elderly patients of RCF. Sixty-five volunteers were selected at random to receive a placebo or a single daily dose of the extract for thirty-six weeks. Different clinical visits were performed to evaluate the main respiratory diseases with an infectious origin, as well as the associated symptoms and their duration. The extract showed a clinical safety profile and significantly reduced the incidence of respiratory infections. Moreover, the treatment decreased the number and duration of the associated symptoms compared with the placebo group. For the first time, we demonstrated the protective effect of Alliaceae extract in respiratory infectious diseases in elderly healthy volunteers, which could be used prophylactically against the most common infectious respiratory diseases.
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Doenças Transmissíveis , Alho , Infecções Respiratórias , Humanos , Idoso , Cebolas , Antioxidantes , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/prevenção & controle , Extratos Vegetais/uso terapêutico , Extratos Vegetais/farmacologia , VoluntáriosRESUMO
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.
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Obesity is a global health issue, in which modifications in gut microbiota composition have a key role. Different therapeutic strategies are being developed in combination with diet and exercise, including the use of plant extracts, such as those obtained from Morus alba L. leaves. Recent studies have revealed their anti-inflammatory and antioxidant properties. The aim of the present work was to evaluate whether the beneficial effects of M. alba L. leaf extract in high-fat diet-induced obesity in mice is correlated with its impact on gut microbiota. The extract reduced body weight gain and attenuated lipid accumulation, as well as increased glucose sensitivity. These effects were associated with an amelioration of the obesity-associated inflammatory status, most probably due to the described antioxidant properties of the extract. Moreover, M. alba L. leaf extract mitigated gut dysbiosis, which was evidenced by the restoration of the Firmicutes/Bacteroidota ratio and the decrease in plasma lipopolysaccharide (LPS) levels. Specifically, the extract administration reduced Alistipes and increased Faecalibaculum abundance, these effects being correlated with the beneficial effects exerted by the extract on the obesity-associated inflammation. In conclusion, anti-obesogenic effects of M. alba L. leaf extract may be mediated through the amelioration of gut dysbiosis.
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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.
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Antineoplásicos , Neoplasias Colorretais , Animais , Camundongos , Tigeciclina/efeitos adversos , beta Catenina/metabolismo , Neoplasias Colorretais/genética , Carcinogênese , Transformação Celular Neoplásica/metabolismo , Via de Sinalização Wnt , Antineoplásicos/efeitos adversos , Imunidade , Antibacterianos/efeitos adversos , Proliferação de CélulasRESUMO
Poly(ADP-ribose) polymerase-1 (PARP-1) is a protein involved in multiple physiological processes. Elevated PARP-1 expression has been found in several tumours, being associated with stemness and tumorigenesis. In colorectal cancer (CRC), some controversy among studies has been described. In this study, we analysed the expression of PARP-1 and cancer stem cell (CSC) markers in CRC patients with different p53 status. In addition, we used an in vitro model to evaluate the influence of PARP-1 in CSC phenotype regarding p53. In CRC patients, PARP-1 expression correlated with the differentiation grade, but this association was only maintained for tumours harbouring wild-type p53. Additionally, in those tumours, PARP-1 and CSC markers were positively correlated. In mutated p53 tumours, no associations were found, but PARP-1 was an independent factor for survival. According to our in vitro model, PARP-1 regulates CSC phenotype depending on p53 status. PARP-1 overexpression in a wild type p53 context increases CSC markers and sphere forming ability. By contrast, those features were reduced in mutated p53 cells. These results could implicate that patients with elevated PARP-1 expression and wild type p53 could benefit from PARP-1 inhibition therapies, meanwhile it could have adverse effects for those carrying mutated p53 tumours.
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Neoplasias Colorretais , Células-Tronco Neoplásicas , Poli(ADP-Ribose) Polimerase-1 , Proteína Supressora de Tumor p53 , Humanos , Neoplasias Colorretais/metabolismo , Células-Tronco Neoplásicas/metabolismo , Fenótipo , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Proteína Supressora de Tumor p53/metabolismo , Poli(ADP-Ribose) Polimerase-1/metabolismoRESUMO
Increasing rates of cancer incidence and the side-effects of current chemotherapeutic treatments have led to the research on novel anticancer products based on dietary compounds. The use of Allium metabolites and extracts has been proposed to reduce the proliferation of tumor cells by several mechanisms. In this study, we have shown the in vitro anti-proliferative and anti-inflammatory effect of two onion-derived metabolites propyl propane thiosulfinate (PTS) and propyl propane thiosulfonate (PTSO) on several human tumor lines (MCF-7, T-84, A-549, HT-29, Panc-1, Jurkat, PC-3, SW-837, and T1-73). We observed that this effect was related to their ability to induce apoptosis regulated by oxidative stress. In addition, both compounds were also able to reduce the levels of some pro-inflammatory cytokines, such as IL-8, IL-6, and IL-17. Therefore, PTS and PTSO may have a promising role in cancer prevention and/or treatment.
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Allium , Humanos , Propano , Dieta , Cebolas , Anti-Inflamatórios/farmacologiaRESUMO
The SARS-CoV-2 infection has increased the number of patients entering Intensive Care Unit (ICU) facilities and antibiotic treatments. Concurrently, the multi-drug resistant bacteria (MDRB) colonization index has risen. Considering that most of these bacteria are derived from gut microbiota, the study of its composition is essential. Additionally, SARS-CoV-2 infection may promote gut dysbiosis, suggesting an effect on microbiota composition. This pilot study aims to determine bacteria biomarkers to predict MDRB colonization risk in SARS-CoV-2 patients in ICUs. Seventeen adult patients with an ICU stay >48 h and who tested positive for SARS-CoV-2 infection were enrolled in this study. Patients were assigned to two groups according to routine MDRB colonization surveillance: non-colonized and colonized. Stool samples were collected when entering ICUs, and microbiota composition was determined through Next Generation Sequencing techniques. Gut microbiota from colonized patients presented significantly lower bacterial diversity compared with non-colonized patients (p < 0.05). Microbiota in colonized subjects showed higher abundance of Anaerococcus, Dialister and Peptoniphilus, while higher levels of Enterococcus, Ochrobactrum and Staphylococcus were found in non-colonized ones. Moreover, LEfSe analysis suggests an initial detection of Dialister propionicifaciens as a biomarker of MDRB colonization risk. This pilot study shows that gut microbiota profile can become a predictor biomarker for MDRB colonization in SARS-CoV-2 patients.
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The present work is focused on the development of an analytical platform to elucidate the metabolic pathway of PTSO from onion, an organosulfur compound well-known for its functional and technological properties and its potential application in animal and human nutrition. This analytical platform consisted of the use of gas chromatography-mass spectrometry (GC-MS) and ultra-high performance liquid chromatography quadrupole with time-of-flight MS (UHPLC-Q-TOF-MS) in order to monitor volatile and non-volatile compounds derived from the PTSO. For the extraction of the compounds of interest, two different sample treatments were developed: liquid-liquid extraction (LLE) and salting-out assisted liquid-liquid extraction (SALLE) for GC-MS and UHPLC-Q-TOF-MS analysis, respectively. Once the analytical platform was optimised and validated, an in vivo study was planned to elucidate PTSO metabolisation, revealing the presence of dipropyl disulfide (DPDS) in liver samples with concentrations between 0.11 and 0.61 µg g-1. The DPDS maximum concentration in the liver was observed at 0.5 h after the intake. DPDS was also present in all plasma samples with concentrations between 2.1 and 2.4 µg mL-1. In regard to PTSO, it was only found in plasma at times above 5 h (0.18 µg mL-1). Both PTSO and DPDS were excreted via urine 24 h after ingestion.
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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.
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Colite , Doenças Inflamatórias Intestinais , Dor Visceral , Camundongos , Animais , Minociclina/farmacologia , Minociclina/uso terapêutico , Dor Visceral/tratamento farmacológico , Qualidade de Vida , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/patologia , Inflamação/tratamento farmacológico , Antibacterianos/farmacologia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , ColoRESUMO
Lactobacillus probiotics contained in dietary supplements or functional foods are well-known for their beneficial properties exerted on host health and diverse pathological situations. Their capacity to improve inflammatory bowel disease (IBD) and regulate the immune system is especially remarkable. Although bacteria-host interactions have been thought to occur directly, the key role that extracellular vesicles (EVs) derived from probiotics play on this point is being unveiled. EVs are lipid bilayer-enclosed particles that carry a wide range of cargo compounds and act in different signalling pathways. Notably, these EVs have been recently proposed as a safe alternative to the utilisation of live bacteria since they can avoid the possible risks that probiotics may entail in vulnerable cases such as immunocompromised patients. Therefore, this review aims to give an updated overview of the existing knowledge about EVs from different Lactobacillus strains, their mechanisms and effects in host health and different pathological conditions. All of the information collected suggests that EVs could be considered as potential tools for the development of future novel therapeutic approaches.
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Vesículas Extracelulares , Doenças Inflamatórias Intestinais , Humanos , Lactobacillaceae , Vesículas Extracelulares/metabolismo , Doenças Inflamatórias Intestinais/terapia , Doenças Inflamatórias Intestinais/metabolismo , Lactobacillus/metabolismo , Sistema ImunitárioRESUMO
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.
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BACKGROUND AND PURPOSE: Melatonin has shown beneficial effects on obesity, both in humans and experimental models, via regulating the altered circadian rhythm and thus ameliorating the gut dysbiosis associated with this metabolic condition. However, its clinical use is limited, mostly due to its short half-life. Agomelatine is an agonist of the melatonin receptors that could be used to manage obesity and offer a better profile than melatonin. EXPERIMENTAL APPROACH: Male C57BL/6 mice were fed a high fat diet and orally treated for five weeks with agomelatine, or melatonin or metformin, used as control drugs. Metabolic profile, inflammatory status, vascular dysfunction and intestinal microbiota composition were assessed. KEY RESULTS: Agomelatine lessened body weight gain, enhanced glucose and lipid metabolisms, and improved insulin resistance. It also reduced the obesity-associated inflammatory status and endothelial dysfunction, probably linked to its effect on gut dysbiosis, consisting of the restoration of bacterial populations with key functions, such as short chain fatty acid production. CONCLUSIONS AND IMPLICATIONS: Agomelatine can be considered as a novel therapeutic tool for the management of human obesity and its associated comorbidities.
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Microbioma Gastrointestinal , Melatonina , Acetamidas , Animais , Dieta Hiperlipídica/efeitos adversos , Disbiose/tratamento farmacológico , Disbiose/microbiologia , Humanos , Masculino , Melatonina/farmacologia , Melatonina/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Naftalenos , Obesidade/metabolismoRESUMO
Nowadays, there is an increasing interest in alternative therapies in the treatment of metabolic syndrome that combine efficacy and safety profiles. Therefore, this study aimed to evaluate the effect of an extract of Thymus serpyllum, containing rosmarinic acid, on high-fat diet (HFD)-induced obesity mice, highlighting the impact of its antioxidant activity on the inflammatory status and gut dysbiosis. The extract was administered daily (50, 100 and 150 mg/kg) in HFD-fed mice. The treatment reduced body weight gain, glucose and lipid metabolic profiles. Moreover, the extract ameliorated the inflammatory status, with the c-Jun N-terminal kinases (JUNK) pathway being involved, and showed a significant antioxidant effect by the reduction of radical scavenging activity and the mitigation of lipid peroxidation. Moreover, the extract was able to modulate the altered gut microbiota, restoring microbial richness and diversity, and augmenting the counts of short-chain fatty acid producing bacteria, which have been associated with the maintenance of gut permeability and weight regulation. In conclusion, the antioxidant activity of Thymus serpyllum extract displayed a positive impact on obesity and its metabolic alterations, also reducing systemic inflammation. These effects may be mediated by modulation of the gut microbiota.