PIM serine/threonine kinases are overexpressed, translocated, or amplified in multiple B-cell lymphoma types. We have explored the frequency and relevance of PIM expression in different B-cell ...lymphoma types and investigated whether PIM inhibition could be a rational therapeutic approach. Increased expression of PIM2 was detected in subsets of mantle cell lymphoma, diffuse large B-cell lymphoma (DLBLC), follicular lymphoma, marginal zone lymphoma-mucosa–associated lymphoid tissue type, chronic lymphocytic leukemia, and nodal marginal zone lymphoma cases. Increased PIM2 protein expression was associated with an aggressive clinical course in activated B-like-DLBCL patients. Pharmacologic and genetic inhibition of PIM2 revealed p4E-BP1(Thr37/46) and p4E-BP1(Ser65) as molecular biomarkers characteristic of PIM2 activity and indicated the involvement of PIM2 kinase in regulating mammalian target of rapamycin complex 1. The simultaneous genetic inhibition of all 3 PIM kinases induced changes in apoptosis and cell cycle. In conclusion, we show that PIM2 kinase inhibition is a rational approach in DLBCL treatment, identify appropriate biomarkers for pharmacodynamic studies, and provide a new marker for patient stratification.
Limosilactobacillus fermentum CECT5716, a probiotic strain isolated from human milk, has reported beneficial effects on different gastrointestinal disorders. Moreover, it has shown its ability to ...restore altered immune responses, in association with microbiome modulation in different pathological conditions. Therefore, our aim was to assess the effects of a Limosilacbacillus fermentum CECT5716 in a rat experimental model of irritable bowel syndrome (IBS) that resembles human IBS. The experimental IBS was induced by deoxycholic acid (DCA) in rats and then, Limosilactobacillus fermentum CECT5716 (109 CFU/day/rat) was administered. Behavioral studies, hyperalgesia and intestinal hypersensitivity determinations were performed and the impact of the probiotic on the inflammatory and intestinal barrier integrity was evaluated. Additionally, the gut microbiota composition was analyzed. Limosilactobacillus fermentum CECT5716 attenuated the anxiety-like behavior as well as the visceral hypersensitivity and referred pain. Moreover, this probiotic ameliorated the gut inflammatory status, re-establishing the altered intestinal permeability, reducing the mast cell degranulation and re-establishing the gut dysbiosis in experimental IBS. Therefore, our results suggest a potential use of Limosilactobacillus fermentum CECT5716 in clinical practice for the management of IBS patients.
The presented work collects results from the evaluation of electrical response to mechanical deformation and formation of defects presented by different polymeric based composite materials with ...potential for applications in Structural Health Monitoring and Strain Detection. With the aim of showing the variety of key materials in sectors like civil aviation, wind energy, automotive or railway that present this ability, specimens of very different nature have been analyzed: a) thermoplastic commercial 3D printing filaments loaded with carbonic fillers; b) epoxy resin loaded with Carbon Nanotubes and c) long carbon fiber reinforced resin composite. Measurements of electrical properties of these materials were taken to evaluate their capability to detect the presence of structural defects of different sizes as well as its spatial location. On the other hand, simultaneous measurements of electrical resistivity and mechanical strain during tensile tests were performed to analyze the potential of materials as strain detectors. All composites studied have shown a positive response (modification of electrical performance) to external mechanical stimulus: induced damage and deformations.
Graphical Abstract
The use of z-drugs has increased worldwide since its introduction. Although the prescribing patterns of hypnotics differ among countries, zolpidem is the most widely used z-drug in the world. ...Zolpidem may be involved in poisoning and deaths. A simple and fast HPLC-PDA method was developed and validated. Zolpidem and the internal standard chloramphenicol were extracted from plasma using a sonication-assisted dispersive liquid–liquid microextraction procedure. The method was validated including selectivity, linearity, precision, accuracy, and recovery. The calibration range (0.15–0.6 µg/mL) covers therapeutic and toxic levels of zolpidem in plasma. The limit of quantification was set at 0.15 µg/mL. Intra- and interday accuracy and precision values were lower than 15% at the concentration levels studied. Excellent recovery results were obtained for all concentrations. The proposed method was successfully applied to ten real postmortem plasma samples. In our series, multiple substances (alcohol and/or other drugs) were detected in most cases of death involving zolpidem. Our analytical method is suitable for routine toxicological analysis.
Scope
Obesity is characterized by a dysfunction in the adipose tissue and an inflammatory subclinical state leading to insulin resistance and increased risk of cardiovascular diseases. It is also ...associated with intestinal dysbiosis that contributes to inflammation development. Lippia citriodora (LCE) contains high levels of polyphenolpropanoids and has shown promising results in obesity. The aim of this study is to investigate a well‐characterized extract of LCE in a model of metabolic syndrome in mice, focusing on its effects on metabolic tissues, endothelial dysfunction, and microbiome.
Methods
Mice are fed a high fat diet (HFD) for six weeks and treated daily with LCE (1, 10, and 25 mg kg−1). Glucose and lipid metabolism is investigated. The inflammatory state in the metabolic tissues and the intestinal microbiota composition are characterized, as well as the endothelium‐dependent vasodilator response to acetylcholine.
Results
LCE reduces fat accumulation and improves plasma glycemic and lipid profiles, as well as the inflammatory process and vascular dysfunction. Moreover, LCE lessens intestinal dysbiosis, as it reduces the Firmicutes/Bacteroidetes ratio and increases Akkermansia abundance in comparison with untreated HFD mice.
Conclusion
The antiobesity therapeutic properties of LCE are most probably mediated by the synergic effects of its bioactive compounds.
The aim of this study is the evaluation of Lippia Citriodora extract (LCE) treatment on diet‐induced obesity in mice. LCE administration ameliorates induced obesity, enhancing the inflammatory status and the vascular functionality. Furthermore, it is the first time that LCE treatment is shown to modulate the gut microbiota. These findings support the use of LCE as a new functional food in metabolic syndrome.
A complete study is presented on the response of thermoplastic and thermoplastic composite materials for bearing cages of bogie trains for rail applications to aging conditions in presence of ...lubricants. Glass Fiber reinforced Polyamaide 66 (GF PA66) is proposed as commercial material already used in the field while Polyether Ether Ketone (PEEK) is proposed as novel polymeric candidate material due to its chemical stability and high mechanical performance. Accelerated aging tests were performed to analyze the response of these materials to external chemical agents under different conditions. Afterwards, a complete set of mechanical and physical tests and characterization procedures were carried out, before and after ageing on suitable samples of the polymers in combination with lubricants, to evaluate the effects of the chemical environment on the mechanical and physical properties of the presented polymers. Results are highly relevant since cages are permanently soaked in lubricant during their operation life. GR PA66 presents better global mechanical properties due to the important glass fiber load (30 %). Nevertheless, the values obtained also show that PEEK remains unalterable under different aging conditions. According to the results it can be suggested that PEEK might be considered as a suitable potential alternative, when necessary, in applications with a high resistance to chemical environment requirements. The lack of published papers reporting behavior of PEEK in the analyzed circumstances highlights the novelty and importance of results obtained in this work.
Recent epidemiological and clinical data suggest that elevated serum homocysteine levels may increase the risk of developing Alzheimer's disease (AD), but the underlying mechanisms are unknown. We ...tested the hypothesis that high serum homocysteine concentration may increase amyloid beta-peptide (Aβ) levels in the brain and could therefore accelerate AD neuropathology. For this purpose, we mated a hyperhomocysteinemic CBS
tm1Unc mouse carrying a heterozygous dominant mutation in cystathionine-beta-synthase (CBS*) with the APP*/PS1* mouse model of brain amyloidosis. The APP*/PS1*/CBS* mice showed significant elevations of serum homocysteine levels compared to the double transgenic APP*/PS1* model of amyloidosis. Results showed that female (but not male) APP*/PS1*/CBS* mice exhibited significant elevations of Aβ40 and Aβ42 levels in the brain. Correlations between homocysteine levels in serum and brain Aβ levels were statistically significant. No increases in beta secretase activity or evidence of neuronal cell loss in the hyperhomocysteinemic mice were found.
The causes of neuronal dysfunction and degeneration in AD are not fully understood, but increased production of Aβ seems to be of major importance. By unveiling a link between homocysteine and Aβ levels, these findings advance our understanding on the mechanisms involved in hyperhomocysteinemia as a risk factor for AD.
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.
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.
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.
Agomelatine can be considered as a novel therapeutic tool for the management of human obesity and its associated comorbidities.
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Background: Propyl propane thiosulfonate (PTSO) is an organosulfur compound from Allium spp. that has shown interesting antimicrobial properties and immunomodulatory effects in different experimental ...models. In this sense, our aim was to evaluate its effect on an experimental model of obesity, focusing on inflammatory and metabolic markers and the gut microbiota. Methods and results: Mice were fed a high-fat diet and orally treated with different doses of PTSO (0.1, 0.5 and 1 mg/kg/day) for 5 weeks. PTSO lessened the weight gain and improved the plasma markers associated with glucose and lipid metabolisms. PTSO also attenuated obesity-associated systemic inflammation, reducing the immune cell infiltration and, thus, the expression of pro-inflammatory cytokines in adipose and hepatic tissues (Il-1ẞ, Il-6, Tnf-α, Mcp-1, Jnk-1, Jnk-2, Leptin, Leptin R, Adiponectin, Ampk, Ppar-α, Ppar-γ, Glut-4 and Tlr-4) and improving the expression of different key elements for gut barrier integrity (Muc-2, Muc-3, Occludin, Zo-1 and Tff-3). Additionally, these effects were connected to a regulation of the gut microbiome, which was altered by the high-fat diet. Conclusion: Allium-derived PTSO can be considered a potential new tool for the treatment of metabolic syndrome.
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