ABSTRACT
Analyzing changes in gene expression within specific brain regions of individuals with Type 2 Diabetes (T2DM) who do not exhibit significant cognitive deficits can yield valuable insights into the mechanisms underlying the progression towards a more severe phenotype. In this study, transcriptomic analysis of the cortex and hippocampus of mice with long-term T2DM revealed alterations in the expression of 28 genes in the cerebral cortex and 15 genes in the hippocampus. Among these genes, six displayed consistent changes in both the cortex and hippocampus: Interferon regulatory factor 7 (Irf7), Hypoxia-inducible factor 3 alpha (Hif-3α), period circadian clock 2 (Per2), xanthine dehydrogenase (Xdh), and Transforming growth factor ß-stimulated clone 22/TSC22 (Tsc22d3) were upregulated, while Claudin-5 (Cldn5) was downregulated. Confirmation of these changes was achieved through RT-qPCR. At the protein level, CLDN5 and IRF7 exhibited similar alterations, with CLDN5 being downregulated and IRF7 being upregulated. In addition, the hippocampus and cortex of the T2DM mice showed decreased levels of IκBα, implying the involvement of NF-κB pathways as well. Taken together, these results suggest that the weakening of the blood-brain barrier and an abnormal inflammatory response via the Interferon 1 and NF-κB pathways underlie cognitive impairment in individuals with long-standing T2DM.
Subject(s)
Cerebral Cortex , Claudin-5 , Diabetes Mellitus, Experimental , Diabetes Mellitus, Type 2 , Hippocampus , Interferon Regulatory Factor-7 , Animals , Cerebral Cortex/metabolism , Hippocampus/metabolism , Claudin-5/metabolism , Claudin-5/genetics , Mice , Diabetes Mellitus, Experimental/metabolism , Interferon Regulatory Factor-7/metabolism , Interferon Regulatory Factor-7/genetics , Male , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/genetics , Mice, Inbred C57BLABSTRACT
The enterolignans, enterolactone and enterodiol, the main metabolites produced from plant lignans by the gut microbiota, have enhanced bioavailability and activity compared to their precursors, with beneficial effects on metabolic and cardiovascular health. Although extensively studied, the biosynthesis, cardiometabolic effects, and other therapeutic implications of mammalian lignans are still incompletely understood. The aim of this review is to provide a comprehensive overview of these phytoestrogen metabolites based on up-to-date information reported in studies from a wide range of disciplines. Established and novel synthetic strategies are described, as are the various lignan precursors, their dietary sources, and a proposed metabolic pathway for their conversion to enterolignans. The methodologies used for enterolignan analysis and the available data on pharmacokinetics and bioavailability are summarized and their cardiometabolic bioactivity is explored in detail. The special focus given to research on the health benefits of microbial-derived lignan metabolites underscores the critical role of lignan-rich diets in promoting cardiovascular health.
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BACKGROUND: Metabolic syndrome (MetS) in adolescence is a risk factor for future cardiovascular disease. The chronic inflammation associated with MetS can be attenuated by the anti-inflammatory effect of polyphenols. We aimed to evaluate total urinary polyphenols as a biomarker of anti-inflammatory diets and their effect on MetS in adolescents. METHODS: In this retrospective analysis of a longitudinal cohort study, the relationship between total polyphenol excretion (TPE) in urine, the inflammatory potential of the diet measured through the Children's Dietary Inflammatory Index (C-DII), and the presence of metabolic syndrome was evaluated. The study population consisted of adolescents enrolled in the SI! Program for Secondary Schools trial, who had completed all the study forms and provided urine samples at baseline and at the two-year follow-up. Multivariate linear regression and multinominal logistic regression models were generated to evaluate the relationship of changes in TPE with changes in the C-DII score and changes in MetS status, respectively. An analysis of the ROC curve was performed to assess the potential of TPE as a biomarker of an anti-inflammatory diet. RESULTS: This study included 662 adolescents, 51.2% were males, and 48.8% were females, with a mean age of 12 (0.38) years at baseline. The relationship between changes in TPE and changes in the C-DII score was stratified by sex with a p-value <0.001 for the interaction. TPE and C-DII were inversely associated in males (-0.13 mg GAE/g creatinine [-0.26; -0.01] per 1-SD increase, p-value = 0.037). In addition, an increase in changes in TPE levels were associated with a reversal in MetS status in all adolescents (1.30 [1.27; 1.34] per 1-SD increase, p-value<0.001). The ROC curve showed that urinary TPE levels can predict dietary inflammatory potential with an AUC = 0.793 (0.725; 0.863) in males. CONCLUSION: Polyphenols excreted in urine are a potential biomarker of anti-inflammatory diets in males and are associated with a reversal of MetS status in adolescents. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, Identifier: NCT03504059, https://clinicaltrials.gov/study/NCT03504059.
Subject(s)
Biomarkers , Diet , Metabolic Syndrome , Polyphenols , Humans , Male , Female , Polyphenols/administration & dosage , Polyphenols/urine , Adolescent , Biomarkers/urine , Metabolic Syndrome/urine , Longitudinal Studies , Retrospective Studies , Diet/methods , Inflammation/urine , Child , Anti-Inflammatory Agents/administration & dosageABSTRACT
The aim of this research was to find out the effect of different combinations of starter and non-starter cultures on the proteolysis of Castellano cheese during ripening. Four cheese batches were prepared, each containing autochthonous lactobacilli and or Leuconostoc, and were compared with each other and with a control batch, that used only a commercial starter. To achieve this, nitrogen fractions (pH 4.4-soluble nitrogen and 12 % trichloroacetic acid soluble nitrogen, polypeptide nitrogen and casein nitrogen), levels of free amino acids and biogenic amines were assessed. Texture and microstructure of cheeses were also evaluated. Significant differences in nitrogen fractions were observed between batches at different stages of ripening. The free amino acid content increased throughout the cheese ripening process, with a more significant increase occurring after the first 30 days. Cheeses containing non-starter lactic acid bacteria exhibited the highest values at the end of the ripening period. Among the main amino acids, GABA was particularly abundant, especially in three of the cheese batches at the end of ripening. The autochthonous lactic acid bacteria were previously selected as non-producers of biogenic amines and this resulted in the absence of these compounds in the cheeses. Analysis of the microstructure of the cheese reflected the impact of proteolysis. Additionally, the texture profile analysis demonstrated that the cheese's hardness intensified as the ripening period progressed. The inclusion of autochthonous non-starter lactic acid bacteria in Castellano cheese production accelerated the proteolysis process, increasing significantly the free amino acids levels and improving the sensory quality of the cheeses.
Subject(s)
Amino Acids , Biogenic Amines , Cheese , Proteolysis , Cheese/microbiology , Cheese/analysis , Amino Acids/analysis , Amino Acids/metabolism , Biogenic Amines/analysis , Food Microbiology , Food Handling/methods , Leuconostoc/metabolism , Leuconostoc/growth & development , Lactobacillus/metabolism , Lactobacillus/growth & development , Nitrogen/analysis , Food Quality , FermentationABSTRACT
BACKGROUND: The identification of novel therapeutic strategies to overcome resistance to the MEK inhibitor trametinib in mutant KRAS lung adenocarcinoma (LUAD) is a challenge. This study analyzes the effects of trametinib on Id1 protein, a key factor involved in the KRAS oncogenic pathway, and investigates the role of Id1 in the acquired resistance to trametinib as well as the synergistic anticancer effect of trametinib combined with immunotherapy in KRAS-mutant LUAD. METHODS: We evaluated the effects of trametinib on KRAS-mutant LUAD by Western blot, RNA-seq and different syngeneic mouse models. Genetic modulation of Id1 expression was performed in KRAS-mutant LUAD cells by lentiviral or retroviral transductions of specific vectors. Cell viability was assessed by cell proliferation and colony formation assays. PD-L1 expression and apoptosis were measured by flow cytometry. The anti-tumor efficacy of the combined treatment with trametinib and PD-1 blockade was investigated in KRAS-mutant LUAD mouse models, and the effects on the tumor immune infiltrate were analyzed by flow cytometry and immunohistochemistry. RESULTS: We found that trametinib activates the proteasome-ubiquitin system to downregulate Id1 in KRAS-mutant LUAD tumors. Moreover, we found that Id1 plays a major role in the acquired resistance to trametinib treatment in KRAS-mutant LUAD cells. Using two preclinical syngeneic KRAS-mutant LUAD mouse models, we found that trametinib synergizes with PD-1/PD-L1 blockade to hamper lung cancer progression and increase survival. This anti-tumor activity depended on trametinib-mediated Id1 reduction and was associated with a less immunosuppressive tumor microenvironment and increased PD-L1 expression on tumor cells. CONCLUSIONS: Our data demonstrate that Id1 expression is involved in the resistance to trametinib and in the synergistic effect of trametinib with anti-PD-1 therapy in KRAS-mutant LUAD tumors. These findings suggest a potential therapeutic approach for immunotherapy-refractory KRAS-mutant lung cancers.
Subject(s)
Adenocarcinoma of Lung , Adenocarcinoma , Lung Neoplasms , Pyridones , Pyrimidinones , Mice , Animals , Programmed Cell Death 1 Receptor , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolism , Down-Regulation , Immune Checkpoint Inhibitors/therapeutic use , B7-H1 Antigen/metabolism , Adenocarcinoma of Lung/drug therapy , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/pathology , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Adenocarcinoma/genetics , Disease Models, Animal , Cell Line, Tumor , Tumor MicroenvironmentABSTRACT
The human gut microbiota is a complex community of micro-organisms that play a crucial role in maintaining overall health. Recent research has shown that gut microbes also have a profound impact on brain function and cognition, leading to the concept of the gut-brain axis. One way in which the gut microbiota can influence the brain is through the bioconversion of polyphenols to other bioactive molecules. Phenolic compounds are a group of natural plant metabolites widely available in the human diet, which have anti-inflammatory and other positive effects on health. Recent studies have also suggested that some gut microbiota-derived phenolic metabolites may have neurocognitive effects, such as improving memory and cognitive function. The specific mechanisms involved are still being studied, but it is believed that phenolic metabolites may modulate neurotransmitter signaling, reduce inflammation, and enhance neural plasticity. Therefore, to exert a protective effect on neurocognition, dietary polyphenols or their metabolites must reach the brain, or act indirectly by producing an increase in bioactive molecules such as neurotransmitters. Once ingested, phenolic compounds are subjected to various processes (eg, metabolization by gut microbiota, absorption, distribution) before they cross the blood-brain barrier, perhaps the most challenging stage of their trajectory. Understanding the role of phenolic compounds in the gut-brain axis has important implications for the development of new therapeutic strategies for neurological and psychiatric disorders. By targeting the gut microbiota and its production of phenolic metabolites, it may be possible to improve brain function and prevent cognitive decline. In this article, the current state of knowledge on the endogenous generation of phenolic metabolites by the gut microbiota and how these compounds can reach the brain and exert neurocognitive effects was reviewed.
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INTRODUCTION: Tafamidis is the only approved transthyretin stabiliser approved for the treatment of variant transthyretin amyloidosis (A-ATTRv) related polyneuropathy (PNP). The aim of this study is to analyse the effectiveness of tafamidis in a real-world setting in Spain. METHODS: This is a national multicenter study in which patients with V30M A-ATTR related PN treated with tafamidis for at least 1 year were included. Clinical, demographic, analytical and neurophysiological variables were analysed. RESULTS: 100 patients were recruited. Overall, 47 patients (47%) were classified as complete responders, 32 (32%) as partial responders and 21 (21%) as non-responders. The median duration of treatment with tafamidis was 35 months. Better treatment response was shown in patients with in polyneuropathy disability score (PND) I, lower neuropathy impairment score (NIS), compound muscle action potential (CMAP) and Norfolk QoL questionnaire. Higher albumin levels and lower NTproBNP levels were also associated with better treatment response. A basal NIS≥15 predicts that the patient could be a non-responder with a 60% probability. CONCLUSIONS: Our results reinforce the tafamidis efficacy to treat A-ATTRv-PNP if started early in the disease course. Patients with the V30M variant, NIS<15 and PND I are the most appropriate subjects for this treatment.
Subject(s)
Amyloid Neuropathies, Familial , Benzoxazoles , Polyneuropathies , Humans , Male , Female , Benzoxazoles/therapeutic use , Amyloid Neuropathies, Familial/drug therapy , Amyloid Neuropathies, Familial/complications , Spain , Aged , Middle Aged , Polyneuropathies/drug therapy , Polyneuropathies/etiology , Treatment Outcome , Prealbumin/genetics , Aged, 80 and over , Peptide Fragments/bloodABSTRACT
OBJECTIVES: Several studies suggest that moderate wine consumption, particularly red wine, may have benefits for cardiovascular health. Red wine contains a variety of bioactive compounds, including polyphenols like phenolic acids, which have demonstrated anti-inflammatory effects in experimental models. The aim of this study was to assess the anti-inflammatory properties of wine, measured as urinary tartaric acid, a new biomarker of wine consumption. DESIGN, SETTINGS, AND PARTICIPANTS: One-year longitudinal study that included 217 participants from the PREDIMED trial. MEASUREMENTS: Plasma inflammatory biomarkers and urinary tartaric acid were analyzed using xMAP technology and high-performance liquid chromatography, respectively. Multivariable regression analyses were performed to assess the relationship between variations over 1-year in urinary tartaric acid concentrations and 1-year changes in serum inflammatory molecules, including adhesion cell molecules, interleukine-6, tumour necrosis factor alpha, and monocyte chemotactic protein 1. Three categories were built according to tertiles of 1-y changes in urinary tartaric acid. RESULTS: Using a ROC curve, urinary tartaric acid was corroborated as a reliable biomarker of wine consumption (AUC = 0.818 (95% CI: 0.76; 0.87). In the continuous analysis, participants with higher increases in tartaric acid significantly reduced their concentrations in soluble vascular adhesion molecule (sVCAM-1) after 1-year of follow-up (-0.20 (-0.38; -9,93) ng/mL per 1-SD increment, p-value = 0.031). Moreover, tertiles 2 and 3 of 1-year changes in tartaric acid presented a significant reduction in soluble intercellular cell adhesion molecule (sICAM-1) as compared to tertile 1 (-0.31 (-0.52; -0.10) ng/mL, p-value = 0.014 and -0.29 (-0.52; -0.07) ng/mL, p-value = 0.023, respectively). Participants in the third tertile also exhibited a reduced concentration of sVCAM-1 compared to those in the first tertile (-0.31 (-0.55; -0.06) ng/mL, p-value = 0.035). CONCLUSIONS: Our findings suggest that wine consumption is associated with lower levels of inflammation due to the anti-inflammatory properties of wine compounds.
Subject(s)
Atherosclerosis , Tartrates , Wine , Humans , Wine/analysis , Longitudinal Studies , Inflammation , Anti-Inflammatory Agents/analysis , BiomarkersABSTRACT
Early identification of ATTRv amyloidosis disease onset is still often delayed due to the lack of validated biomarkers of this disease. Light chain neurofilament (NfL) have shown promising results in early diagnosis in this disease, but data is still needed, including with alternative measuring methods. Our aim was to study the levels of NfL measured by ELISA. Furthermore, interstitial matrix metalloproteinase type 1 (MMP-1) serum levels were measured as a potential new biomarker in ATTRv. Serum NfL and MMP-1 were measured using ELISA assays in 90 participants (29 ATTR-V30M patients, 31 asymptomatic V30M-TTR variant carriers and 30 healthy controls). Median NfL levels among ATTRv amyloidosis patients were significantly higher (116 pg/mL vs 0 pg/mL in both comparison groups). The AUC comparing ATTRv amyloidosis patients and asymptomatic carriers was 0.90 and the NfL concentration of 93.55 pg/mL yielded a sensitivity of 79% and a specificity of 87%. NfL levels had a significant positive correlation with NIS values among patients. We found a negative significant correlation between eGFR and NfL levels. Finally, MMP1 levels were not different between groups. Evidence of NfL use for early diagnosis of ATTR-PN amyloidosis is growing. ELISA seems a reliable and available technique for it quantification. Decreased GFR could influence NfL plasma levels.
Subject(s)
Amyloid Neuropathies, Familial , Matrix Metalloproteinase 1 , Humans , Amyloid Neuropathies, Familial/diagnosis , Early Diagnosis , BiomarkersABSTRACT
This report describes the mitochondrial genome of the parasite Gnathostoma binucleatum (G. binucleatum), which was obtained from naturally infected freshwater fish in Sinaloa, Mexico (22°46'00.1â³N 105°40'21.8â³W). G. binucleatum is responsible for human gnathostomiasis and is endemic to Mexico. It belongs to the Spirurida order of the Secernentea class of Nematoda.
ABSTRACT
SCOPE: Diets rich in polyphenols has been associated with better cognitive performance. The aim of this study is to assess the relationship between microbial phenolic metabolites (MPM) in urine and cognition in the context of an older population at high cardiovascular risk. METHODS AND RESULTS: A cross-sectional analysis is conducted in 400 individuals of the PREDIMED-Plus study. Liquid chromatography coupled to mass spectrometry is used to identify urinary MPM. Mediterranean diet (MedDiet) adherence is estimated with a 17-item questionnaire and cognitive function is evaluated with a battery of neuropsychological tests. Multivariable-adjusted linear regression models are fitted to assess the relationship of urinary MPM with the MedDiet and cognitive tests. Protocatechuic acid and enterolactone glucuronide are associated with higher adherence to the MedDiet. Regarding cognitive function, protocatechuic acid, vanillic acid glucuronide, 3-hydroxybenzoic acid, enterodiol glucuronide, and enterolactone glucuronide are directly associated with a global composite score of all the cognitive tests. Furthermore, protocatechuic acid and enterolactone glucuronide are associated with higher scores in the Mini-Mental State Examination, whereas enterodiol glucuronide is associated with improved Clock Drawing Test scores. CONCLUSIONS: These results suggest that the MedDiet is linked to MPM associated with better cognitive performance in an older population.
Subject(s)
4-Butyrolactone/analogs & derivatives , Diet, Mediterranean , Glucuronides , Hydroxybenzoates , Lignans , Humans , Cross-Sectional Studies , Cognition , Diet, Mediterranean/psychologyABSTRACT
BACKGROUND: Vitamin B12 is an essential nutrient that is involved in numerous physiological processes, and its deficiency can lead to various complications, including neurological and haematological disorders. Some studies have suggested that vitamin B12 may have anti-inflammatory effects, but the mechanisms underlying this relationship are not yet fully understood. We investigated the relationship between circulating vitamin B12 and inflammatory markers interleukin (IL)-6 and C-reactive protein (CRP). The association of peripheral levels of vitamin B12 with IL-6 and CRP was assessed in 136 human samples from a high cardiovascular risk population. To corroborate the results from the human trial, the analysis was replicated in naturally aged mice. RESULTS: Individuals with higher serum levels of vitamin B12 showed lower concentrations of IL-6 and CRP after adjustment for potential confounders, and an inverse association was also found between serum IL-6 and vitamin B12 levels in naturally aged mice. CONCLUSION: Circulating vitamin B12 was inversely associated with IL-6 and CRP in humans and with IL-6 in mice, suggesting that it may exert an anti-inflammatory effect through modulation of these pro-inflammatory molecules. © 2023 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.
Subject(s)
Cardiovascular Diseases , Vitamin B 12 Deficiency , Humans , Animals , Mice , Vitamin B 12 , Cardiovascular Diseases/etiology , Interleukin-6 , Risk Factors , Biomarkers , C-Reactive Protein/metabolism , Heart Disease Risk Factors , Anti-Inflammatory Agents , Folic AcidABSTRACT
AIMS: Clinical studies have produced conflicting evidence on the effects of the consumption of tomatoes on blood pressure, and there are limited data from epidemiologic studies. This study assesses whether tomato consumption (Solanum lycopersicum L.) is associated with Systolic (SBP) and Diastolic Blood Pressure (DBP), and the risk of hypertension in a prospective 3-year longitudinal study in older adults at high cardiovascular risk. METHODS: The present study was carried out within the PREDIMED (Prevención con Dieta Mediterránea) trial involving 7,056 (82.5% hypertensive) participants. The consumption of tomato (g/d) was measured using a validated Food Frequency Questionnaire (FFQ) and categorized into 4 groups: lowest (<44â g), intermediate (44-82â g), upper-intermediate (82 -110â g), and highest (>110â g). Multilevel linear mixed models examined blood pressure and tomato consumption association. Cox proportional-hazards models analyzed hypertension risk in 1,097 non-hypertensive participants, studying risk reductions versus the lowest tomato consumers. RESULTS: An inverse association between tomato consumption and diastolic blood pressure was observed between the intermediate group ß = -0.65â mmHg [95% CI:-1.20, -0.10] and the lowest consumption group. A significant inverse association was observed for blood pressure in grade 1 hypertension participants in the intermediate tomato consumption group. The risk of hypertension decreased with consumption of >110â g/d tomato (highest vs lowest consumption; HR, 0.64 [95% CI, 0.51-0.89]). CONCLUSIONS: Tomato consumption, including tomato-based products, is beneficial in preventing and managing hypertension. Higher tomato intake reduces hypertension risk by 36%, and moderate consumption lowers blood pressure, especially in grade 1 hypertension.
Tomato consumption may play a favourable clinical role in the prevention and management of elevated blood pressure. Tomato consumption was associated with both blood pressure measurements in mildly elevated blood pressure participants. A higher consumption of tomato was associated with a reduction in the risk of high blood pressure, equivalent to a large-sized fruit.
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BACKGROUND: Hereditary transthyretin amyloidosis (ATTRv) is a rare genetic disease that negatively affects patients' quality of life through the involvement of various organs and tissues. Despite a large amount of research on medical and psychosocial interventions, the impact of occupational therapy (OT) on patients with ATTRv is not well understood. OBJECTIVE: The aim of this study was to develop an OT programme to improve the daily functioning and quality of life of patients with ATTRv. METHODS: Fourteen patients with ATTRv were interviewed. Together they developed short- and medium-term occupational goals. Patients received the OT intervention for six months. Outcomes were measured using scores for activities of daily living and psychological well-being. RESULTS: The study found that OT can have a positive impact as a complementary intervention to medical and other psychosocial treatments. Of the 14 patients, 12 maintained the same scores in activities of daily living. Two deteriorated and eight improved their psychological scores. CONCLUSION: This study highlights the need for further research in this area and the importance of OT in the management of patients with ATTRv. Early intervention is of paramount importance and further research is needed to evaluate the long-term effects of OT interventions in patients with ATTRv.
Subject(s)
Activities of Daily Living , Amyloid Neuropathies, Familial , Humans , Quality of Life , Amyloid Neuropathies, Familial/therapy , Qualitative Research , Rare DiseasesABSTRACT
The Folin-Ciocalteu assay is a reference method for the quantification of total (poly)phenols in food. This review explains the fundamental mechanism of the redox reaction on which the method is based and looks at some of the practical considerations concerning its application. To accurately estimate the antioxidant capacity of (poly)phenolic compounds, a thorough knowledge of their structural characteristics is essential, as the two are closely associated. Therefore, to help researchers interpret the results of the Folin-Ciocalteu method, this review also summarizes some of the main phenolic structural features. Finally, we have used the Folin-Ciocalteu method to estimate the total phenolic intake associated with high adherence to a Mediterranean diet, ranked as one of the healthiest dietary patterns, which is characterized by a high consumption of (poly)phenol-rich food such as wine, virgin olive oil, fruits, vegetables, whole grains, nuts, and legumes.
Subject(s)
Phenol , Phenols , Phenol/analysis , Phenols/chemistry , Plant Extracts/analysis , Olive Oil/analysis , Fruit/chemistry , VegetablesABSTRACT
BACKGROUND & AIMS: Vitamin B12 plays a crucial role in cognition, but its effect might be regulated by the presence of other micronutrients, such as folate. The aim was to evaluate the effects of vitamin B12 on cognitive performance according to adherence to the Mediterranean diet, and whether the Mediterranean diet also results in increased folate or vitamin B12 levels. METHODS: This is a cohort study nested in a randomized controlled clinical trial performed in Hospital Clinic in Barcelona, Spain. A total of 170 participants of the PREDIMED trial (Barcelona - Hospital Clinic site) aged 55-80 years at high cardiovascular risk were included. Adherence to the Mediterranean diet was assessed using a validated 14-item questionnaire, memory function was evaluated with a battery of neuropsychological tests and serum vitamin B12 and folate were determined using an automated electrochemiluminiscence immunoassay system. RESULTS: In the multivariable adjusted linear regression model, serum vitamin B12 concentration presented a significant correlation with memory function (r2 = 0.57; P = 0.028) in participants with high adherence to the Mediterranean diet whereas the correlation was weak and inverse for those who presented a low adherence to the Mediterranean diet (r2 = 0.37, P = 0.731). Mediterranean diet adherence showed a positive association with serum folate, but not with serum vitamin B12. CONCLUSIONS: In an older Mediterranean population at high cardiovascular risk, changes in serum vitamin B12 correlate with better memory function only in the context of a high adherence to the Mediterranean pattern, suggesting that the effects of vitamin B12 goes further than a mere nutritional requirement. INSTITUTIONAL REVIEW BOARD STATEMENT: The study was conducted according to the guidelines of the Declaration of Helsinki and was approved by the Institutional Review Board of the 11 participating centres. The study was registered with the International Standard Randomized Controlled Trial Number (ISRCTN) 35739639 (https://www.isrctn.com/ISRCTN35739639).
Subject(s)
Diet, Mediterranean , Humans , Aged , Cohort Studies , Folic Acid , Vitamin B 12 , VitaminsABSTRACT
Background: Harnessing the anti-tumor immune system response by targeting the program cell death protein (PD-1) and program cell death ligand protein (PD-L1) axis has been a major breakthrough in non-small cell lung cancer (NSCLC) therapy. Nonetheless, conventional imaging tools cannot accurately assess response in immunotherapy-treated patients. Using a lung cancer syngeneic mouse model responder to immunotherapy, we aimed to demonstrate that [89Zr]-anti-PD-1 immuno-PET is a safe and feasible imaging modality to assess the response to PD-1/PD-L1 blockade in NSCLC. Materials and methods: A syngeneic mouse model responder to anti-PD-1 therapy was used. Tumor growth and response to PD-1 blockade were monitored by conventional 2-deoxy-2-[18F]fluoro-D-glucose ([18F]-FDG) PET scans. Additionally, tumor lymphocyte infiltration was analyzed by the use of an [89Zr]-labeled anti-PD-1 antibody and measured as 89Zr tumor uptake. Results: Conventional [18F]-FDG-PET scans failed to detect the antitumor activity exerted by anti-PD-1 therapy. However, [89Zr]-anti-PD-1 uptake was substantially higher in mice that responded to PD-1 blockade. The analysis of tumor-infiltrating immune cell populations and interleukins demonstrated an increased anti-tumor effect elicited by activation of effector immune cells in PD-1-responder mice. Interestingly, a positive correlation between [89Zr]-anti-PD-1 uptake and the proportion of tumor-infiltrating lymphocytes (TILs) was found (Cor = 0.8; p = 0.001). Conclusion: Our data may support the clinical implementation of immuno-PET as a promising novel imaging tool to predict and assess the response of PD-1/PD-L1 inhibitors in patients with NSCLC.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Mice , Animals , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Carcinoma, Non-Small-Cell Lung/diagnostic imaging , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Positron Emission Tomography Computed Tomography , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Programmed Cell Death 1 Receptor/metabolism , Fluorodeoxyglucose F18/metabolism , B7-H1 Antigen/metabolismABSTRACT
Drug combinations are key to circumvent resistance mechanisms compromising response to single anti-cancer targeted therapies. The implementation of combinatorial approaches involving MEK1/2 or KRASG12C inhibitors in the context of KRAS-mutated lung cancers focuses fundamentally on targeting KRAS proximal activators or effectors. However, the antitumor effect is highly determined by compensatory mechanisms arising in defined cell types or tumor subgroups. A potential strategy to find drug combinations targeting a larger fraction of KRAS-mutated lung cancers may capitalize on the common, distal gene expression output elicited by oncogenic KRAS. By integrating a signature-driven drug repurposing approach with a pairwise pharmacological screen, here we show synergistic drug combinations consisting of multi-tyrosine kinase PKC inhibitors together with MEK1/2 or KRASG12C inhibitors. Such combinations elicit a cytotoxic response in both in vitro and in vivo models, which in part involves inhibition of the PKC inhibitor target AURKB. Proteome profiling links dysregulation of MYC expression to the effect of both PKC inhibitor-based drug combinations. Furthermore, MYC overexpression appears as a resistance mechanism to MEK1/2 and KRASG12C inhibitors. Our study provides a rational framework for selecting drugs entering combinatorial strategies and unveils MEK1/2- and KRASG12C-based therapies for lung cancer.
Subject(s)
Lung Neoplasms , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Drug Repositioning , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolism , Drug Combinations , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Mutation , Cell Line, TumorABSTRACT
Orthotopic liver transplantation (OLT) was the first treatment able to modify the natural course of hereditary transthyretin (ATTRv) amyloidosis, which is a rare and fatal disorder caused by the accumulation of misfolded transthyretin (TTR) variants in different organs and tissues and which leads to a progressive and multisystem dysfunction. Because the liver is the main source of TTR, OLT dramatically reduces the production of the pathogenic TTR variant, which should prevent amyloid formation and halt disease progression. However, amyloidosis progression may occur after OLT due to wild-type TTR deposition, especially in the nerves and heart. In this review, we discuss the disease features influencing OLT outcomes and the clinical manifestations of ATTRv amyloidosis progression post-OLT to improve our understanding of disease worsening after OLT and optimize the follow-up and clinical management of these patients. By conducting a literature review on the PubMed database, we identified patient characteristics that have been associated with worse post-OLT outcomes, including late-onset V50M and non-V50M variants, age >40 years, long disease duration, advanced neuropathy and autonomic dysfunction, and malnutrition. Regarding post-OLT mortality, deaths occurring within the first year after OLT were mainly associated with fatal graft complications and infectious diseases, whereas cardiovascular-related deaths usually occurred later. Considering the diverse clinical manifestations of ATTRv amyloidosis progression post-OLT, including worsening neuropathy and/or cardiomyopathy, autonomic dysfunction, and oculoleptomeningeal involvement, we present advice on the most relevant tests for assessing disease progression post-OLT. Finally, we discuss the use of new therapies based on TTR stabilizers and TTR mRNA silencers for the treatment of ATTRv amyloidosis patients post-OLT.