"Novel chemo-enzymatic synthesis, structural elucidation and first antiprotozoal activity profiling of the atropoisomeric dimers of trans-8-Hydroxycalamenene".

Leishmaniasis and malaria are two debilitating protozoan diseases affecting millions globally, particularly in tropical and subtropical regions. Current therapeutic options face significant challenges due to emerging drug-resistant strains, necessitating the discovery of novel antiprotozoal agents. This study explores, for the first time, the antiprotozoal potential of calamenenes and their dimers, naturally occurring sesquiterpenes found in essential oils, through a novel chemo-enzymatic synthesis approach. Using the laccase from Trametes versicolor, atropoisomeric dimers of (-)- and (+)-8-trans-hydroxycalamenene were synthesized from commercially available (-)- and (+)-menthol. Structural elucidation was achieved via 2D-NMR spectroscopy, electronic circular dichroism, and DFT calculations. In vitro profiling against Leishmania spp and drug-resistant Plasmodium falciparum revealed that calamenene dimers exhibited significantly higher antiprotozoal activity compared to their monomeric counterparts, highlighting the potential of dimeric terpenoids as promising antiprotozoal agents. This work lays the foundation for developing novel antimalarial drugs based on calamenene scaffolds, encouraging further interactome studies to optimize their pharmacological properties.

No Evidence Was Found for the Presence of Terreolides, Terreumols or Saponaceolides H-S in the Fruiting Bodies of Tricholoma terreum (Basidiomycota, Agaricales).

Two different collections of the gilled wild fungus Tricholoma terreum, collected in Italy, were subjected to phytochemical analysis. The fungal material was confidently identified by analysis of the ITS genomic sequences. Using both HR-LC-MS and NMR techniques, no evidence was found for the presence in the fruiting bodies of terreolides, terreumols or saponaceolides H-S, in striking contrast with the isolation of these terpenoids by Chinese authors from a mushroom collected in France and identified as T. terreum. The main cytotoxic terpenoid identified and isolated from the extracts of the specimens investigated in this work was the C30 derivative saponaceolide B, which had been previously isolated from T. saponaceum and other T. terreum collections. Although saponaceolide B is a rather labile molecule, easily degradable by heat or in acidic conditions, our study indicated that none of the extraction protocols used produced saponaceolide H-S or terreolide/terreumol derivatives, thus excluding the possibility that the latter compounds could be extraction artifacts. Considered together, these findings point to the need for the unambiguous identification of mushroom species belonging to the complex genus Tricholoma, characterized by high variability in the composition of metabolites. Moreover, based on our data, T. terreum must be considered an edible mushroom.

Prevalence of smoking habits, attitudes and knowledge on counteractive strategies among a sample of healthcare employees: results of the smoking-free health environments project in the province of Palermo, Italy.

Introduction: Tobacco use is responsible for over 7 million deaths annually, making smoking the leading cause of preventable mortality globally. Over the last two decades in Italy, the prevalence of smoking among physicians has consistently decreased, while it remains higher and is gradually decreasing among non-physician healthcare workers. The aim of this study was to investigate the Prevalence of smoking habits, attitudes, and knowledge on counteractive strategies among employees in the Primary Healthcare Facilities in the Province of Palermo, Italy. Methods: A cross-sectional survey was conducted between June 2020 and December 2020 through a previously validated anonymous questionnaire structured in four sections including 34 items. Data were analyzed using Stata/MP 12.1 statistical software. Results: Overall, 2,645 participants answered the questionnaire. The prevalence of either current or former smokers was 18.6%. Based on the multivariable analysis conducted, a significantly higher frequency of current smokers was observed among male participants (AdjOR: 1.29; CI95%: 1.02-1.64) and those belonging to the Surgical Unit (AdjOR: 1.92; CI95%: 1.27-2.90). Conversely, the prevalence of current smokers was significantly lower among those with at least one child (AdjOR: 0.67; CI95%: 0.49-0.91), with an educational qualification equal to or greater than a graduation degree (AdjOR: 0.56; CI95%: 0.43-0.73), those who considered second-hand smoke harmful (AdjOR: 0.06; CI95%: 0.008-0.60), those who had observed smoking or detected the smell of smoke in their workplace (AdjOR: 0.64; CI95%: 0.45-0.91). Furthermore, the prevalence of current smokers was significantly lower among participants who believed that healthcare professionals could play a crucial role in influencing their patients' lifestyles (AdjOR: 0.67; CI95%: 0.50-0.90) and among those who recommend their patients to quit smoking (AdjOR: 0.35; CI95%: 0.24-0.51). Discussion: The results of the current research demonstrate that, despite the decline in smoking prevalence among physicians, the rate of smokers among healthcare facility employees remains unacceptably high. This underscores the need to re-evaluate current anti-tobacco strategies in the workplace.

From Waste to Value: Recent Insights into Producing Vanillin from Lignin.

Vanillin, one of the most widely used and appreciated flavoring agents worldwide, is the main constituent of vanilla bean extract, obtained from the seed pods of various members belonging to the Orchidaceae family. Due to the great demand in the food confectionery industry, as well as in the perfume industry, medicine, and more, the majority of vanillin used today is produced synthetically, and only less than one percent of the world's vanilla flavoring market comes directly from the traditional natural sources. The increasing global demand for vanillin requires alternative and overall sustainable new production methods, and the recovery from biobased polymers, like lignin, is an environmentally friendly alternative to chemical synthesis. The present review provides firstly an overview of the different types of vanillin, followed by a description of the main differences between natural and synthetic vanillin, their preparation, the market of interest, and the authentication issues and the related analytical techniques. Then, the review explores the real potentialities of lignin for vanillin production, presenting firstly the well-assessed classical methods and moving towards the most recent promising approaches through chemical, biotechnological and photocatalytic methodologies, together with the challenges and the principal issues associated with each technique.

One-pot process for the biotransformation of vegetable oils into natural deca- and dodecalactones.

Deca- and dodecalactones are highly desired natural compounds that are essential for creating flavor formulations with fruity, peachy, creamy, and floral notes. Although natural ingredients are preferred by consumers, these lactones cannot be extracted from natural sources. Therefore, the biotechnological processes that produce these compounds in their natural form are crucial for the flavor industry. Here, we report a study on the biotransformation of vegetable oils into natural deca- and dodecalactones. The proposed process is performed one-pot, through the sequential use of three different biotransformation steps, namely the lipase-mediated hydrolysis of the triglycerides, the use of probiotic bacteria for the hydration of the unsaturated fatty acids and the transformation of the obtained hydroxy-fatty acids into lactones derivatives employing Yarrowia lipolytica. By using a specific vegetable oil in combination with a selected bacterial strain, it is possible to obtain a preferred lactone derivative such as γ-dodecalactone, dairy lactone, tuberose lactone, or δ-decalactone in a concentration ranging from 0.9 to 1.5 g/L. Overall, our method is suitable for the industrial production of these lactones as it is easily scalable, it can be performed in only one bioreactor and it makes use of generally recognized as safe (GRAS) microorganisms.

Basidiomycota strains as whole-cell biocatalysts for the synthesis of high-value natural benzaldehydes.

Substituted benzaldehydes are the most commonly used natural-occurring flavours in the world. The consumer's preference for 'natural or organic' aromas has increased the request for flavours possessing the 'natural' status. The resulting shortage of aromatic aldehydes of extractive origin, such as vanillin, veratraldehyde and piperonal, can be offset by developing a new biotechnological synthesis method. Here, we report a study on the microbiological reduction of five natural benzoic acid derivatives, namely p-anisic, vanillic, veratric, piperonylic and eudesmic acids, to produce the corresponding fragrant aldehydes. We found that different Basidiomycota strains can efficiently perform this transformation, with good chemical selectivity and tolerance to the toxicity of substrates and products. Besides confirming the carboxylic acid reductase activity of the already studied fungi Pycnoporus cinnabarinus, we discovered that other species such as Pleurotus eryngii, Pleurotus sapidus and Laetiporus sulphureus as well as the non-ligninolytic fungi Lepista nuda are valuable microorganisms for the synthesis of anisaldehyde, vanillin, veratraldehyde, piperonal and 3,4,5-trimethoxybenzaldehyde from the corresponding acids. According to our findings, we propose a reliable process for the preparation of the above-mentioned aldehydes, in natural form. KEY POINTS: • Fragrant benzaldehydes were obtained by biotransformation. • Basidiomycota strains reduced substituted benzoic acid to the corresponding aldehydes. • Anisaldehyde, vanillin, veratraldehyde, piperonal and 3,4,5-trimethoxybenzaldehyde were prepared in natural form.

Phospholipase D Immobilization on Lignin Nanoparticles for Enzymatic Transformation of Phospholipids.

Lignin nanoparticles (LNPs) are promising components for various materials, given their controllable particle size and spherical shape. However, their origin from supramolecular aggregation has limited the applicability of LNPs as recoverable templates for immobilization of enzymes. In this study, we show that stabilized LNPs are highly promising for the immobilization of phospholipase D (PLD), the enzyme involved in the biocatalytic production of high-value polar head modified phospholipids of commercial interest, phosphatidylglycerol, phosphatidylserine and phosphatidylethanolamine. Starting from hydroxymethylated lignin, LNPs were prepared and successively hydrothermally treated to obtain c-HLNPs with high resistance to organic solvents and a wide range of pH values, covering the conditions for enzymatic reactions and enzyme recovery. The immobilization of PLD on c-HLNPs (PLD-c-HLNPs) was achieved through direct adsorption. We then successfully exploited this new enzymatic preparation in the preparation of pure polar head modified phospholipids with high yields (60-90 %). Furthermore, the high stability of PLD-c-HLNPs allows recycling for a number of reactions with appreciable maintenance of its catalytic activity. Thus, PLD-c-HLNPs can be regarded as a new, chemically stable, recyclable and user-friendly biocatalyst, based on a biobased inexpensive scaffold, to be employed in sustainable chemical processes for synthesis of value-added phospholipids.

Machine learning based local recurrence prediction in colorectal cancer using polarized light imaging.

Significance: Current treatment for stage III colorectal cancer (CRC) patients involves surgery that may not be sufficient in many cases, requiring additional adjuvant systemic therapy. Identification of this latter cohort that is likely to recur following surgery is key to better personalized therapy selection, but there is a lack of proper quantitative assessment tools for potential clinical adoption. Aim: The purpose of this study is to employ Mueller matrix (MM) polarized light microscopy in combination with supervised machine learning (ML) to quantitatively analyze the prognostic value of peri-tumoral collagen in CRC in relation to 5-year local recurrence (LR). Approach: A simple MM microscope setup was used to image surgical resection samples acquired from stage III CRC patients. Various potential biomarkers of LR were derived from MM elements via decomposition and transformation operations. These were used as features by different supervised ML models to distinguish samples from patients that locally recurred 5 years later from those that did not. Results: Using the top five most prognostic polarimetric biomarkers ranked by their relevant feature importances, the best-performing XGBoost model achieved a patient-level accuracy of 86%. When the patient pool was further stratified, 96% accuracy was achieved within a tumor-stage-III sub-cohort. Conclusions: ML-aided polarimetric analysis of collagenous stroma may provide prognostic value toward improving the clinical management of CRC patients.

Mueller matrix polarization parameters correlate with local recurrence in patients with stage III colorectal cancer.

The peri-tumoural stroma has been explored as a useful source of prognostic information in colorectal cancer. Using Mueller matrix (MM) polarized light microscopy for quantification of unstained histology slides, the current study assesses the prognostic potential of polarimetric characteristics of peri-tumoural collagenous stroma architecture in 38 human stage III colorectal cancer (CRC) patient samples. Specifically, Mueller matrix transformation and polar decomposition parameters were tested for association with 5-year patient local recurrence outcomes. The results show that some of these polarimetric parameters were significantly different (p value < 0.05) for the recurrence versus the no-recurrence patient cohorts (Mann-Whitney U test). MM parameters may thus be prognostically valuable towards improving clinical management/treatment stratification in CRC patients.

Distinguishing Gastric/Esophageal Adenocarcinoma from Pancreatic Adenocarcinoma Using Methylation-Based Droplet Digital PCR.

The goal of this study was to develop a methylation-based droplet digital PCR to separate 2 cancer classes that do not have sensitive and specific immunohistochemical stains: gastric/esophageal and pancreatic adenocarcinomas. The assay used methylation-independent primers and methylation-dependent probes to assess a single differentially methylated CpG site; analyses of array data from The Cancer Genome Atlas network showed that high methylation at the cg06118999 probe supports the presence of cells originating from the stomach or esophagus (eg, as in gastric metastasis), whereas low methylation suggests that these cells are rare to absent (eg, pancreatic metastasis). On validation using formalin-fixed paraffin-embedded primary and metastatic samples from our institution, methylation-based droplet digital PCR targeting the corresponding CpG dinucleotide generated evaluable data for 60 of the 62 samples (97%) and correctly classified 50 of the 60 evaluable cases (83.3%), mostly adenocarcinomas from the stomach or pancreas. This ddPCR was created to be easy-to-interpret, rapid, inexpensive, and compatible with existing platforms at many clinical laboratories. We suggest that similarly accessible PCRs could be developed for other differentials in pathology that do not have sensitive and specific immunohistochemical stains.

Exploiting bioactive natural products of marine origin: Evaluation of the meroterpenoid metachromin V as a novel potential therapeutic drug for colorectal cancer.

Colorectal cancer (CRC) is the second most common cause of cancer death, leading to almost 1 million deaths per year. Despite constant progress in surgical and therapeutic protocols, the 5-year survival rate of advanced CRC patients remains extremely poor. Colorectal Cancer Stem Cells (CRC-CSCs) are endowed with unique stemness-related properties responsible for resistance, relapse and metastasis. The development of novel therapeutics able to tackle CSCs while avoiding undesired toxicity is a major need for cancer treatment. Natural products are a large reservoir of unexplored compounds with possible anticancer bioactivity, sustainability, and safety. The family of meroterpenoids derived from sponges share interesting bioactive properties. Bioassay-guided fractionation of a meroterpenoids extract led to the isolation of three compounds, all cytotoxic against several cancer cell lines: Metachromins U, V and W. In this study, we evaluated the anticancer potential of the most active one, Metachromins V (MV), on patient-derived CRC-CSCs. MV strongly impairs CSCs-viability regardless their mutational background and the cytotoxic effect is maintained on therapy-resistant metastatic CSCs. MV affects cell cycle progression, inducing a block in G2 phase in all the cell lines tested and more pronouncedly in CRC-CSCs. Moreover, MV triggers an important reorganization of the cytoskeleton and a strong reduction of Rho GTPases expression, impairing CRC-CSCs motility and invasion ability. By Proteomic analysis identified a potential molecular target of MV: CCAR1, that regulates apoptosis under chemotherapy treatments and affect ß-catenin pathway. Further studies will be needed to confirm and validate these data in in vivo experimental models.

Fractionation of Raw and Parboiled Rice Husks with Deep Eutectic Solvents and Characterization of the Extracted Lignins towards a Circular Economy Perspective.

In the present work, rice husks (RHs), which, worldwide, represent one of the most abundant agricultural wastes in terms of their quantity, have been treated and fractionated in order to allow for their complete valorization. RHs coming from the raw and parboiled rice production have been submitted at first to a hydrothermal pretreatment followed by a deep eutectic solvent fractionation, allowing for the separation of the different components by means of an environmentally friendly process. The lignins obtained from raw and parboiled RHs have been thoroughly characterized and showed similar physico-chemical characteristics, indicating that the parboiling process does not introduce obvious lignin alterations. In addition, a preliminary evaluation of the potentiality of such lignin fractions as precursors of cement water reducers has provided encouraging results. A fermentation-based optional preprocess has also been investigated. However, both raw and parboiled RHs demonstrated a poor performance as a microbiological growth substrate, even in submerged fermentation using cellulose-degrading fungi. The described methodology appears to be a promising strategy for the valorization of these important waste biomasses coming from the rice industry towards a circular economy perspective.

Digital quantitative tissue image analysis of hypoxia in resected pancreatic ductal adenocarcinomas.

Background: Tumor hypoxia is theorized to contribute to the aggressive biology of pancreatic ductal adenocarcinoma (PDAC). We previously reported that hypoxia correlated with rapid tumor growth and metastasis in patient-derived xenografts. Anticipating a prognostic relevance of hypoxia in patient tumors, we developed protocols for automated semi-quantitative image analysis to provide an objective, observer-independent measure of hypoxia. We further validated this method which can reproducibly estimate pimonidazole-detectable hypoxia in a high-through put manner. Methods: We studied the performance of three automated image analysis platforms in scoring pimonidazole-detectable hypoxia in resected PDAC (n = 10) in a cohort of patients enrolled in PIMO-PANC. Multiple stained tumor sections were analyzed on three independent image-analysis platforms, Aperio Genie (AG), Definiens Tissue Studio (TS), and Definiens Developer (DD), which comprised of a customized rule set. Results: The output from Aperio Genie (AG) had good concordance with manual scoring, but the workflow was resource-intensive and not suited for high-throughput analysis. TS analysis had high levels of variability related to misclassification of cells class, while the customized rule set of DD had a high level of reliability with an intraclass coefficient of more than 85%. Discussion: This work demonstrates the feasibility of developing a robust, high-performance pipeline for an automated, quantitative scoring of pimonidazole-detectable hypoxia in patient tumors.

Peptide-Mediated Targeted Delivery of Aloe-Emodin as Anticancer Drug.

Breast cancer is one of the most diffuse cancers in the world and despite the availability of the different drugs employed against it, the need for new and particularly more specific molecules is ever growing. In this framework, natural products are increasingly assuming an important role as new anticancer drugs. Aloe-emodin (AE) is one of the best characterized molecules in this field. The functionalization of bioactive natural products with selected peptide sequences to enhance their bioavailability and specificity of action is a powerful and promising strategy. In this study, we analyzed the cell specificity, cell viability effects, intracellular distribution, and immune cell response of a new peptide conjugate of Aloe-emodin in SKBR3 and A549 cell lines by means of viability tests, flow cytometry, and confocal microscopy. The conjugate proved to be more effective at reducing cell viability than AE in both cell lines. Furthermore, the results showed that it was mainly internalized within the SKBR3 cells, showing a nuclear localization, while A459 cells displayed mainly a cytoplasmic distribution. A preserving effect of the conjugate on NKs' cell function was also observed. The designed conjugate showed a promising specific activity towards HER2-expressing cells coupled with an enhanced water solubility and a higher cytotoxicity; thus, the resulting proof-of-concept molecule can be further improved as an anticancer compound.

Polarimetric biomarkers of peri-tumoral stroma can correlate with 5-year survival in patients with left-sided colorectal cancer.

Using a novel variant of polarized light microscopy for high-contrast imaging and quantification of unstained histology slides, the current study assesses the prognostic potential of peri-tumoral collagenous stroma architecture in 32 human stage III colorectal cancer (CRC) patient samples. We analyze three distinct polarimetrically-derived images and their associated texture features, explore different unsupervised clustering algorithm models to group the data, and compare the resultant groupings with patient survival. The results demonstrate an appreciable total accuracy of ~ 78% with significant separation (p < 0.05) across all approaches for the binary classification of 5-year patient survival outcomes. Surviving patients preferentially belonged to Cluster 1 irrespective of model approach, suggesting similar stromal microstructural characteristics in this sub-population. The results suggest that polarimetrically-derived stromal biomarkers may possess prognostic value that could improve clinical management/treatment stratification in CRC patients.

Mutational signatures in esophageal squamous cell carcinoma from eight countries with varying incidence.

Esophageal squamous cell carcinoma (ESCC) shows remarkable variation in incidence that is not fully explained by known lifestyle and environmental risk factors. It has been speculated that an unknown exogenous exposure(s) could be responsible. Here we combine the fields of mutational signature analysis with cancer epidemiology to study 552 ESCC genomes from eight countries with varying incidence rates. Mutational profiles were similar across all countries studied. Associations between specific mutational signatures and ESCC risk factors were identified for tobacco, alcohol, opium and germline variants, with modest impacts on mutation burden. We find no evidence of a mutational signature indicative of an exogenous exposure capable of explaining differences in ESCC incidence. Apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC)-associated mutational signatures single-base substitution (SBS)2 and SBS13 were present in 88% and 91% of cases, respectively, and accounted for 25% of the mutation burden on average, indicating that APOBEC activation is a crucial step in ESCC tumor development.

Phase II Trial of Trametinib and Panitumumab in RAS/RAF Wild Type Metastatic Colorectal Cancer.

INTRODUCTION: MEK inhibition may overcome resistance to EGFR inhibition in patients with RAS wildtype (wt) metastatic colorectal cancer (mCRC). We evaluated antitumor activity of trametinib (MEK1/2 inhibitor) with panitumumab (EGFR monoclonal antibody) in a phase II trial. METHODS: Patients with KRAS, NRAS, and BRAF wt mCRC with prior 5-FU, irinotecan, oxaliplatin, +/- bevacizumab and no prior anti-EGFR therapy were treated with trametinib 1.5 mg oral daily and panitumumab 4.8 mg/kg IV every 2 weeks. Primary endpoint was clinical benefit rate (CB; CR, PR, or SD ≥24 weeks) by RECIST v1.1. A 2-stage minimax design was used. Serial plasma circulating free DNA (cfDNA) was collected and profiled using Oncomine Lung cfDNA assay. RESULTS: Fourteen patients were enrolled from November 2015 to April 2019. CB rate was 38% (5/13) and median progression free survival (PFS) was 4.4 months (95% CI, 2.9-7.1). Confirmed overall response rate was 38% (5/13). Treatment-related AE (trAE) included acneiform rash (85%), diarrhea (62%), maculopapular rash (54%), mucositis (46%), and others. Dose modifications and interruptions of trametinib occurred in 69% and panitumumab in 54% of patients. The trial did not progress to stage II accrual due to tolerability and short duration of response. RAS or BRAF mutations cfDNA were detected in 3/13 patients (23%) before radiographic disease progression. CONCLUSION: The addition of trametinib to panitumumab led to a high rate of tumor shrinkage in RAS/RAF wt metastatic colorectal cancer, with poor tolerability due to a high incidence of skin toxicity. Median PFS was similar to panitumumab alone in historical control data.

Patient-derived tumor xenograft and organoid models established from resected pancreatic, duodenal and biliary cancers.

Patient-derived xenograft (PDX) and their xenograft-derived organoid (XDO) models that recapitulate the genotypic and phenotypic landscape of patient cancers could help to advance research and lead to improved clinical management. PDX models were established from 276 pancreato-duodenal and biliary cancer resections. Initial, passage 0 (P0) engraftment rates were 59% (118/199) for pancreatic, 86% (25/29) for duodenal, and 35% (17/48) for biliary ductal tumors. Pancreatic ductal adenocarcinoma (PDAC), had a P0 engraftment rate of 62% (105/169). KRAS mutant and wild-type PDAC models were molecularly profiled, and XDO models were generated to perform initial drug response evaluations. Subsets of PDAC PDX models showed global copy number variants and gene expression profiles that were retained with serial passaging, and they showed a spectrum of somatic mutations represented in patient tumors. PDAC XDO models were established, with a success rate of 71% (10/14). Pathway activation of KRAS-MAPK in PDXs was independent of KRAS mutational status. Four wild-type KRAS models were characterized by one with EGFR (L747-P753 del), two with BRAF alterations (N486_P490del or V600E), and one with triple negative KRAS/EGFR/BRAF. Model OCIP256, characterized by BRAF (N486-P490 del), had activated phospho-ERK. A combination treatment of a pan-RAF inhibitor (LY3009120) and a MEK inhibitor (trametinib) effectively suppressed phospho-ERK and inhibited growth of OCIP256 XDO and PDX models. PDAC/duodenal adenocarcinoma have high success rates forming PDX/organoid and retaining their phenotypic and genotypic features. These models may be effective tools to evaluate novel drug combination therapies.

Actinomycetes: A Never-Ending Source of Bioactive Compounds-An Overview on Antibiotics Production.

The discovery of penicillin by Sir Alexander Fleming in 1928 provided us with access to a new class of compounds useful at fighting bacterial infections: antibiotics. Ever since, a number of studies were carried out to find new molecules with the same activity. Microorganisms belonging to Actinobacteria phylum, the Actinomycetes, were the most important sources of antibiotics. Bioactive compounds isolated from this order were also an important inspiration reservoir for pharmaceutical chemists who realized the synthesis of new molecules with antibiotic activity. According to the World Health Organization (WHO), antibiotic resistance is currently one of the biggest threats to global health, food security, and development. The world urgently needs to adopt measures to reduce this risk by finding new antibiotics and changing the way they are used. In this review, we describe the primary role of Actinomycetes in the history of antibiotics. Antibiotics produced by these microorganisms, their bioactivities, and how their chemical structures have inspired generations of scientists working in the synthesis of new drugs are described thoroughly.

Combined mental task and metaboreflex impair cerebral oxygenation in patients with type 2 diabetes mellitus.

Cardiovascular regulation is altered by type 2 diabetes mellitus (DM2), producing an abnormal response to muscle metaboreflex. During physical exercise, cerebral blood flow is impaired in patients with DM2, and this phenomenon may reduce cerebral oxygenation (COX). We hypothesized that the simultaneous execution of a mental task (MT) and metaboreflex activation would reduce COX in patients with DM2. Thirteen individuals suffering from DM2 (6 women) and 13 normal age-matched controls (CTL, 6 women) participated in this study. They underwent five different tests, each lasting 12 min: postexercise muscle ischemia (PEMI) to activate the metaboreflex, control exercise recovery (CER), PEMI + MT, CER + MT, and MT alone. COX was evaluated using near-infrared spectroscopy with sensors applied to the forehead. Central hemodynamics was assessed using impedance cardiography. We found that when MT was superimposed on the PEMI-induced metaboreflex, patients with DM2 could not increase COX to the same extent reached by the CTL group (101.13% ± 1.08% vs. 104.23% ± 2.51%, P < 0.05). Moreover, patients with DM2 had higher mean blood pressure and systemic vascular resistance as well as lower stroke volume and cardiac output levels compared with the CTL group, throughout our experiments. It was concluded that patients with DM2 had reduced capacity to enhance COX when undertaking an MT during metaboreflex. Results also confirm that patients with DM2 had dysregulated hemodynamics during metaboreflex, with exaggerated blood pressure response and vasoconstriction. This may have implications for these patients' lack of inclination to exercise.