The differential effects of palmitic acid and oleic acid on the metabolic response of hypothalamic astrocytes from male and female mice.

Diets rich in saturated fats are more detrimental to health than those containing mono- or unsaturated fats. Fatty acids are an important source of energy, but they also relay information regarding nutritional status to hypothalamic metabolic circuits and when in excess can be detrimental to these circuits. Astrocytes are the main site of central fatty acid ß-oxidation, and hypothalamic astrocytes participate in energy homeostasis, in part by modulating hormonal and nutritional signals reaching metabolic neurons, as well as in the inflammatory response to high-fat diets. Thus, we hypothesized that how hypothalamic astrocytes process-specific fatty acids participates in determining the differential metabolic response and that this is sex dependent as males and females respond differently to high-fat diets. Male and female primary hypothalamic astrocyte cultures were treated with oleic acid (OA) or palmitic acid (PA) for 24 h, and an untargeted metabolomics study was performed. A clear predictive model for PA exposure was obtained, while the metabolome after OA exposure was not different from controls. The observed modifications in metabolites, as well as the expression levels of key metabolic enzymes, indicate a reduction in the activity of the Krebs and glutamate/glutamine cycles in response to PA. In addition, there were specific differences between the response of astrocytes from male and female mice, as well as between hypothalamic and cerebral cortical astrocytes. Thus, the response of hypothalamic astrocytes to specific fatty acids could result in differential impacts on surrounding metabolic neurons and resulting in varied systemic metabolic outcomes.

Leishmania donovani Induces Multiple Dynamic Responses in the Metabolome Associated with Amastigote Differentiation and Maturation Inside the Human Macrophage.

Leishmania donovani infection of macrophages drives profound changes in the metabolism of both the host macrophage and the parasite, which undergoes different phases of development culminating in replication and propagation. However, the dynamics of this parasite-macrophage cometabolome are poorly understood. In this study, a multiplatform metabolomics pipeline combining untargeted, high-resolution CE-TOF/MS and LC-QTOF/MS with targeted LC-QqQ/MS was followed to characterize the metabolome alterations induced in L. donovani-infected human monocyte-derived macrophages from different donors at 12, 36, and 72 h post-infection. The set of alterations known to occur during Leishmania infection of macrophages, substantially expanded in this investigation, characterized the dynamics of the glycerophospholipid, sphingolipid, purine, pentose phosphate, glycolytic, TCA, and amino acid metabolism. Our results showed that only citrulline, arginine, and glutamine exhibited constant trends across all studied infection time points, while most metabolite alterations underwent a partial recovery during amastigote maturation. We determined a major metabolite response pointing to an early induction of sphingomyelinase and phospholipase activities and correlated with amino acid depletion. These data represent a comprehensive overview of the metabolome alterations occurring during promastigote-to-amastigote differentiation and maturation of L. donovani inside macrophages that contributes to our understanding of the relationship between L. donovani pathogenesis and metabolic dysregulation.

Multiplatform Metabolomics Characterization Reveals Novel Metabolites and Phospholipid Compositional Rules of Haemophilus influenzae Rd KW20.

Haemophilus influenzae is a gram-negative bacterium of relevant clinical interest. H. influenzae Rd KW20 was the first organism to be sequenced and for which a genome-scale metabolic model (GEM) was developed. However, current H. influenzae GEMs are unable to capture several aspects of metabolome nature related to metabolite pools. To directly and comprehensively characterize the endometabolome of H. influenzae Rd KW20, we performed a multiplatform MS-based metabolomics approach combining LC-MS, GC-MS and CE-MS. We obtained direct evidence of 15-20% of the endometabolome present in current H. influenzae GEMs and showed that polar metabolite pools are interconnected through correlating metabolite islands. Notably, we obtained high-quality evidence of 18 metabolites not previously included in H. influenzae GEMs, including the antimicrobial metabolite cyclo(Leu-Pro). Additionally, we comprehensively characterized and evaluated the quantitative composition of the phospholipidome of H. influenzae, revealing that the fatty acyl chain composition is largely independent of the lipid class, as well as that the probability distribution of phospholipids is mostly related to the conditional probability distribution of individual acyl chains. This finding enabled us to provide a rationale for the observed phospholipid profiles and estimate the abundance of low-level species, permitting the expansion of the phospholipidome characterization through predictive probabilistic modelling.

The Effect of Hyperosmolar Water-Soluble Contrast for the Management of Adhesive Small Bowel Obstruction: A Systematic Review and Meta-Analysis.

OBJECTIVE: To better understand the efficacy of water-soluble contrast (WSC) in the treatment of adhesive small bowel obstruction (SBO). BACKGROUND: Guidelines recommend using WSC to treat adhesive SBO nonoperatively by acting as a cathartic agent. The evidence supporting this practice is mixed. METHODS: A systematic review and meta-analysis of published articles describing the effect of WSC compared with control treatments was performed for the period of January 1, 1990 to November 1, 2021. Study quality was assessed using the Cochrane risk-of-bias and the Newcastle-Ottawa tools. The therapeutic effect of WSC was assessed by operative rates and hospital length of stay (HLOS) in nonsurgical patients. RESULTS: The initial search yielded 4879 articles, of which, 28 were selected for full text review. We identified 11 eligible randomized controlled trials (RCTs) which included 817 patients and 9 observational studies of 3944 patients. HLOS in nonsurgical patients decreased by 1.95 days (95% confidence interval: 0.56-3.3) in the RCTs and could not be assessed in the observational studies. WSC did not significantly affect operative rates in the RCTs (19.8% vs. 21.4%) but did reduce rates in the observational studies (11% vs. 16%, risk ratio: 0.56, 95% confidence interval: 0.39-0.82). CONCLUSION: WSC studies may reduce HLOS for patients who have SBO and do not require surgery. However, the current literature is heterogenous with considerable design limitations. High-quality RCTs are needed using standardized protocols to determine the full benefit of WSC for the management of SBO.

Optimal Strategies for Colorectal Cancer Screening.

OPINION STATEMENT: Colorectal cancer (CRC) imposes significant morbidity and mortality, yet it is also largely preventable with evidence-based screening strategies. In May 2021, the US Preventive Services Task Force updated guidance, recommending screening begin at age 45 for average-risk individuals to reduce CRC incidence and mortality in the United States (US). The Task Force recommends screening with one of several screening strategies: high-sensitivity guaiac fecal occult blood test (HSgFOBT), fecal immunochemical test (FIT), multi-target stool DNA (mt-sDNA) test, computed tomographic (CT) colonography (virtual colonoscopy), flexible sigmoidoscopy, flexible sigmoidoscopy with FIT, or traditional colonoscopy. In addition to these recommended options, there are several emerging and novel CRC screening modalities that are not yet approved for first-line screening in average-risk individuals. These include blood-based screening or "liquid biopsy," colon capsule endoscopy, urinary metabolomics, and stool-based microbiome testing for the detection of colorectal polyps and/or CRC. In order to maximize CRC screening uptake in the US, patients and providers should engage in informed decision-making about the benefits and limitations of recommended screening options to determine the most appropriate screening test. Factors to consider include the invasiveness of the test, test performance, screening interval, accessibility, and cost. In addition, health systems should have a programmatic approach to CRC screening, which may include evidence-based strategies such as patient education, provider education, mailed screening outreach, and/or patient navigation, to maximize screening participation.

Quantitative data collection approaches in subject-reported oral health research: a scoping review.

BACKGROUND: This scoping review reports on studies that collect survey data using quantitative research to measure self-reported oral health status outcome measures. The objective of this review is to categorize measures used to evaluate self-reported oral health status and oral health quality of life used in surveys of general populations. METHODS: The review is guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) with the search on four online bibliographic databases. The criteria include (1) peer-reviewed articles, (2) papers published between 2011 and 2021, (3) only studies using quantitative methods, and (4) containing outcome measures of self-assessed oral health status, and/or oral health-related quality of life. All survey data collection methods are assessed and papers whose methods employ newer technological approaches are also identified. RESULTS: Of the 2981 unduplicated papers, 239 meet the eligibility criteria. Half of the papers use impact scores such as the OHIP-14; 10% use functional measures, such as the GOHAI, and 26% use two or more measures while 8% use rating scales of oral health status. The review identifies four data collection methods: in-person, mail-in, Internet-based, and telephone surveys. Most (86%) employ in-person surveys, and 39% are conducted in Asia-Pacific and Middle East countries with 8% in North America. Sixty-six percent of the studies recruit participants directly from clinics and schools, where the surveys were carried out. The top three sampling methods are convenience sampling (52%), simple random sampling (12%), and stratified sampling (12%). Among the four data collection methods, in-person surveys have the highest response rate (91%), while the lowest response rate occurs in Internet-based surveys (37%). Telephone surveys are used to cover a wider population compared to other data collection methods. There are two noteworthy approaches: 1) sample selection where researchers employ different platforms to access subjects, and 2) mode of interaction with subjects, with the use of computers to collect self-reported data. CONCLUSION: The study provides an assessment of oral health outcome measures, including subject-reported oral health status and notes newly emerging computer technological approaches recently used in surveys conducted on general populations. These newer applications, though rarely used, hold promise for both researchers and the various populations that use or need oral health care.

Correction: Simão, A.Y., et al. Evaluation of the Cytotoxicity of Ayahuasca Beverages. Molecules 2020, 25, 5594.

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Reference Revamp: A 1-2 Model for Training and Tiered Services.

The UCLA Science Libraries improved upon our single service points by creating a team-based, tiered research assistance model to foster student employee skill development. This model was further developed to expand training for public services staff, enabling librarians and student research assistants to move beyond desk-based services. This multi-phased approach involved restructured training and the development of collaborative, tiered services. Librarians utilized train-the-trainer sessions, detailed documentation toolkits, and a robust outreach plan to ensure success. After initial implementation of this new model, librarians observed above average use of the service and excellent user feedback. Its versatility has also played a direct role in the successful transition from physical to virtual services in light of the COVID-19 pandemic.

Comprehensive Examination of the Mouse Lung Metabolome Following Mycobacterium tuberculosis Infection Using a Multiplatform Mass Spectrometry Approach.

The mechanisms whereby Mycobacterium tuberculosis (Mtb) rewires the host metabolism in vivo are surprisingly unexplored. Here, we used three high-resolution mass spectrometry platforms to track altered lung metabolic changes associated with Mtb infection of mice. The multiplatform data sets were merged using consensus orthogonal partial least squares-discriminant analysis (cOPLS-DA), an algorithm that allows for the joint interpretation of the results from a single multivariate analysis. We show that Mtb infection triggers a temporal and progressive catabolic state to satisfy the continuously changing energy demand to control infection. This causes dysregulation of metabolic and oxido-reductive pathways culminating in Mtb-associated wasting. Notably, high abundances of trimethylamine-N-oxide (TMAO), produced by the host from the bacterial metabolite trimethylamine upon infection, suggest that Mtb could exploit TMAO as an electron acceptor under anaerobic conditions. Overall, these new pathway alterations advance our understanding of the link between Mtb pathogenesis and metabolic dysregulation and could serve as a foundation for new therapeutic intervention strategies. Mass spectrometry data has been deposited in the Metabolomics Workbench repository (data-set identifier: ST001328).

Oncolytic Virotherapy in Glioma Tumors.

Glioma tumors are one of the most devastating cancer types. Glioblastoma is the most advanced stage with the worst prognosis. Current therapies are still unable to provide an effective cure. Recent advances in oncolytic immunotherapy have generated great expectations in the cancer therapy field. The use of oncolytic viruses (OVs) in cancer treatment is one such immune-related therapeutic alternative. OVs have a double oncolytic action by both directly destroying the cancer cells and stimulating a tumor specific immune response to return the ability of tumors to escape the control of the immune system. OVs are one promising alternative to conventional therapies in glioma tumor treatment. Several clinical trials have proven the feasibility of using some viruses to specifically infect tumors, eluding undesired toxic effects in the patient. Here, we revisited the literature to describe the main OVs proposed up to the present moment as therapeutic alternatives in order to destroy glioma cells in vitro and trigger tumor destruction in vivo. Oncolytic viruses were divided with respect to the genome in DNA and RNA viruses. Here, we highlight the results obtained in various clinical trials, which are exploring the use of these agents as an alternative where other approaches provide limited hope.

Evaluation of the Cytotoxicity of Ayahuasca Beverages.

Ayahuasca is a beverage consumed at shamanic ceremonies and currently has gained popularity on recreational scenarios. It contains beta-carboline alkaloids and N,N-dimethyltryptamine, which possesses hallucinogenic effects. Only a few studies have elicited the psychoactive effects and the dose of such compounds on neurological dopaminergic cells or animals. In this work, we aimed to study the cytotoxic effects of these compounds present in ayahuasca beverages and on five different teas (Banisteriopsis caapi, Psychotria viridis, Peganum harmala, Mimosa tenuiflora and Dc Ab (commercial name)) preparations on dopaminergic immortalized cell lines. Moreover, a characterization of the derivative alkaloids was also performed. All the extracts were characterized by chromatographic systems and the effect of those compounds in cell viability and total protein levels were analyzed in N27 dopaminergic neurons cell line. This is the first article where cytotoxicity of ayahuasca tea is studied on neurological dopaminergic cells. Overall, results showed that both cell viability and protein contents decreased when cells were exposed to the individual compounds, as well as to the teas and to the two mixtures based on the traditional ayahuasca beverages.

Metabolomic Study of Hibernating Syrian Hamster Brains: In Search of Neuroprotective Agents.

Syrian hamsters undergo a reversible hyperphosphorylation of protein τ during hibernation, providing a unique natural model that may unveil the physiological mechanisms behind this critical process involved in the development of Alzheimer's disease and other tauopathies. The hibernation cycle of these animals fluctuates between a pair of stages: 3-4 days of torpor bouts interspersed with periods of euthermia called arousals that last several hours. In this study, we investigated for the first time the metabolic changes in brain tissue during hibernation. A total of 337 metabolites showed statistically significant differences during hibernation. Based on these metabolites, several pathways were found to be significantly regulated and, therefore, play a key role in the regulation of hibernation processes. The increase in the levels of ceramides containing more than 20 C atoms was found in torpor animals, reflecting a higher activity of CerS2 during hibernation, linked to neurofibrillary tangle generation and structural changes in the Golgi apparatus. Our results open up the debate about the possible significance of some metabolites during hibernation, which may possibly be related to τ phosphorylation and dephosphorylation events. In general, this study may provide insights into novel neuroprotective agents because the alterations described throughout the hibernation process are reversible.

Repression of drought-induced cysteine-protease genes alters barley leaf structure and responses to abiotic and biotic stresses.

To survive under water deficiency, plants alter gene expression patterns, make structural and physiological adjustments, and optimize the use of water. Rapid degradation and turnover of proteins is required for effective nutrient recycling. Here, we examined the transcriptional responses of the C1A cysteine protease family to drought in barley and found that four genes were up-regulated in stressed plants. Knock-down lines for the protease-encoding genes HvPap-1 and HvPap-19 showed unexpected changes in leaf cuticle thickness and stomatal pore area. The efficiency of photosystem II and the total amount of proteins were almost unaltered in stressed transgenic plants while both parameters decreased in stressed wild-type plants. Although the patterns of proteolytic activities in the knock-down lines did not change, the amino acid accumulation increased in response to drought, concomitant with a higher ABA content. Whilst jasmonic acid (JA) and JA-Ile concentrations increased in stressed leaves of the wild-type and the HvPap-1 knock-down lines, their levels were lower in the HvPap-19 knock-down lines, suggesting the involvement of a specific hormone interaction in the process. Our data indicate that the changes in leaf cuticle thickness and stomatal pore area had advantageous effects on leaf defense against fungal infection and mite feeding mediated by Magnaporthe oryzae and Tetranychus urticae, respectively.

Effect of Homeopathic Medicines on Intestinal Coccidia and Immune Response Cells in Spotted Rose Snapper (Lutjanus guttatus).

BACKGROUND: Homeopathy has been widely applied in freshwater species but rarely in marine fish. Farm stress destabilises host-pathogen equilibrium, favouring parasites and disease. Coccidian endoparasites cause intestinal infections and cell degeneration. MATERIALS AND METHODS: Naturally parasite-infested juvenile snapper Lutjanus guttatus (n = 430; weight 1.9 ± 0.01 g; length 4.9 ± 0.03 cm) specimens were distributed in group sizes of 43, in 10 fiberglass tanks (100 L) with aeration and continuous water change. Five groups in duplicate were assessed: Passival (PaV); Passival and Phosphoricum acid Similia (PaV-PhA); Passival and Silicea terra Similia (PaV-SiT); Endecto and Infecçoes (End-Inf) and a control (Ethanol) for 45 days. Feed was sprinkled with treatment (5% v/w) and dried to avoid ethanol side-effects. Statistical results were expressed as mean ± standard error of the mean. RESULTS: Intestinal coccidia were recorded histopathologically, with the least incidence attained at T45 with End-Inf treatment (p < 0.001), coinciding with the highest lymphocyte (p = 0.015) count. Fish treated with PaV-PhA recorded a higher percentage of neutrophils (p = 0.015), and those treated with PaV-PhA, PaV-SiT and End-Inf revealed a decrease in lesions, degree of alteration and change in intestine and stomach tissues (p < 0.05). The number of mucous cells in gills was greater (p < 0.001) for End-Inf (43 ± 0.58), PaV-SiT (40 ± 2.89) and PaV-PhA (39 ± 3.46) as compared respectively with T0 and control (19 ± 0.58 and 28 ± 2.31). PaV and PaV-SiT increased carbohydrate reserves in liver (28.4 ± 1.39% and 22.4 ± 0.12%, respectively) compared with T0 and control (3.4 ± 0.32 and 5.6 ± 0.66%). The highest survival rate was 97.7 ± 0.16% in fish treated with PaV and End-Inf. CONCLUSION: Homeopathic treatments had a positive effect on fish health. Besides the accumulation of metabolic reserves in the liver, homeopathic treatment was associated with mucin increase in gills as well as raised production of lymphocytes and neutrophils in blood, which could act as macrophages against intestinal coccidia.

The Relationship of Motivation and Neurocognition with Functionality in Schizophrenia: A Meta-analytic Review.

The role that neurocognition plays in functionality in schizophrenia has been widely examined, although in recent years increasing attention has been paid to the influence of motivation instead. This study provides a review of the relationship of neurocognition and motivation with functionality in schizophrenia, taking into account objective/subjective functionality assessment, demographic variables, and the different terms used when referring to motivation. A search of electronic databases identified 34 studies that met the inclusion criteria for review. Correlation coefficients between motivation and functionality and between neurocognition and functionality were extracted. For a better understanding, potential moderator variables were also extracted. Meta-analysis showed that both motivation and neurocognition assessments were strongly associated with functioning, with correlations between motivation and functional outcomes being stronger. However, more than three-quarters of the variance in outcome remained unexplained by the moderating factors examined. The paper concludes with recommendations for clinical practice and future research.

HvPap-1 C1A Protease and HvCPI-2 Cystatin Contribute to Barley Grain Filling and Germination.

Proteolysis is an essential process throughout the mobilization of storage proteins in barley (Hordeum vulgare) grains during germination. It involves numerous types of enzymes, with C1A Cys proteases the most abundant key players. Manipulation of the proteolytic machinery is a potential way to enhance grain yield and quality, and it could influence the mobilization of storage compounds along germination. Transgenic barley plants silencing or over-expressing the cathepsin F-like HvPap-1 Cys protease show differential accumulation of storage molecules such as starch, proteins, and free amino acids in the grain. It is particularly striking that the HvPap-1 artificial microRNA lines phenotype show a drastic delay in the grain germination process. Alterations to the proteolytic activities in the over-expressing and knock-down grains associated with changes in the level of expression of several C1A peptidases were also detected. Similarly, down-regulating cystatin Icy-2, one of the proteinaceous inhibitors of the cathepsin F-like protease, also has important effects on grain filling. However, the ultimate physiological influence of manipulating a peptidase or an inhibitor cannot be always predicted, since the plant tries to compensate the modified proteolytic effects by modulating the expression of some other peptidases or their inhibitors.

New insight on obesity and adipose-derived stem cells using comprehensive metabolomics.

Obesity affects the functional capability of adipose-derived stem cells (ASCs) and their effective use in regenerative medicine through mechanisms that are still poorly understood. In the present study we used a multiplatform [LC/MS, GC/MS and capillary electrophoresis/MS (CE/MS)], metabolomics, untargeted approach to investigate the metabolic alteration underlying the inequalities observed in obesity-derived ASCs. The metabolic fingerprint (metabolites within the cells) and footprint (metabolites secreted in the culture medium), from obesity- and non-obesity-derived ASCs of humans or mice, were characterized to provide valuable information. Metabolites associated with glycolysis, the tricarboxylic acid cycle, the pentose phosphate pathway and the polyol pathway were increased in the footprint of obesity-derived human ASCs, indicating alterations in carbohydrate metabolism, whereas, from the murine model, deep differences in lipid and amino acid catabolism were highlighted. Therefore, new insights on the ASCs' metabolome were provided that enhance our understanding of the processes underlying ASCs' stemness capacity and its relationship with obesity, in different cell models.

Metabolomic Fingerprinting in the Comprehensive Study of Liver Changes Associated with Onion Supplementation in Hypercholesterolemic Wistar Rats.

The consumption of functional ingredients has been suggested to be a complementary tool for the prevention and management of liver disease. In this light, processed onion can be considered as a source of multiple bioactive compounds with hepatoprotective properties. The liver fingerprint of male Wistar rats (n = 24) fed with three experimental diets (control (C), high-cholesterol (HC), and high-cholesterol enriched with onion (HCO) diets) was obtained through a non-targeted, multiplatform metabolomics approach to produce broad metabolite coverage. LC-MS, CE-MS and GC-MS results were subjected to univariate and multivariate analyses, providing a list of significant metabolites. All data were merged in order to figure out the most relevant metabolites that were modified by the onion ingredient. Several relevant metabolic changes and related metabolic pathways were found to be impacted by both HC and HCO diet. The model highlighted several metabolites (such as hydroxybutyryl carnitine and palmitoyl carnitine) modified by the HCO diet. These findings could suggest potential impairments in the energy-lipid metabolism, perturbations in the tricarboxylic acid cycle (TCA) cycle and ß-oxidation modulated by the onion supplementation in the core of hepatic dysfunction. Metabolomics shows to be a valuable tool to evaluate the effects of complementary dietetic approaches directed to hepatic damage amelioration or non-alcoholic fatty liver disease (NAFLD) prevention.

Multiplatform metabolomic fingerprinting as a tool for understanding hypercholesterolemia in Wistar rats.

PURPOSE: The aim was to investigate the impact of hypercholesterolemic diet on the metabolome of male Wistar rats by a multiplatform metabolomic fingerprinting. METHODS: Male Wistar rats were fed with two different diets [control (C) and high-cholesterol diet (HC)-containing 2 % cholesterol and 0.5 % cholic acid]. After 7 weeks of experimental feeding, the rats were euthanized for blood collection and plasma recovery. The metabolite fingerprint was then achieved by applying a multiplatform comprising LC-MS, GC-MS and CE-MS. RESULTS: Multivariate statistical analysis showed a clear separation between the C and HC groups. Individual differences in metabolites were evaluated using univariate statistical analysis, and multiple metabolites were identified and confirmed in the plasma. A global profiling integrates for the first time pathways affected by high-cholesterol diet intake and allowed us to elucidate some of the associated alterations underlying the hypercholesterolemia event in Wistar rats. CONCLUSIONS: HC feeding stimulated the alteration of multiple pathways in Wistar rats, warning of the risk of developing important diseases, which can be modulated by the diet. Further studies are required to investigate the possibilities to revert or ameliorate the negative effects triggered by HC intake.