Clusiaxanthone and tocotrienol Series from Clusia pernambucensis and their antileishmanial activity

Phytochemical analysis of the ethyl acetate extract from the stem bark of Clusia pernambucensis G. Mariz, Clusiaceae, a Brazilian Cerrado species, led to the isolation and full characterization of a new xanthone, 1,7-dihydroxy-2-(3-methyl-2-butenyl)-6',6'-dimethylpyrano(2',3':3,4)xanthone, namely clusiaxanthone. Four previously unreported tocotrienols from this species were also isolated. A derivative was obtained from clusiaxanthone, 1-hydroxy,7-methoxy-2-(3-methyl2-butenyl)-6',6'-dimethylpyrano(2',3':3,4)xanthone (7-O-methylclusiaxanthone), and an additional derivative was obtained from Z- δ -tocotrienoloic acid. The structures of these compounds were established based on data from ¹H and 13C nuclear magnetic resonance (1D and 2D NMR), high resolution electrospray ionization mass spectrometry (HRESIMS) and infrared spectroscopy. The clusiaxanthone and its derivative were able to control macrophage infection by Leishmania (Leishmania) amazonensis amastigotes (IC50 = 66.9 and 57.4 µM, respectively). The cytotoxicity of the compounds was assessed in BALB/c mouse peritoneal macrophages.A análise fitoquímica do extrato acetato de etila da casca do caule de Clusia pernambucensis G. Mariz, Clusiaceae, uma espécie do Cerrado brasileiro, conduziu ao isolamento e caracterização completa de uma nova xantona, 1,7-dihidróxi-2-(3-metil-2-butenil)-6',6'-dimetilpirano(2',3':3,4) xantona, denominada clusiaxantona. Quatro tocotrienóis ainda não relatados nesta espécie também foram isolados. Um derivado foi obtido a partir da clusiaxantona, 1-hidróxi,7-metóxi-2-(3-metil2-butenil)-6',6'-dimetilpirano(2',3':3,4)xantona (7-O-metil-clusiaxantona), e um segundo derivado foi obtido a partir do ácido Z- δ -tocotrienolóico. As estruturas foram estabelecidas com base em dados de ressonância magnética nuclear de ¹H e 13C (NMR 1D e 2D), espectrometria de massa com ionização por electrospray de alta resolução (HRESIMS) e espectroscopia no infravermelho. No controle da infecção de macrófagos com amastigotas de Leishmania (Leishmania) amazonensis, os compostos ativos foram clusiaxantona e seu derivado (CI50 = 66,9 e 57,4 µM, respectivamente). A citotoxicidade dos compostos foi determinada em macrófagos peritoneais de camundongos BALB/c

Worldwide trends in underweight and obesity from 1990 to 2022: a pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults

Background Underweight and obesity are associated with adverse health outcomes throughout the life course. We estimated the individual and combined prevalence of underweight or thinness and obesity, and their changes, from 1990 to 2022 for adults and school-aged children and adolescents in 200 countries and territories. Methods We used data from 3663 population-based studies with 222 million participants that measured height and weight in representative samples of the general population. We used a Bayesian hierarchical model to estimate trends in the prevalence of different BMI categories, separately for adults (age ≥20 years) and school-aged children and adolescents (age 5–19 years), from 1990 to 2022 for 200 countries and territories. For adults, we report the individual and combined prevalence of underweight (BMI <18·5 kg/m2) and obesity (BMI ≥30 kg/m2). For schoolaged children and adolescents, we report thinness (BMI <2 SD below the median of the WHO growth reference) and obesity (BMI >2 SD above the median). Findings From 1990 to 2022, the combined prevalence of underweight and obesity in adults decreased in 11 countries (6%) for women and 17 (9%) for men with a posterior probability of at least 0·80 that the observed changes were true decreases. The combined prevalence increased in 162 countries (81%) for women and 140 countries (70%) for men with a posterior probability of at least 0·80. In 2022, the combined prevalence of underweight and obesity was highest in island nations in the Caribbean and Polynesia and Micronesia, and countries in the Middle East and north Africa. Obesity prevalence was higher than underweight with posterior probability of at least 0·80 in 177 countries (89%) for women and 145 (73%) for men in 2022, whereas the converse was true in 16 countries (8%) for women, and 39 (20%) for men. From 1990 to 2022, the combined prevalence of thinness and obesity decreased among girls in five countries (3%) and among boys in 15 countries (8%) with a posterior probability of at least 0·80, and increased among girls in 140 countries (70%) and boys in 137 countries (69%) with a posterior probability of at least 0·80. The countries with highest combined prevalence of thinness and obesity in school-aged children and adolescents in 2022 were in Polynesia and Micronesia and the Caribbean for both sexes, and Chile and Qatar for boys. Combined prevalence was also high in some countries in south Asia, such as India and Pakistan, where thinness remained prevalent despite having declined. In 2022, obesity in school-aged children and adolescents was more prevalent than thinness with a posterior probability of at least 0·80 among girls in 133 countries (67%) and boys in 125 countries (63%), whereas the converse was true in 35 countries (18%) and 42 countries (21%), respectively. In almost all countries for both adults and school-aged children and adolescents, the increases in double burden were driven by increases in obesity, and decreases in double burden by declining underweight or thinness. Interpretation The combined burden of underweight and obesity has increased in most countries, driven by an increase in obesity, while underweight and thinness remain prevalent in south Asia and parts of Africa. A healthy nutrition transition that enhances access to nutritious foods is needed to address the remaining burden of underweight while curbing and reversing the increase in obesit

Machine Learning Identifies Stemness Features Associated with Oncogenic Dedifferentiation.

Cancer progression involves the gradual loss of a differentiated phenotype and acquisition of progenitor and stem-cell-like features. Here, we provide novel stemness indices for assessing the degree of oncogenic dedifferentiation. We used an innovative one-class logistic regression (OCLR) machine-learning algorithm to extract transcriptomic and epigenetic feature sets derived from non-transformed pluripotent stem cells and their differentiated progeny. Using OCLR, we were able to identify previously undiscovered biological mechanisms associated with the dedifferentiated oncogenic state. Analyses of the tumor microenvironment revealed unanticipated correlation of cancer stemness with immune checkpoint expression and infiltrating immune cells. We found that the dedifferentiated oncogenic phenotype was generally most prominent in metastatic tumors. Application of our stemness indices to single-cell data revealed patterns of intra-tumor molecular heterogeneity. Finally, the indices allowed for the identification of novel targets and possible targeted therapies aimed at tumor differentiation

A blood-based, six metabolite signature for relapsing-remitting multiple sclerosis

Background: Multiple sclerosis (MS) is a serious debilitating health problem. Monitoring of the disease more closely with a non-invasive marker in the clinic will be of immense benefit. Metabolomics provides a new powerful approach to discover diagnostic and therapeutic biomarkers by analyzing global changes in an individual\u27s metabolic profile. Objectives: The aim of this study was to identify serum metabolites as disease biomarker(s) for relapsing-remitting multiple sclerosis (RRMS) using untargeted metabolomics approach. Methods: Using ultra-performance liquid chromatography linked to gas chromatography and tandem mass spectrometry (Metabolon, Durham, NC), we measured serum metabolites from 35 RRMS subjects without any drug treatment (mean age: 45 years and mean duration of disease 18.2 years; 64% female) and 14 healthy subjects with no disease (mean age: 40 years; 64% female). Results: A total of 621 known metabolites were detected with significance changes observed in 60 metabolites (53 up-regulated and 7 down-regulated) in the serum of RRMS compared to HS. Partial least-squares discriminant analysis of the metabolites reveals a separation of these groups. Bioinformatics analysis revealed 4 metabolic pathways being impacted and altered in RRMS including glycerophospholipid metabolism, citrate cycle (TCA), taurine and hypotaurine and pyruvate metabolism. Casual Network Analysis in IPA identified sphingosine and transforming growth factor beta as a master regulator of altered metabolites in RRMS. Further to identify the potential biomarker specific for RRMS, we identified 14 metabolites, which were selected for prediction model creation. Six out of 14 metabolites were validated in an independent cohort (HS=34, RRMS=40), which could be predicted as potential biomarker for RRMS. Conclusion: Identified and validated 6 metabolites signature have potential to be developed into a clinically useful diagnostic or biomarker tool, that could also contribute to further understanding of disease mechanisms

Blood-based untargeted metabolomics in rrms revealed the testable therapeutic target

Background: Relapsing-remitting (RRMS), a most common form of MS, is characterized by acute attacks alternated by partial or complete recovery periods. Objectives: The major focus of our research is to identify the therapeutic target using metabolomics. Metabolomics is a fast emerging field which can provide a direct “functional readout of the physiological state” of an organism. Identification of bloodbased metabolic pathway(s) in relapsing-remitting form of MS (RRMS) could be targeted for therapy development. Methods: Using ultra-performance liquid chromatography linked to gas chromatography and tandem mass spectrometry (Metabolon, Durham, NC), we measured serum metabolites from 35 RRMS subjects without any drug treatment (mean age: 45 years and mean duration of disease 18.2 years; 64% female) and 14 healthy subjects with no disease (mean age: 40 years; 64% female). Results: Using untargeted ultra-performance liquid and gas mass spectrometry, we measured serum metabolites from 33 RRMS patients, and 14 healthy subjects (HS). A total of 621 known metabolites were detected, and 60 metabolites were significantly altered in the serum of RRMS compared to HS. Bioinformatics analysis revealed four metabolic pathways altered in RRMS including glycerophospholipid, citrate cycle, sphingolipids, and pyruvate metabolism. PBMCs isolated from RRMS patients exhibited higher glycolysis suggesting altered metabolic state of immune cells. As a proof of principle, we are abrogating glycolysis in EAE group using glycolytic inhibitor (once daily) and found a significant reduction (

Blood-based untargeted metabolomics in rrms revealed the testable therapeutic target

Background: Relapsing-remitting (RRMS), a most common form of MS, is characterized by acute attacks alternated by partial or complete recovery periods. Objectives: The major focus of our research is to identify the therapeutic target using metabolomics. Metabolomics is a fast emerging field which can provide a direct “functional readout of the physiological state” of an organism. Identification of bloodbased metabolic pathway(s) in relapsing-remitting form of MS (RRMS) could be targeted for therapy development. Methods: Using ultra-performance liquid chromatography linked to gas chromatography and tandem mass spectrometry (Metabolon, Durham, NC), we measured serum metabolites from 35 RRMS subjects without any drug treatment (mean age: 45 years and mean duration of disease 18.2 years; 64% female) and 14 healthy subjects with no disease (mean age: 40 years; 64% female). Results: Using untargeted ultra-performance liquid and gas mass spectrometry, we measured serum metabolites from 33 RRMS patients, and 14 healthy subjects (HS). A total of 621 known metabolites were detected, and 60 metabolites were significantly altered in the serum of RRMS compared to HS. Bioinformatics analysis revealed four metabolic pathways altered in RRMS including glycerophospholipid, citrate cycle, sphingolipids, and pyruvate metabolism. PBMCs isolated from RRMS patients exhibited higher glycolysis suggesting altered metabolic state of immune cells. As a proof of principle, we are abrogating glycolysis in EAE group using glycolytic inhibitor (once daily) and found a significant reduction (

Blood-based untargeted metabolomics in relapsing-remitting multiple sclerosis revealed testable therapeutic target

Relapsing-remitting (RRMS), a most common form of MS, is characterized by acute attacks alternated by partial or complete recovery periods. The major focus of our research is to identify the therapeutic target using metabolomics. Metabolomics is a fast emerging field which can provide a direct “functional readout of the physiological state” of an organism. Identification of blood-based metabolic pathway(s) in relapsing-remitting form of MS (RRMS) which could be used for therapy. Using untargeted ultra-performance liquid and gas mass spectrometry, we measured serum metabolites from 33 RRMS patients, and 14 healthy subjects (HS). A total of 621 known metabolites were detected and 60 metabolites were significantly altered in the serum of RRMS compared to HS. Bioinformatics analysis revealed four metabolic pathways altered in RRMS including glycerophospholipid, citrate cycle, sphingolipids, and pyruvate metabolism. PBMCs isolated from RRMS patients exhibited higher glycolysis suggesting altered metabolic state of immune cells. EAE mice treated with glycolytic inhibitor 2-deoxyglucose (2-DG; once daily), resulted in a significantly delayed (