Metabolic Studies Research Articles

The role of Nuclear Magnetic Resonance (NMR) spectroscopy in cattle metabolism

Nuclear Magnetic Resonance (NMR) spectroscopy is a powerful analytical tool that has significantly advanced the understanding of cattle metabolism. Nuclear Magnetic Resonance (NMR) spectroscopy plays a pivotal role in the study of cattle metabolism, offering distinct advantages over other spectrometric methods. NMR spectroscopy is a powerful analytical tool that provides detailed molecular insights by exploiting the magnetic properties of atomic nuclei. Unlike mass spectrometry and infrared spectroscopy, NMR does not require extensive sample preparation or destruction, preserving the integrity of biological samples. This non-invasive nature is particularly beneficial for longitudinal studies in cattle, where metabolic changes over time are of interest. One of the key strengths of NMR spectroscopy is its ability to simultaneously detect and quantify a broad range of metabolites in complex biological matrices, such as blood, urine, and tissue extracts. This comprehensive metabolic profiling is crucial for understanding the biochemical pathways and physiological states in cattle. NMR's high reproducibility and quantitative accuracy further enhance its suitability for metabolic studies, enabling precise monitoring of metabolic fluctuations in response to dietary changes, environmental stressors, or disease conditions. NMR spectroscopy also offers unique advantages in elucidating structural information about metabolites. Through multidimensional NMR techniques, researchers can determine the molecular structure and conformation of metabolites, providing deeper insights into metabolic functions and interactions. This structural elucidation is often challenging with other spectrometric methods, which may lack the resolution or require derivatization of samples. Moreover, NMR spectroscopy's non-destructive nature allows for the analysis of living tissues and in vivo studies, facilitating real-time monitoring of metabolic processes. This capability is instrumental in studying dynamic metabolic responses and adaptations in cattle under different physiological states. Additionally, the development of advanced NMR techniques, such as high-resolution magic angle spinning (HR-MAS) and hyperpolarization, has further expanded the scope of NMR applications in metabolic research. NMR spectroscopy stands out as a superior method for studying cattle metabolism due to its non-destructive approach, comprehensive metabolic profiling, structural elucidation capabilities, and potential for in vivo analysis. These advantages make NMR an indispensable tool in advancing our understanding of cattle metabolism and improving livestock health and productivity. Keywords: Nuclear Magnetic Resonance (NMR), Cattles, Metabolomics.

Metabolic reprogramming in hepatocellular carcinoma: a bibliometric and visualized study from 2011 to 2023.

Metabolic reprogramming has been found to be a typical feature of tumors. Hepatocellular carcinoma (HCC), a cancer with high morbidity and mortality, has been extensively studied for its metabolic reprogramming-related mechanisms. Our study aims to identify the hotspots and frontiers of metabolic reprogramming research in HCC and to provide guidance for future scientific research and decision-making in HCC metabolism. Relevant studies on the metabolic reprogramming of HCC were derived from the Web of Science Core Collection (WoSCC) database up until November 2023. The bibliometrix tools in R were used for scientometric analysis and visualization. From 2011 to 2023, a total of 575 publications were obtained from WoSCC that met the established criteria. These publications involved 3,904 researchers and 948 organizations in 37 countries, with an average annual growth rate of 39.11% in research. These studies were published in 233 journals, with Cancers (n = 29) ranking first, followed by Frontiers in Oncology (n = 20) and International Journal of Molecular Sciences (n = 19). The top ten journals accounted for 26% of the 575 studies. The most prolific authors were Wang J (n = 14), Li Y (n = 12), and Liu J (n = 12). The country with the most publications is China, followed by the United States, Italy, and France. Fudan University had the largest percentage of research results with 15.48% (n = 89). Ally A's paper in Cell has the most citations. A total of 1,204 keywords were analyzed, with the trend themes such as "glycolysis," "tumor microenvironment," "Warburg effect," "mitochondria," "hypoxia ," etc. Co-occurrence network and cluster analysis revealed the relationships between keywords, authors, publications, and journals. Moreover, the close collaboration between countries in this field was elucidated. This bibliometric and visual analysis delves into studies related to metabolic reprogramming in HCC between 2012 and 2023, elucidating the characteristics of research in this field, which has gradually moved away from single glycolipid metabolism studies to the integration of overall metabolism in the body, pointing out the trend of research topics, and the dynamics of the interaction between the tumor microenvironment and metabolic reprogramming will be the future direction of research, which provides blueprints and inspirations for HCC prevention and treatment programs to the researchers in this field.

The neurobiological mechanism underlying ketamine’s rapid-acting antidepressant effect

Depression is one of the most common disabling mental disorders. However, first-line treatments for depression are typically slow-acting. Ketamine, a glutamatergic modulator with rapid antidepressant effects, has proven effective in treating both refractory depression and suicidal tendencies. The neurobiological mechanisms underlying the effects of antidepressants have become a research hotspot; yet, the exact processes remain unclear. Brain imaging studies have provided important evidence from macroscopic perspectives, such as brain structure and function, while biochemical studies have made significant discoveries from microscopic perspectives, including proteomics and genomics. Previous reviews have summarized a broad range of biomarkers related to the ketamine response, encompassing studies in imaging, electrophysiology, metabolism, immunology, genetics, and neurotrophy. In this review, we systematically summarize a number of potential biomarkers for predicting and modulating the efficacy of ketamine, from both macroperspectives (such as neuroimaging and neuroelectrophysiological markers) and microperspectives (such as neurobiochemical and genetic markers). Although research in this area is still in its infancy, these biomarkers can help clinicians identify whether ketamine intervention is needed for treatment-resistant depression, thereby reducing the burden on patients and society. However, the majority of biomarkers are still in the preclinical exploratory stage, and existing findings are limited. To realize the clinical application of these biomarkers, future studies should combine biomarkers of different types to investigate the relationships and interactions between them. This approach aims to optimize clinical outcomes by enhancing the involvement of biological targets in new models.

Advances in mass spectrometry imaging for plant metabolomics-Expanding the analytical toolbox.

Mass spectrometry imaging (MSI) has become increasingly popular in plant science due to its ability to characterize complex chemical, spatial, and temporal aspects of plant metabolism. Over the past decade, as the emerging and unique features of various MSI techniques have continued to support new discoveries in studies of plant metabolism closely associated with various aspects of plant function and physiology, spatial metabolomics based on MSI techniques has positioned it at the forefront of plant metabolic studies, providing the opportunity for far higher resolution than was previously available. Despite these efforts, profound challenges at the levels of spatial resolution, sensitivity, quantitative ability, chemical confidence, isomer discrimination, and spatial multi-omics integration, undoubtedly remain. In this Perspective, we provide a contemporary overview of the emergent MSI techniques widely used in the plant sciences, with particular emphasis on recent advances in methodological breakthroughs. Having established the detailed context of MSI, we outline both the golden opportunities and key challenges currently facing plant metabolomics, presenting our vision as to how the enormous potential of MSI technologies will contribute to progress in plant science in the coming years.

Challenges of Spatially Resolved Metabolism in Cancer Research.

Stable isotope-resolved metabolomics comprises a critical set of technologies that can be applied to a wide variety of systems, from isolated cells to whole organisms, to define metabolic pathway usage and responses to perturbations such as drugs or mutations, as well as providing the basis for flux analysis. As the diversity of stable isotope-enriched compounds is very high, and with newer approaches to multiplexing, the coverage of metabolism is now very extensive. However, as the complexity of the model increases, including more kinds of interacting cell types and interorgan communication, the analytical complexity also increases. Further, as studies move further into spatially resolved biology, new technical problems have to be overcome owing to the small number of analytes present in the confines of a single cell or cell compartment. Here, we review the overall goals and solutions made possible by stable isotope tracing and their applications to models of increasing complexity. Finally, we discuss progress and outstanding difficulties in high-resolution spatially resolved tracer-based metabolic studies.

Effect of N-acetyl cysteine in children with metabolic dysfunction-associated steatotic liver disease-A pilot study.

Prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease (NAFLD), and its sequelae of more severe forms such as metabolic dysfunction-associated steatohepatitis (MASH) is rapidly increasing in children with the rise in obesity. Successful and sustainable treatments for MASLD are lacking in children. We determined the therapeutic effect of N-acetyl cysteine (NAC) on biomarkers of oxidative stress, inflammation and insulin resistance (IR), liver enzymes, liver fat fraction (LFF) and (LS) in children with obesity and biopsy-confirmed MASLD. Thirteen children (n = 13; age: 13.6 ± 2.8 years; NAS score >2) underwent a double-blind, placebo-controlled trial of NAC (either 600 or 1200 mg NAC/day) or placebo for 16 weeks. Measurements included LFF (magnetic resonance imaging), LS (ultrasound elastography), and body composition. Erythrocyte glutathione (GSH), liver enzymes, insulin, glucose, adiponectin, high-sensitivity c-reactive protein (hs-CRP), and interleukin-6 (IL-6) were also measured. HOMA-IR was calculated. Sixteen-week NAC treatment improved (baseline adjusted between-group p < .05 for all) markers of inflammation (IL-6 and hs-CRP), oxidative stress (GSH), and insulin resistance (HOMA-IR) and reduced liver enzymes, LFF and LS. Body weight and body composition did not show beneficial changes. Sixteen-week NAC treatment was well tolerated in children with obesity and MASLD and led to improvements in oxidative stress, inflammation and IR and liver outcomes. The results from this pilot study support further investigation of NAC as a therapeutic agent in children with MASLD.

Metabolomic profiling of barley extracts obtained via different solvents and evaluation of their anti-inflammatory efficacy

Barley (Hordeum vulgare L.) stands out for its special nutritional value compared to other cereals, garnering significant attention in recent years. In this study, a comprehensive chemical and biological evaluation of different barley cultivars extracted with different solvents was performed. Ultra-high performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UHPLC-ESI-QTOF-MS/MS) was used in the phytochemical study. The molecular docking with absorption, distribution, metabolism, excretion, and toxicity (ADMET) study and multivariate analysis alongside the quantification of total phenolic contents (TPC) were performed. Furthermore, the anti-inflammatory action was in vitro assessed by measuring COX-1, COX-2, and 5-LOX inhibition. This study seeks to establish a suitable solvent for extracting anti-inflammatory properties from diverse barley cultivars. The methanol extract obtained from the G.131 cultivar, followed by the 80% methanol extract from the G.136 cultivar, exhibited the most favorable IC50 values in comparison to the reference drugs indomethacin and celecoxib. The phytochemical profile revealed more than 60 compounds that belonged to nitrogen-containing compounds, phenolic compounds, organic acids, flavonoids, and their glycosides, hordatines, and other classes. The TPC and COX-2 inhibition was positively correlated with isoscoparin, coumaroyle–OH–eagmatine, isoorientin, isovitexin 7-O-rhamnosylglucoside, isoscoparin 7-O-glucoside, and isoorientin-7-O-[6-feruloyl]-glucoside. These findings along with their pharmacodynamics study suggested a potential synergistic and significant contribution of these compounds with the anti-inflammatory activity.

Towards a Territorial and Political Ecology of “circular bioeconomy”: a 30-year review of metabolism studies

Towards a Territorial and Political Ecology of “circular bioeconomy”: a 30-year review of metabolism studies

In vitro metabolic studies and machine learning analysis of mass spectrometry data: A dual strategy for differentiating alpha-pyrrolidinohexiophenone (α-PHP) and alpha-pyrrolidinoisohexanophenone (α-PiHP) in urine analysis

Synthetic cathinones are some of the most prevalent new psychoactive substances (NPSs) globally, with alpha-pyrrolidinoisohexanophenone (α-PiHP) being particularly noted for its widespread use in the United States, Europe, and Taiwan. However, the analysis of isomeric NPSs such as α-PiHP and alpha-pyrrolidinohexiophenone (α-PHP) is challenging owing to similarities in their retention times and mass spectra. This study proposes a dual strategy based on in vitro metabolic experiments and machine learning-based classification modelling for differentiating α-PHP and α-PiHP in urine samples: (1) in vitro metabolic experiments using pooled human liver microsomes and liquid chromatography tandem quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) were conducted to identify the key metabolites of α-PHP and α-PiHP from the high-resolution MS/MS spectra. After 5 h incubation, 71.4 % of α-PHP and 64.7 % of α-PiHP remained unmetabolised. Nine phase I metabolites were identified for each compound, including primary β-ketone reduction (M1) metabolites. Comparing the metabolites and retention times confirmed the efficacy of in vitro metabolic experiments for differentiating NPS isomers. Subsequently, analysis of seven real urine samples revealed the presence for various metabolites, including M1, that could be used as suitable detection markers at low concentrations. The aliphatic hydroxylation (M2) metabolite peak counts and metabolite retention times were used to determine α-PiHP use. (2) Classification models for the parent compounds and M1 metabolites were developed using principal component analysis for feature extraction and logistic regression for classification. The training and test sets were devised from the spectra of standard samples or supernatants from in vitro metabolism experiments with different incubation times. Both models had classification accuracies of 100 % and accurately identified α-PiHP and its M1 metabolite in seven real urine samples. The proposed methodology effectively distinguished between such isomers and confirmed their presence at low concentrations. Overall, this study introduces a novel concept that addresses the complexities in analysing isomeric NPSs and suggests a path towards enhancing the accuracy and reliability of NPS detection.

Metabolic profiling of a new synthetic cannabinoid receptor agonist, ADMB-FUBIATA, with human liver microsomes, human primary hepatocytes and human recombinant CYP450 enzymes using LC-quadrupole-orbitrap MS

A novel synthetic cannabinoid receptor agonist (SCRA), ADMB-FUBIATA, featuring an acetamide-linked structure, has emerged on the illicit drug market. To provide dependable verification of its consumption and identify reliable biomarkers, we investigated an in vitro metabolism study of ADMB-FUBIATA incubated with human primary hepatocytes (HPHs) for the first time and correlated our findings with those from human liver microsomes (HLMs). In this work, ADMB-FUBIATA (10 μM) was incubated with HLM and HPH for 1 and 5 h, respectively, and then subjected to LC-quadrupole-orbitrap MS. A total of 25 metabolites across 8 metabolic pathways were identified after incubation with HLM and HPH, respectively. Monohydroxylation and N-dealkylation were the major metabolic pathways, and formation to ketone was first identified. In addition, the metabolism of ADMB-FUBIATA were found to be mediated by multiple CYP450 enzymes, predominantly CYP2C19, 2D6, and 3A4. This research also initially characterized the fragmentation patterns of the metabolites of ADMB-FUBIATA, elaborating on their structural relationship with ADMB-FUBIATA analogs. To effectively monitor ADMB-FUBIATA abuse, metabolites M4 and M1 were proposed as reliable biomarkers by cross-validating the HLM and HPH incubation results.

P-085 Transcriptomic and proteomic characterization of unexplained male infertility: alterations in energy metabolism

Abstract Study question Which are the transcriptomic and proteomic profiles of spermatozoa belonging to patients with Unexplained Male Infertility (UMI)? Summary answer Transcriptomic and proteomic profiles of UMI patients differ from the fertile men, having the energy metabolism altered. What is known already About 30% of infertile couples suffer from “Unexplained Infertility” (UI). Considering that the male factor contributes to 50% of infertility cases, it is estimated that half of all couple UI cases are due to unexplained male infertility (UMI). Men are diagnosed with UMI when despite having “normal” seminal parameters they are unable to conceive. Due to the lack of UMI classification criteria and the seminogram-only-based infertility diagnosis, little is known about the mechanisms underlying UMI. Study design, size, duration 80 normozoospermic human semen samples with proven fertility and 80 samples from patients with UMI were used for this study. Ejaculates were obtained from Clínica Quirón Bilbao between 2012 and 2018, and after capacitation they were pooled to perform protein and RNA extractions. Participants/materials, setting, methods For transcriptomic analysis, libraries were prepared using the SMARTer Stranded Total RNA-Seq Kit v3. Sequencing was performed on NextSeq 2000 system (1x 50 bp, 50 cycles, P3 kit) at Centre de Regulació Genómica (CRG). For the proteomic analysis, Tandem MassTag (TMT) 6-plex isotopic labeling strategy was adopted, and generated peptides were run in a Q Exactive mass spectrometer. To find differentially expressed genes and proteins between both groups EdgeR and Perseus softwares were employed. Main results and the role of chance In the present study, a total of 156.124 transcripts and 1722 proteins were identified in human sperm. Principal Component Analysis (PCA) confirmed the existence of distinguishable differences in the transcriptomic and proteomic profile of control and UMI samples. Specifically, 3112 differentially expressed transcripts and 385 differentially expressed proteins were identified. Among the differentially expressed proteins, 49 were correlated with RNA expression. Coherent RNA-protein signatures were mainly related to axonemal dynein complex assembly and flagellated sperm motility. Proteins involved in energy metabolism were enriched in UMI protein signatures but were not well correlated with the RNA. Furthermore, genes involved in protein transport and chromosome condensation were highly enriched in UMI group but were not detected by proteomics profiling. According to our results, there is a lack of RNA-protein correlation at human sperm. However, differential transcriptomic and proteomic profiles were found when comparing fertile normozoospermic samples to UMI samples. Concretely, our results suggest that altered energy metabolism may be one of the key factors in patients leading with UMI. Thus, the study of human sperm metabolism may be essential to find new targets of male infertility. Limitations, reasons for caution The lack of a consensus on the classification criteria of UMI makes this group of patients very heterogeneous. Further studies are needed to identify and validate specific transcripts and/or proteins that may alter specific metabolic processes and cause infertility. Wider implications of the findings The study of human sperm metabolism may be essential to understand the causes of many UMI cases. In this context, the identification of key protein or transcripts could be very helpful to predict the success of the assisted reproductive treatments. Trial registration number Not applicable

Cold tolerance and metabolism of red-haired pine bark beetle Hylurgus ligniperda (Coleoptera: Curculionidae) during the overwintering period.

Hylurgus ligniperda invaded Shandong, China, through imported forest timber, posing a threat to China's forest health. Exotic insects with broad environmental tolerance, including low temperatures, may have a better chance of surviving the winters and becoming invasive. Understanding the cold-tolerance strategies of H. ligniperda may help to design sustainable pest management approaches. In this study, we aim to investigate the cold-tolerance ability and relevant physiological indicators in overwintering H. ligniperda adults to determine any possible overwintering strategies. Supercooling points (SCPs) for adults H. ligniperda differed significantly across months and reached the lowest level in the mid- and post-overwintering period, the minimum SCPs -6.45 ± 0.18 °C. As the cold exposure temperature decreased, the survival rate of adults gradually decreased, and no adult survived more than 1 day at -15 °C, and the LLT50 for 1 day was -7.1 °C. Since H. ligniperda adults can survive internal ice formation, they are freeze-tolerant insects. Throughout the overwintering period, the SCPs and the water, protein, sorbitol, and glycerol content in adults decreased initially and then increased. We reported significant correlations between total protein, sorbitol, trehalose, and glycerol content in the beetles and SCPs. Glycogen, lipid, protein, trehalose, and sorbitol content in adult beetles may directly affect their cold-tolerance capacity and survival during winter. This study provides a physiological and biochemical basis for further study of metabolism and cold-tolerance strategies in H. ligniperda adults, which may help predict population dynamics and distribution potential of pests.

Multiple factors trigger the formation and resuscitation of the VBNC state in alcohol-producing Klebsiella pneumoniae.

Klebsiella pneumoniae can enter a viable but nonculturable (VBNC) state to survive in unfavorable environments. Our research found that high-, medium-, and low-alcohol-producing K. pneumoniae strains are associated with nonalcoholic fatty liver disease. However, the presence of the three Kpn strains has not been reported in the VBNC state or during resuscitation. In this study, the effects of different strains, salt concentrations, oxygen concentrations, temperatures, and nutrients in K. pneumoniae VBNC state were evaluated. The results showed that high-alcohol-producing K. pneumoniae induced a slower VBNC state than medium-alcohol-producing K. pneumoniae, and low-alcohol-producing K. pneumoniae. A high-salt concentration and micro-oxygen environment accelerated the loss of culturability. Simultaneously, both real-time quantitative PCR and droplet digital PCR were developed to compare the quantitative comparison of three Kpn strain VBNC states by counting single-copy gene numbers. At 22°C or 37°C, the number of culturable cells decreased significantly from about 108 to 105-106 CFU/mL. In addition, imipenem, ciprofloxacin, polymyxin, and phiW14 inhibited cell resuscitation but could not kill VBNC-state cells. These results revealed that the different environments evaluated play different roles in the VBNC induction process, and new effective strategies for eliminating VBNC-state cells need to be further studied. These findings provide a better understanding of VBNC-state occurrence, maintenance, detection, and absolute quantification, as well as metabolic studies of resuscitation resistance and ethanol production.IMPORTANCEBacteria may enter VBNC state under different harsh environments. Pathogenic VBNC bacteria cells in clinical and environmental samples pose a potential threat to public health because cells cannot be found by routine culture. The alcohol-producing Kpn VBNC state was not reported, and the influencing factors were unknown. The formation and recovery of VBNC state is a complete bacterial escape process. We evaluated the influence of multiple induction conditions on the formation of VBNC state and recovery from antibiotic and bacteriophage inhibition, and established a sensitive molecular method to enumerate the VBNC cells single-copy gene. The method can improve the sensitivity of pathogen detection in clinical, food, and environmental contamination monitoring, and outbreak warning. The study of the formation and recovery of VBNC-state cells under different stress environments will also promote the microbiological research on the development, adaptation, and resuscitation in VBNC-state ecology.

The effect of itraconazole, a strong CYP3A4 inhibitor, on the pharmacokinetics of the first-in-class ACKR3/CXCR7 antagonist, ACT-1004-1239.

Cytochrome P450 (CYP) 3A4 is an enzyme involved in the metabolism of many drugs that are currently on the market and is therefore a key player in drug-drug interactions (DDIs). ACT-1004-1239 is a potent and selective, first-in-class ACKR3/CXRC7 antagonist being developed as a treatment for demyelinating diseases including multiple sclerosis. Based on the human absorption, distribution, metabolism, and excretion (ADME) study results, ACT-1004-1239 is predominantly metabolized by CYP3A4. This study investigated the effect of the strong CYP3A4 inhibitor, itraconazole, on the pharmacokinetics of single-dose ACT-1004-1239 in healthy male subjects. In the open-label, fixed-sequence DDI study, a total of 16 subjects were treated. Each subject received a single dose of 10 mg ACT-1004-1239 (Treatment A) in the first period followed by concomitant administration of multiple doses of 200 mg itraconazole and a single dose of 10 mg ACT-1004-1239 in the second period. We report a median of difference in tmax (90% confidence interval, CI) of 0.5 h (0.0, 1.0) comparing both treatments. The geometric mean ratio (GMR) (90% CI) of Cmax and AUC0-∞ was 2.16 (1.89, 2.47) and 2.77 (2.55, 3.00), respectively. The GMR (90% CI) of t1/2 was 1.46 (1.26, 1.70). Both treatments were well-tolerated with an identical incidence in subjects reporting treatment-emergent adverse events (TEAE). The most frequently reported TEAEs were headache and nausea. In conclusion, ACT-1004-1239 is classified as a moderately sensitive CYP3A4 substrate (i.e., increase of AUC ≥2- to <5-fold), and this should be considered in further clinical studies if CYP3A4 inhibitors are concomitantly administered.

Fatty Acid Esters and Acyclic Monoterpenoid from Justicia insularis Leaf Fractions Attenuated Malaria Pathogenesis Through Docking with Plasmodium falciparum Serine Hydroxymethyl Transferase and Plasmodium falciparum Erythrocyte Membrane Protein 1 Proteins

Background Justicia insularis (Acanthaceae) T. Anderson is ethnopharmacologically used in Nigeria for the treatment of diseases including malaria. Therefore, this study was designed to investigate in vivo antiplasmodial effect of J. insularis leaf in Plasmodium berghei-infected mice, characterize its constituents, and carryout in silico studies of its compounds. Methods Standard protocols were followed in the processing of the plant leaves, extraction, fractionation, isolation, and characterization, evaluation of in vivo antiplasmodial assay, retrieval of Plasmodium falciparum serine hydroxymethyl transferase (PfSHMT) and Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP-1) proteins, absorption, distribution, metabolism, excretion, and toxicity (ADMET), and docking studies. Gas chromatography-mass spectrometry (GC-MS) was employed to isolate and characterize the compounds; SWISSADME and ADMET lab 2 enhanced the evaluation of pharmacokinetic properties, PyRx for docking analysis; Biovia discovery studio for 2D visualization, and PyMol software for 3D visualization of the ligand-protein interactions. Results The dichloromethane (61.59%) and ethyl acetate (73.15%) fractions had the best therapeutic indices and compared favorably with chloroquine (81.58%) in the curative antiplasmodial assay. The GC-MS analysis revealed 20 already reported antiplasmodial compounds with hexanoic acid 1,1-dimethylethyl ester, octadecanoic acid docosyl ester, and trans-β-ocimene as the lead compounds based on their binding affinities, permeation of the blood-brain-barrier, non-inhibition of metabolizing enzymes, ease of excretion, non-carcinogenicity, as well as non-violation of Lipinski's criteria. Conclusion Octadecanoic acid docosyl ester and hexanoic acid 1,1-dimethylethyl ester bonded the tetrahydrofolate-binding sites of PfSHMT, caused inhibition of DNA synthesis, and apoptosis, whereas trans-β-ocimene inhibited PfEMP-1, reversed the attachment of parasitized red blood cells to micro-vascular endothelium as their mechanism of action for parasitemia clearance. Moreover, these lead compounds reported for the first time in the dichloromethane and EtoAc fractions of this plant are responsible for the remarkable antiplasmodial activity observed in this study.

Metabolic brain connectivity reorganization in Alzheimer's disease patients: a systematic review.

Metabolic connectivity has been studied in various neurodegenerative diseases, particularly Alzheimer's disease (AD), but there is a wealth of accumulated evidence and sometimes conflicting results, depending on the methodology applied. Therefore, the aim of this systematic review was to summarize the results obtained regarding metabolic brain connectivity using [18F]-FDG-PET in AD patients compared to cognitively normal subjects. A systematic and exhaustive search of data available in the literature was carried out by querying the PubMed and Web of Science databases. Studies had to meet the following criteria: 1) a metabolic connectivity study with [18F]-FDG-PET in AD patients; 2) the inclusion of a control group of healthy subjects or cognitively normal controls; and 3) use of seed-based, independent/principal component analyses or methods derived from graph theory. This systematic review followed the PRISMA method. A total of 49 full-text publications were included, involving 3589 AD patients, 3272 prodromal AD patients and 3898 cognitively normal subjects. These results show that AD patients have a reorganization of metabolic connectivity on a global scale, with a decrease in or even the loss of networks seen in the healthy brain and an increase in more local, less efficient connectivity. This reorganization affects not only areas commonly affected in AD but also remote regions known to be usually spared in this pathology. Changes in metabolic connectivity in AD patients do not simply constitute a decrease in global connectivity but rather more complex local and global changes ultimately affecting all brain regions.

Photocytotoxic and cellular metabolism studies of curcuminoid-BF2 nanoaggregates in human carcinoma cells

Heavy atom-free photosensitizers represent a paradigm shift in the field of photodynamic therapy (PDT), offering a safer and more versatile alternative to traditional photosensitizers. As research progresses, the development of novel heavy-atom free compounds holds the potential to enhance the effectiveness and broaden the application of PDT, enabling the way for more targeted and less toxic cancer treatments. In this article, we report the application of heavy atom free curcuminoid BF2 (Diethylamine-CUR-BF2) containing acid sensitive amine group. Diethylamine-CUR-BF2 absorbs in deep red region at ∼618 nm and has high molar absorption coefficient. Nanoaggregates of Diethylamine-CUR-BF2 dispersed in aqueous medium showed high singlet oxygen production efficiency. The release kinetics of Diethylamine-CUR-BF2 showed efficient release of photosensitizer in slight acidic medium (at pH=5.0). Further, applications of Diethylamine-CUR-BF2 nanoaggregates in photocytotoxic studies using MCF-7 and A549 cells showed IC50 values 5.15 ± 1.4 μM and 8.05 ± 0.4 μM respectively. Cell death mechanism explored for photocytotoxicity studies utilizing Diethylamine-CUR-BF2 nanoaggregates is found to be apoptosis which is considered as normal programmed cell death pathway. Additionally, NADH FLIM studies revealed that the compound had an impact on cellular metabolism, prompting a shift from OXPHOS to glycolysis.

Variability in Ice Cover Does Not Affect Annual Metabolism Estimates in a Small Eutrophic Reservoir

AbstractTemperate reservoirs and lakes worldwide are experiencing decreases in ice cover, which will likely alter the net balance of gross primary production (GPP) and respiration (R) in these ecosystems. However, most metabolism studies to date have focused on summer dynamics, thereby excluding winter dynamics from annual metabolism budgets. To address this gap, we analyzed 6 years of year‐round high‐frequency dissolved oxygen data to estimate daily rates of net ecosystem production (NEP), GPP, and R in a eutrophic, dimictic reservoir that has intermittent ice cover. Over 6 years, the reservoir exhibited slight heterotrophy during both summer and winter. We found winter and summer metabolism rates to be similar: summer NEP had a median rate of −0.06 mg O2 L−1 day−1 (range: −15.86 to 3.20 mg O2 L−1 day−1), while median winter NEP was −0.02 mg O2 L−1 day−1 (range: −8.19 to 0.53 mg O2 L−1 day−1). Despite large differences in the duration of ice cover among years, there were minimal differences in NEP among winters. Overall, the inclusion of winter data had a limited effect on annual metabolism estimates in a eutrophic reservoir, likely due to short winter periods in this reservoir (ice durations 0–35 days), relative to higher‐latitude lakes. Our work reveals a smaller difference between winter and summer NEP than in lakes with continuous ice cover. Ultimately, our work underscores the importance of studying full‐year metabolism dynamics in a range of aquatic ecosystems to help anticipate the effects of declining ice cover across lakes worldwide.

Identification of biomarkers related to tryptophan metabolism in osteoarthritis

BackgroundOA (osteoarthritis) is a common joint disease characterized by damage to the articular cartilage and affects the entire joint tissue, with its main manifestations being joint pain, stiffness, and limited movement.Currently,we know that OA is a complex process composed of inflammatory and metabolic factors.It is reported that the occurrence and development of OA is related to the change of tryptophan metabolism.Therefore, the study of tryptophan metabolism and OA related genes is hopeful to find a new therapeutic target for OA. MethodsDifferentially expressed genes (DEGs) in GSE55235 were gained via differential expression analysis (OA samples vs normal samples). The tryptophan metabolic related DEGs (TMR-DEGs) were obtained by overlapping tryptophan metabolism related genes (TMRGs) and DEGs. Further, biomarkers were screening via Least absolute shrinkage and selection operator (LASSO), naive bayes (NB) and supportvector machine-recursive feature elimination (SVM-RFE) algorithm to establish a diagnostic model. Afterward, Gene Set Enrichment Analysis (GSEA) and drug prediction were performed based on diagnostic biomarkers by multiple software and databases. Eventually, expression level of biomarker public databases was verified using real-time quantitative polymerase chain reaction (RT-qPCR). ResultsThree tryptophan metabolism related biomarkers (TDO2, AOX1 and SLC3A2) were identified in OA. GSEA analysis demonstrated that biomarkers were associated with the function of ‘FoxO signaling pathway’, ‘spliceosome’ and ‘ribosome’. There were seven drugs with therapeutic potential on TDO2 and AOX1. Ultimately, compared with normal group, expression of AOX1 and SLC3A2 in OA group remarkable lower. ConclusionOverall, three tryptophan metabolic related diagnostic biomarkers that associated with OA were obtained, which provided a original direction for the diagnosis and treatment of OA.

Stepping Stones In Prevention of Kidney Stone Disease In Pakistan

The prevalence and incidence of kidney stone disease (KSD) has increased in Pakistan since last 5 decades, it is not only the cause of pain, hematuria and fever but is also an important cause of chronic kidney disease, Morbidity and mortality as well if left untreated. It is recurrent disease and can be manifestation of systemic diseases, (D.M, obesity, HTN) genetic and environmental factors play a role in etiology of disease. In spite of modern methods of surgical removal available in Pakistan there is constant increase in number of patients. Economic burden of disease is quite significant, so established metaphylaxsis program is essential part of management of this surgical and medical disease. Main therapies based on history, stone analysis, 24 hour urine metabolic study constitutes the basis of prevention. Increasing fluid intake dietary modification, Pharmacotherapy is the main stay of metaphylaxsis. Compliance of the patient and establishment of specialized stone clinics should be managed jointly by urologist, nephrologist, dietitians, metabolic laboratory expert and Medical Social officers. Prevention is possible in many cases if these patients are managed jointly by multidisciplinary team.