PLoS Biol. 2024 Dec 17;22(12):e3002943. doi: 10.1371/journal.pbio.3002943. Online ahead of print.

ABSTRACT

Repeated antigen exposure leads to T-cell exhaustion, a transcriptionally and epigenetically distinct cellular state marked by loss of effector functions (e.g., cytotoxicity, cytokine production/release), up-regulation of inhibitory receptors (e.g., PD-1), and reduced proliferative capacity. Molecular pathways underlying T-cell exhaustion have been defined for CD8+ cytotoxic T cells, but which factors drive exhaustion in CD4+ T cells, that are also required for an effective immune response against a tumor or infection, remains unclear. Here, we utilize quantitative proteomic, phosphoproteomic, and metabolomic analyses to characterize the molecular basis of the dysfunctional cell state induced by chronic stimulation of CD4+ memory T cells. We identified a dynamic response encompassing both known and novel up-regulated cell surface receptors, as well as dozens of unexpected transcriptional regulators. Integrated causal network analysis of our combined data predicts the histone acetyltransferase p300 as a driver of aspects of this phenotype following chronic stimulation, which we confirmed via targeted small molecule inhibition. While our integrative analysis also revealed large-scale metabolic reprogramming, our independent investigation confirmed a global remodeling away from glycolysis to a dysfunctional fatty acid oxidation-based metabolism coincident with oxidative stress. Overall, these data provide both insights into the mechanistic basis of CD4+ T-cell exhaustion and serve as a valuable resource for future interventional studies aimed at modulating T-cell dysfunction.

PMID:39689157 | DOI:10.1371/journal.pbio.3002943

J Clin Invest. 2024 Dec 17:e183353. doi: 10.1172/JCI183353. Online ahead of print.

ABSTRACT

Heterozygous truncating variants in the sarcomere protein titin (TTN) are the most common genetic cause of heart failure. To understand mechanisms that regulate abundant cardiomyocyte TTN expression we characterized highly conserved intron 1 sequences that exhibited dynamic changes in chromatin accessibility during differentiation of human cardiomyocytes from induced pluripotent stem cells (hiPSC-CMs). Homozygous deletion of these sequences in mice caused embryonic lethality while heterozygous mice demonstrated allele-specific reduction in Ttn expression. A 296 bp fragment of this element, denoted E1, was sufficient to drive expression of a reporter gene in hiPSC-CMs. Deletion of E1 downregulated TTN expression, impaired sarcomerogenesis, and decreased contractility in hiPSC-CMs. Site-directed mutagenesis of predicted NKX2-5- and MEF2-binding sites within E1 abolished its transcriptional activity. Embryonic mice expressing E1 reporter gene constructs validated in vivo cardiac-specific activity of E1 and the requirement for NKX2-5 and MEF2 binding sequences. Moreover, isogenic hiPSC-CMs containing a rare E1 variant in the predicted MEF2 binding motif that was identified in a patient with unexplained DCM showed reduced TTN expression. Together these discoveries define an essential, functional enhancer that regulates TTN expression. Manipulation of this element may advance therapeutic strategies to treat DCM caused by TTN haploinsufficiency.

PMID:39688912 | DOI:10.1172/JCI183353

J Exp Bot. 2024 Dec 17:erae509. doi: 10.1093/jxb/erae509. Online ahead of print.

ABSTRACT

The orientation of cell divisions is crucial for normal development of all plant organs throughout their lifecycle. Despite the importance of understanding the intricate molecular mechanisms guiding this process, relatively few pathways have been characterized to date. Here we want to outline what is known about the molecular regulation guiding changes in division orientation in the root apical meristem of the model plant Arabidopsis thaliana, from the upstream transcriptional modules to the downstream executors that lead to division plane establishment. We specifically focus on the gaps in our knowledge about this highly coordinated process and propose that a new approach should be taken to characterize how changes in division orientation are controlled in more holistic detail.

PMID:39688908 | DOI:10.1093/jxb/erae509

Elife. 2024 Dec 17;12:RP91596. doi: 10.7554/eLife.91596.

ABSTRACT

The enhancer-promoter looping model, in which enhancers activate their target genes via physical contact, has long dominated the field of gene regulation. However, the ubiquity of this model has been questioned due to evidence of alternative mechanisms and the lack of its systematic validation, primarily owing to the absence of suitable experimental techniques. In this study, we present a new MNase-based proximity ligation method called MChIP-C, allowing for the measurement of protein-mediated chromatin interactions at single-nucleosome resolution on a genome-wide scale. By applying MChIP-C to study H3K4me3 promoter-centered interactions in K562 cells, we found that it had greatly improved resolution and sensitivity compared to restriction endonuclease-based C-methods. This allowed us to identify EP300 histone acetyltransferase and the SWI/SNF remodeling complex as potential candidates for establishing and/or maintaining enhancer-promoter interactions. Finally, leveraging data from published CRISPRi screens, we found that most functionally verified enhancers do physically interact with their cognate promoters, supporting the enhancer-promoter looping model.

PMID:39688903 | DOI:10.7554/eLife.91596

Elife. 2024 Dec 17;13:e95597. doi: 10.7554/eLife.95597.

ABSTRACT

The giant striated muscle protein titin integrates into the developing sarcomere to form a stable myofilament system that is extended as myocytes fuse. The logistics underlying myofilament assembly and disassembly have started to emerge with the possibility to follow labeled sarcomere components. Here, we generated the mCherry knock-in at titin's Z-disk to study skeletal muscle development and remodeling. We find titin's integration into the sarcomere tightly regulated and its unexpected mobility facilitating a homogeneous distribution of titin after cell fusion - an integral part of syncytium formation and maturation of skeletal muscle. In adult mCherry-titin mice, treatment of muscle injury by implantation of titin-eGFP myoblasts reveals how myocytes integrate, fuse, and contribute to the continuous myofilament system across cell boundaries. Unlike in immature primary cells, titin proteins are retained at the proximal nucleus and do not diffuse across the whole syncytium with implications for future cell-based therapies of skeletal muscle disease.

PMID:39688479 | DOI:10.7554/eLife.95597

Glia. 2024 Dec 17. doi: 10.1002/glia.24660. Online ahead of print.

ABSTRACT

Myelin formation by oligodendrocytes regulates the conduction velocity and functional integrity of neuronal axons. While individual oligodendrocytes form myelin sheaths around multiple axons and control the functions of neural circuits where the axons are involved, it remains unclear if oligodendrocytes selectively form myelin sheaths around specific subtypes of axons. Using the combination of rabies virus-mediated single oligodendrocyte labeling and immunostaining with tissue clearing, we revealed that approximately half of the oligodendrocytes preferentially myelinate axons originating from Purkinje cells in the white matter of adult mouse cerebella. The preference for Purkinje cell axons was more pronounced during development when the process of myelination within cerebellar white matter was initiated; over 90% of oligodendrocytes preferentially myelinated Purkinje cell axons. Preferential myelination of Purkinje cell axons was further confirmed by immuno-electron microscopy and transgenic mice that label early-born oligodendrocytes. Transgenic mice that label oligodendrocytes differentiated at the early development showed that early-born oligodendrocytes preferentially myelinate Purkinje cell axons in the matured cerebellar white matter. In contrast, transgenic mice that label oligodendrocytes differentiated after the peak of cerebellar myelination showed that the later-differentiated oligodendrocytes dominantly myelinated non-Purkinje cell axons. These results demonstrate that a significant proportion of oligodendrocytes preferentially myelinate functionally distinct axons in the cerebellar white matter, and the axonal preference of myelination by individual oligodendrocytes is established depending on the timing of their differentiation during development. Our data provide the evidence that there is a critical time window of myelination that a specific subtype of axons are dominantly myelinated by the oligodendrocytes.

PMID:39688302 | DOI:10.1002/glia.24660

World J Clin Cases. 2024 Dec 16;12(35):6826-6833. doi: 10.12998/wjcc.v12.i35.6826.

ABSTRACT

BACKGROUND: Tuberculosis is a chronic infectious disease and an important public health problem. Despite progress in controlling tuberculosis, the incidence of tuberculosis in China is still very high, with 895000 new cases annually. This case report describes the investigation of a case of severe disseminated tuberculosis in a young adult with normal immune function, conducted to ascertain why a Mycobacterium tuberculosis (M. tuberculosis) strain caused such severe disease.

CASE SUMMARY: A previously healthy 28-year-old woman presented to our hospital with a 1-month history of fever and fatigue. She was diagnosed with severe disseminated pulmonary tuberculosis, spinal tuberculosis with paravertebral abscesses, and tuberculous meningitis. M. tuberculosis was isolated from bronchoalveolar lavage fluid. She was treated with standard antituberculous therapy and underwent debridement, bone graft, and internal fixation surgery for spinal tuberculosis. She responded to therapy and regained her ability to walk following the surgery. We analysed the whole-genome sequence of the strain and designated it BLM-A21. Additional M. tuberculosis genomes were selected from the Virulence Factor Database (http://www.mgc.ac.cn/cgi-bin/VFs/genus.cgi?Genus=Mycobacterium) for comparison. An evolutionary tree of the BLM-A21 strain was built using PhyML maximum likelihood software. Further gene analysis revealed that, except for the pks1 gene, BLM-A21 had similar virulence genes to the CDC 1551 and H37Rv strains, which have lower dissemination.

CONCLUSION: We speculate that the pks1 virulence gene in BLM-A21 may be the key virulence gene responsible for the widespread dissemination of M. tuberculosis infection in this previously healthy adult with normal immune function.

PMID:39687648 | PMC:PMC11525909 | DOI:10.12998/wjcc.v12.i35.6826

Front Plant Sci. 2024 Dec 2;15:1452592. doi: 10.3389/fpls.2024.1452592. eCollection 2024.

ABSTRACT

INTRODUCTION: The space environment is mutagenic and may induce genomic and phenotypic variations. Exploring the changes in transposon activity in the rice genome under space radiation is of great significance.

METHODS: To analyze the activation characteristics of Ty3-retrotransposons and genetic stability of insertion sites in rice progeny after spaceflight, seeds of Nipponbare, DN416, and DN423 were exposed on board the SJ-10 recoverable satellite for 12.5 days. The differential methylation and transcription levels of Ty3-retrotransposons in the genome of Nipponbare's F0 generation after spaceflight, as well as the genetic stability of Ty3-retrotransposon insertion sites in DN416 and DN423 from F3 to F5 generations, was analyzed.

RESULTS: The study found that the retrotransposons of ancient and young transposon families underwent demethylation from the tillering to heading stages of Nipponbare plants, which were F0 generation of space-exposed seeds, when the Nipponbare seeds were hit by single space high charge and energy (HZE) particles with LET ≥ 100 keV/μm. the transcription levels significantly increased in ancient transposon families (osr30, osr40, and rire10) and young transposon families (dagul, rn215-125, osr37, RLG_15, osr34, rire8, rire3, rire2, and hopi) (p ≤ 0.05) when LET > 100 keV/μm. Furthermore, the young Ty3-retrotransposons, which included the hopi, squiq, dasheng, rire2, rire3, rire8, osr34, rn_215-125, dagul, and RLG_15 families, underwent 1 to 8 transpositions in the F3 to F5 of DN416 and DN423 mutants, and some of these transposon insertion sites were stably inherited.

DISCUSSION: The research holds great significance for understanding the activation characteristics of Ty3-retrotransposons in the rice genome induced by space radiation and the genetic characteristics of transposon insertion sites in its progeny.

PMID:39687316 | PMC:PMC11646775 | DOI:10.3389/fpls.2024.1452592

Front Educ (Lausanne). 2023;8:1279921. doi: 10.3389/feduc.2023.1279921. Epub 2023 Nov 27.

ABSTRACT

Course-based research pedagogy involves positioning students as contributors to authentic research projects as part of an engaging educational experience that promotes their learning and persistence in science. To develop a model for assessing and grading students engaged in this type of learning experience, the assessment aims and practices of a community of experienced course-based research instructors were collected and analyzed. This approach defines four aims of course-based research assessment - 1) Assessing Laboratory Work and Scientific Thinking; 2) Evaluating Mastery of Concepts, Quantitative Thinking and Skills; 3) Appraising Forms of Scientific Communication; and 4) Metacognition of Learning - along with a set of practices for each aim. These aims and practices of assessment were then integrated with previously developed models of course-based research instruction to reveal an assessment program in which instructors provide extensive feedback to support productive student engagement in research while grading those aspects of research that are necessary for the student to succeed. Assessment conducted in this way delicately balances the need to facilitate students' ongoing research with the requirement of a final grade without undercutting the important aims of a CRE education.

PMID:39687267 | PMC:PMC11649310 | DOI:10.3389/feduc.2023.1279921

iScience. 2024 Nov 19;27(12):111433. doi: 10.1016/j.isci.2024.111433. eCollection 2024 Dec 20.

ABSTRACT

Neuroblastoma exhibits two cellular phenotypes: therapy-sensitive adrenergic (ADRN) and therapy-resistant mesenchymal (MES). To understand treatment response, it is important to elucidate how these phenotypes impact the dynamics of cancer cell populations and whether they represent distinct cell types or dynamic cell states. Here, we use an integrated experimental and mathematical modeling approach. We experimentally measure the fractions of ADRN and MES phenotypes under baseline (untreated) conditions and under repeated treatment cycles. We develop evolutionary game theoretic models predicting how the populations would respond if ADRN and MES phenotypes (1) are distinct cell types or (2) represent dynamic cell states and fit these models to the experimental data. We find that, although cells may undergo an ADRN to MES phenotypic switch under treatment, the best-fit model sees ADRN and MES as distinct cell types. Differential proliferation and survival of these two cell types, and not cell-state switching, drive therapeutic response.

PMID:39687008 | PMC:PMC11648246 | DOI:10.1016/j.isci.2024.111433

PeerJ. 2024 Dec 13;12:e18692. doi: 10.7717/peerj.18692. eCollection 2024.

ABSTRACT

BACKGROUND: Dietary therapy strategies play an important role in the treatment of pediatric patients with Crohn's disease (CD), but the relative efficacy of different dietary therapy strategies for Crohn's remission is unknown. This study aims to compare the effectiveness and tolerance of these dietary therapy strategies for active pediatric CD.

METHODS: We searched the medical literature up to August 30, 2024 to identify randomized controlled trials (RCTs) of dietary therapy strategies for pediatric CD. The primary outcomes were clinical remission rate and tolerance, secondary outcomes included differences between pre- and post-treatment levels of albumin, C-reactive protein (CRP), and fecal calprotectin levels. A network meta-analysis (NMA) was performed by using the frequentist model. For binary outcome variables and continuous outcome variables, odds ratios (OR) and mean differences (MD) with corresponding 95% confidence intervals (CI) were utilized, respectively. The ranking of dietary therapy strategies was determined based on the surface under the cumulative ranking area (SUCRA) for each comparison analyzed.

RESULTS: Overall, 14 studies involving 564 participants were included. In terms of clinical remission rate, the partial enteral nutrition (PEN) plus Crohn's disease exclusion diet (PEN+CDED) (OR = 7.86, 95% CI [1.85-33.40]) and exclusive enteral nutrition (EEN) (OR = 3.74, 95% CI [1.30-10.76]) exhibited significant superiority over PEN alone. The tolerance of PEN+CDED was significantly higher than that of EEN (OR = 0.07, 95% CI [0.01-0.61]). According to the surface under the cumulative ranking area (SUCRA) values, the PEN+CDED intervention (90.5%) achieved the highest ranking in clinical remission rate. In terms of tolerance, PEN+CDED ranked first (88.0%), while EEN ranked last (16.3%).

CONCLUSIONS: In conclusion, PEN+CDED was associated with the highest clinical remission rate and tolerance among the various dietary therapy strategies evaluated. Despite limitations in the studies, this systematic review provides evidence that PEN+CDED can be used as an alternative treatment to exclusive enteral nutrition and is more suitable for long-term management in children.

PMID:39686992 | PMC:PMC11648686 | DOI:10.7717/peerj.18692

Front Educ (Lausanne). 2024;9:1442318. doi: 10.3389/feduc.2024.1442318. Epub 2024 Aug 20.

ABSTRACT

Over the last two decades, there have been numerous initiatives to improve undergraduate student outcomes in STEM. One model for scalable reform is the inclusive Research Education Community (iREC). In an iREC, STEM faculty from colleges and universities across the nation are supported to adopt and sustainably implement course-based research - a form of science pedagogy that enhances student learning and persistence in science. In this study, we used pathway modelling to develop a qualitative description that explicates the HHMI Science Education Alliance (SEA) iREC as a model for facilitating the successful adoption and continued advancement of new curricular content and pedagogy. In particular, outcomes that faculty realize through their participation in the SEA iREC were identified, organized by time, and functionally linked. The resulting pathway model was then revised and refined based on several rounds of feedback from over 100 faculty members in the SEA iREC who participated in the study. Our results show that in an iREC, STEM faculty organized as a long-standing community of practice leverage one another, outside expertise, and data to adopt, implement, and iteratively advance their pedagogy. The opportunity to collaborate in this manner and, additionally, to be recognized for pedagogical contributions sustainably engages STEM faculty in the advancement of their pedagogy. Here, we present a detailed pathway model of SEA that, together with underpinning features of an iREC identified in this study, offers a framework to facilitate transformations in undergraduate science education.

PMID:39686966 | PMC:PMC11649309 | DOI:10.3389/feduc.2024.1442318

Physiol Plant. 2024 Nov-Dec;176(6):e70010. doi: 10.1111/ppl.70010.

ABSTRACT

Cannabis sativa L., a plant originating from Central Asia, is a versatile crop with applications spanning textiles, construction, pharmaceuticals, and food products. This study aimed to compile and analyze publicly available Cannabis RNA-Seq data and develop an integrated database tool to help advance Cannabis research in various topics such as fiber production, cannabinoid biosynthesis, sex determination, and plant development. We identified 515 publicly available RNA-Seq samples that, after stringent quality control, resulted in a high-quality dataset of 394 samples. Utilizing the Jamaican Lion genome as reference, we constructed a comprehensive database and developed the Cannabis Expression Atlas (https://cannatlas.venanciogroup.uenf.br/), a web application for visualization of gene expression, annotation, and functional classification. Key findings include the quantification of 27,640 Cannabis genes and their classification into seven expression categories: not-expressed, low-expressed, housekeeping, tissue-specific, group-enriched, mixed, and expressed-in-all tissues. The study revealed substantial variability and coherence in gene expression across different tissues and chemotypes. We found 2,382 tissue-specific genes, including 177 transcription factors. The Cannabis Expression Atlas constitutes a valuable tool for exploring gene expression patterns and offers insights into Cannabis biology, supporting research in plant breeding, genetic engineering, biochemistry, and functional genomics.

PMID:39686909 | DOI:10.1111/ppl.70010

Sensors (Basel). 2024 Nov 21;24(23):7443. doi: 10.3390/s24237443.

ABSTRACT

Paratuberculosis is a debilitating disease of ruminants that causes significant economic loss in both cattle and sheep. Early detection of the disease is crucial to controlling the disease; however, current diagnostic tests lack sensitivity. This study evaluated the potential for volatile organic compounds (VOCs) detected by gas chromatography and an electronic nose (eNose) for use as diagnostic tools to differentiate between Map-infected and non-infected cattle and sheep. Solid-phase micro-extraction gas chromatography-mass spectrometry (SPME GC-MS) was used to quantify VOCs from the headspace of faecal samples (cattle and sheep), and partial least squares-discriminant analysis (PLS-DA) was used to determine the suitability as a diagnostic tool. Both the cattle and sheep models had high specificity and sensitivity, 98.1% and 92.3%, respectively, in cattle, and both were 100% in sheep. The eNose was also able to discriminate between Map-infected and non-infected sheep and cattle with 88.9% specificity and 100% sensitivity in sheep and 100% specificity and sensitivity in cattle. This is the first time that VOC analysis by eNose and GCMS has been used for identification of Map in cattle and sheep faeces. GCMS also allowed the identification of putative disease biomarkers, and the eNose diagnostic capability suggests it is a promising tool for point-of-care diagnosis for Map detection on farms.

PMID:39685980 | DOI:10.3390/s24237443

Int J Mol Sci. 2024 Nov 21;25(23):12489. doi: 10.3390/ijms252312489.

ABSTRACT

Susanne Sievers and Daniela Zühlke were not included as authors in the original publication [...].

PMID:39684940 | DOI:10.3390/ijms252312489

Int J Mol Sci. 2024 Dec 8;25(23):13189. doi: 10.3390/ijms252313189.

ABSTRACT

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major global health challenge, primarily due to the increasing prevalence of drug resistance. Consequently, the development of drugs with novel modes of action (MOAs) is urgently required. In this study, we discovered and characterized two potent inhibitors, Pi-1-58 and Pi-2-26, targeting the prokaryotic ubiquitin-like protein (Pup) ligase PafA of Mtb. Pi-1-58 was identified through computer-aided drug screening. The binding mode of Pi-1-58 and PafA was investigated through molecular docking, followed by experimental validations. Based on the core structure of Pi-1-58, we developed a more potent inhibitor, Pi-2-26, through structure-guided drug design. Both Pi-1-58 and Pi-2-26 exhibited selective and specific inhibition of PafA according to biochemical and cell-based assays. Importantly, the inhibitors demonstrated significant inhibition on Mtb survival in the presence of nitric oxide, mimicking the in vivo nitrogen limited environment that Mtb encountered in macrophage. Our findings provide a comprehensive understanding of the structural and functional aspects of these PafA inhibitors and establish a solid foundation for the development of novel therapeutics against tuberculosis.

PMID:39684899 | DOI:10.3390/ijms252313189

Int J Mol Sci. 2024 Dec 7;25(23):13172. doi: 10.3390/ijms252313172.

ABSTRACT

The thraustochytrids are a group of marine protists known for their significant ecological roles as decomposers and parasites as well as for their potential biotechnological applications, yet their evolutionary and structural diversity remains poorly understood. Our review critically examines the phylogeny of this taxa, utilizing available up-to-date knowledge and their taxonomic classifications. Additionally, advanced imaging techniques, including electron microscopy, are employed to explore the ultrastructural characteristics of these organisms, revealing key features that contribute to their adaptive capabilities in varying marine environments. The integration of this knowledge with available omics data highlights the huge biotechnological potential of thraustochytrids, particularly in producing ω-3 fatty acids and other bioactive compounds. Our review underscores the importance of a systems biology approach in understanding thraustochytrids biology and highlights the urgent need for novel, accurate omics research to unlock their full biotechnological potential. Overall, this review aims to foster a deeper appreciation of thraustochytrids by synthesizing information on their evolution, ultrastructure, and practical applications, thereby providing a foundation for future studies in microbiology and biotechnology.

PMID:39684882 | DOI:10.3390/ijms252313172

Int J Mol Sci. 2024 Dec 6;25(23):13137. doi: 10.3390/ijms252313137.

ABSTRACT

Promoters, as core elements in the regulation of gene expression, play a pivotal role in genetic engineering and synthetic biology. The accurate prediction and optimization of promoter strength are essential for advancing these fields. Here, we present the first promoter strength database tailored to Halomonas, an extremophilic microorganism, and propose a novel promoter design and prediction method based on generative adversarial networks (GANs) and multi-model fusion. The GAN model effectively learns the key features of Halomonas promoter sequences, such as the GC content and Moran's coefficients, to generate biologically plausible promoter sequences. To enhance prediction accuracy, we developed a multi-model fusion framework integrating deep learning and machine learning approaches. Deep learning models, incorporating BiLSTM and CNN architectures, capture k-mer and PSSM features, whereas machine learning models utilize engineered string and non-string features to construct comprehensive feature matrices for the multidimensional analysis and prediction of promoter strength. Using the proposed framework, newly generated promoters via mutation were predicted, and their functional validity was experimentally confirmed. The integration of multiple models significantly reduced the experimental validation space through an intersection-based strategy, achieving a notable improvement in top quantile prediction accuracy, particularly within the top five quantiles. The robustness and applicability of this model were further validated on diverse datasets, including test sets and out-of-sample promoters. This study not only introduces an innovative approach for promoter design and prediction in Halomonas but also lays a foundation for advancing industrial biotechnology. Additionally, the proposed strategy of GAN-based generation coupled with multi-model prediction demonstrates versatility, offering a valuable reference for promoter design and strength prediction in other extremophiles. Our findings highlight the promising synergy between artificial intelligence and synthetic biology, underscoring their profound academic and practical implications.

PMID:39684846 | DOI:10.3390/ijms252313137

Int J Mol Sci. 2024 Nov 28;25(23):12799. doi: 10.3390/ijms252312799.

ABSTRACT

Despite the growing interest in using natural compounds for disease prevention and treatment, Allium ursinum (wild garlic), known for its therapeutic properties, has not been extensively studied for its chemical composition and biological activities. Therefore, this study aims to explore the in vitro antioxidant, antibacterial, and antitumor activities of A. ursinum extracts according to their functional phytochemical profile, while assessing whether ultrasound-assisted extraction (UAE) enhances bioactive properties in comparison to conventional maceration (CM). Both extracts were characterized by spectrophotometric methods and LC-ESI+-MS. The antioxidant activity was assessed via the CUPRAC and hydrogen peroxide scavenging assays, the antimicrobial properties via the disk-diffusion method against five pathogenic strains, and the antitumor activity via the MTT assay on four cancer cell lines. The major constituents of the methanolic extracts from leaves were kaempferol derivatives and alliin. The quercetin derivative rutin was also found. Maceration assisted using UAE yielded 20% more bioactive compounds in comparison to CM alone. Employing UAE in the extraction significantly increased antioxidant and antimicrobial proprieties, in line with its chemical composition. The antitumor cytotoxic activity was low to moderate, regardless of method, as explained by the absence of highly cytotoxic compounds. Wild garlic extracts possessed strong antioxidant and substantial antibacterial activities.

PMID:39684509 | DOI:10.3390/ijms252312799

Int J Mol Sci. 2024 Nov 27;25(23):12767. doi: 10.3390/ijms252312767.

ABSTRACT

The tryptophan-kynurenine (KYN) pathway has long been recognized for its essential role in generating metabolites that influence various physiological processes. Traditionally, these metabolites have been categorized into distinct, often opposing groups, such as pro-oxidant versus antioxidant, excitotoxic/neurotoxic versus neuroprotective. This dichotomous framework has shaped much of the research on conditions like neurodegenerative and neuropsychiatric disorders, as well as cancer, where metabolic imbalances are a key feature. The effects are significantly influenced by various factors, including the concentration of metabolites and the particular cellular milieu in which they are generated. A molecule that acts as neuroprotective at low concentrations may exhibit neurotoxic effects at elevated levels. The oxidative equilibrium of the surrounding environment can alter the function of KYN from an antioxidant to a pro-oxidant. This narrative review offers a comprehensive examination and analysis of the contemporary understanding of KYN metabolites, emphasizing their multifaceted biological functions and their relevance in numerous physiological and pathological processes. This underscores the pressing necessity for a paradigm shift in the comprehension of KYN metabolism. Understanding the context-dependent roles of KYN metabolites is vital for novel therapies in conditions like Alzheimer's disease, multiple sclerosis, and cancer. Comprehensive pathway modulation, including balancing inflammatory signals and enzyme regulation, offers promising avenues for targeted, effective treatments.

PMID:39684480 | DOI:10.3390/ijms252312767