Search Results (176)

Breast cancer (BC) is a neoplasm characterized by high heterogeneity and is influenced by intrinsic molecular subtypes and clinical stage, aspects that remain underexplored in the Colombian population. This study aimed to characterize metabolic alterations associated with subtypes and disease progression in a group of newly diagnosed, treatment-naive Colombian women using an untargeted metabolomics approach. To improve metabolite coverage, samples were analyzed using LC-QTOF-MS and GC-QTOF-MS, along with amino acid profiling. The Luminal B subtype exhibited elevated levels of long-chain acylcarnitines and higher free fatty acid concentrations than the other subtypes. It also presented elevated levels of carbohydrates and essential glycolytic intermediates, suggesting that this subtype may adopt a hybrid metabolic phenotype characterized by increased glycolytic flux as well as enhanced fatty acid catabolism. Tumor, Node, and Metastasis (TNM) staging analysis revealed progressive metabolic reprogramming of BC. In advanced stages, a sustained increase in phosphatidylcholines and a decrease in lysophosphatidylcholines were observed, reflecting lipid alterations associated with key roles in tumor progression. In early stages (I-II), plasma metabolites with high discriminatory power were identified, such as glutamic acid, ribose, and glycerol, which are associated with dysfunctions in energy and carbohydrate metabolism. These results highlight metabolomics as a promising tool for the early diagnosis, clinical follow-up, and molecular characterization of BC. Full article

Background and Objectives: Urothelial bladder carcinoma includes a spectrum of malignant lesions with heterogeneous molecular, biological, and clinical features and a variable risk of progression from non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive disease (MIBC) and ultimately to metastatic urothelial carcinoma (mUC). Sarcopenia, a condition secondary to a catabolic state, is characterized by progressive loss of skeletal muscle mass and function and is highly prevalent across all stages of bladder cancer. This review aims to synthesize current evidence regarding the clinical impact of sarcopenia and its dynamic changes throughout the disease course. Materials and Methods: A narrative literature review was conducted using PubMed, Scopus, and Cochrane databases, incorporating the most relevant published sources. Search terms included “bladder carcinoma”, “sarcopenia”, “body composition”, “NMIBC”, and “MIBC”. Case reports and congress abstracts were excluded. Results: In NMIBC treated with intravesical Bacillus Calmette–Guérin (BCG), sarcopenia has been shown to have a negative predictive value in some studies. Among patients receiving neoadjuvant chemotherapy (NAC) for MIBC, sarcopenia has been associated with increased toxicity, dose reductions, and treatment delays. In the context of radical surgery, sarcopenia correlates with increased postoperative mortality and a higher rate of severe complications. In mUC, low muscle mass is a negative prognostic factor regardless of treatment type and is associated with chemotherapy-related hematologic toxicity, although it does not appear to predict immune-related adverse events (irAEs). Conclusions: Sarcopenia is a highly prevalent and clinically relevant phenotype of urothelial bladder cancer patients, impacting prognosis, treatment response, and chemotherapy toxicity. Incorporating sarcopenia with other relevant components of body composition (BC) and systemic inflammatory markers may facilitate the development of more robust risk scores. Current evidence is primarily limited by the retrospective design of most studies. Future prospective research is needed to clarify the prognostic role of sarcopenia and support its integration into routine clinical decision-making. Full article

Synovial inflammation is recognised as a pathological driver of osteoarthritis (OA), a degenerative joint disease involving cartilage degradation and joint pain. Since extracellular vesicles (EVs) have emerged as key mediators of cellular cross-talk, this study characterised synovial fluid EVs (SFEVs) in OA patients with varying disease severity and determined their functional effects on OA articular chondrocytes. Synovial fluid and articular cartilage were collected from patients undergoing knee surgery. SFEVs were isolated via ultracentrifugation and characterised by nanoparticle tracking analysis, ExoView, and Luminex analysis of protein cargo. Patients were stratified into mild/moderate- and severe-OA groups based on Oxford Knee Score and EQ5D. Chondrocytes were treated with SFEVs, and transcriptomic and secretome responses were analysed using RNA sequencing, Luminex, and ELISA. SFEVs from patients with severe OA were more abundant, smaller and exhibited increased tetraspanin expression. Synovial fluid and SFEVs induced distinct transcriptomic changes in chondrocytes. SFEVs from patients with severe OA promoted a pro-inflammatory and catabolic chondrocyte phenotype, with upregulation of CRTAC1, COL6A3, TNC, and CXCL5, greater secretion of IL-6, MMP1, MMP3 and MMP13, and pro-nociceptive mediators (NGF and Substance P). These findings suggest that SFEVs may contribute to OA progression by exacerbating cartilage damage and promoting pain sensitisation. Full article

‘Candidatus Phytoplasma mali’ is associated with apple proliferation, a devastating disease in fruit production. Using genome analysis, a gene encoding a hemolysin-like protein was identified. It was postulated that this protein could be an effector. However, the function of this protein is unknown. It is shown that the hemolysin-like protein binds to a GTP binding protein, Toc33, of Arabidopsis thaliana in yeast two-hybrid analysis and that the Toc33-binding domain is located in the C-terminus of the domain of unknown function (DUF21) of the protein. The biochemical studies reveal that the protein can hydrolyze phosphate of purine and pyrimidine nucleotides. Transgenic Nicotiana benthamiana plants expressing the protein show no discernible change in phenotype. Phytoplasma have a much-reduced genome, lacking important genes for catabolic pathways or nucleotide production; therefore, the hemolysin-like protein plays a role in the uptake of plant nucleotides from their host and hydrolyzes these nucleotides for energy and their own biosynthesis. Full article

Background/Objectives: We aimed to discover genes with bimodal expression linked to patient outcomes, to reveal underlying oncogenotypes and identify new therapeutic insights in lung adenocarcinoma (LUAD). Methods: We performed meta-analysis to screen LUAD datasets for prognostic genes with bimodal expression patterns. Kynureninase (KYNU), a key enzyme in tryptophan catabolism, emerged as a top candidate. We then examined its relationship with LUAD mutations, metabolic alterations, immune microenvironment states, and expression patterns in human and mouse models using bulk and single-cell transcriptomics, metabolomics, and preclinical model datasets. Pan-cancer prognostic associations were also assessed. Results: Model-based clustering of KYNU expression outperformed median-based dichotomization in prognostic accuracy. KYNU was elevated in tumors with KEAP1 and STK11 co-mutations but remained a strong independent prognostic marker. Metabolomic analysis showed that KYNU-high tumors had increased anthranilic acid, a catalytic product, while maintaining stable kynurenine levels, suggesting a compensatory mechanism sustaining immunosuppressive signaling. Single-cell and bulk data showed KYNU expression was cancer cell-intrinsic in immune-cold tumors and myeloid-derived in immune-infiltrated tumors. In murine LUAD models, Kynu expression was predominantly immune-derived and uncoupled from Nrf2/Lkb1 signaling, indicating poor model fidelity. KYNU’s prognostic associations extended across cancer types, with poor outcomes in pancreatic and kidney cancers but favorable outcomes in melanoma, underscoring the need for lineage-specific considerations in therapy development. Conclusions:KYNU is a robust prognostic biomarker and potential immunometabolic target in LUAD, especially in STK11 and KEAP1 co-mutated tumors. Its cancer cell-intrinsic expression and immunosuppressive metabolic phenotype offer translational potential, though species-specific expression patterns pose challenges for preclinical modeling. Full article

Background: Vitiligo is featured by the manifestation of white maculae and primarily results from inflammatory/immune-selective aggression to melanocytes. The trigger mechanism leading to the activation of resident immune cells in the skin still lacks a molecular description. There is growing evidence linking altered mitochondrial metabolism to vitiligo, suggesting that an underlying metabolic defect may enable a direct activation of the immune system. Recent evidence demonstrated the association of vitiligo with disorders related to systemic metabolism, including insulin resistance (IR) and lipid disarrangements. However, IR, defined as a cellular defect in the insulin-mediated control of glucose metabolism, and its possible role in vitiligo pathogenesis has not been proven yet. Methods: In this study, we compared the Ins/IGF-1 intracellular signaling of dermal and epidermal cells isolated from non-lesional vitiligo skin to that belonging to cells obtained from healthy donors. Results: We demonstrated that due to the intensified glucose uptake, S6, and insulin receptor substrate 1 (IRS1) chronic phosphorylation, their inducibilities were downsized, a condition that coincides with the definition of insulin resistance at the cellular level. Correspondingly, the mitogenic and metabolic activities normally provoked by Ins/IGF-1 exposure resulted in significantly compromised vitiligo cells (p ≤ 0.05). Besides all the vitiligo-derived skin cells manifesting an energetic disequilibrium consisting of a low ATP, catabolic processes activation, and chronic oxidative stress, the functional consequences of this state appear amplified in the keratinocyte lineage. Conclusion: The presented data argue for insulin and IGF-1 resistance collocating dysfunctional glucose metabolism in the mechanisms of vitiligo pathogenesis. In vitiligo keratinocytes, the intrinsic impairment of intracellular metabolic activities, particularly when associated with stimulation with Ins/IGF-1, converges into an aberrant pro-inflammatory phenotype that may initiate immune cell recruitment. Full article

Small extracellular vesicles (sEVs) derived from different osteoarthritic (OA) tissues regulate OA-related biological processes through transporting their content (proteins, miRNAs, etc.) to recipient cells. This study aimed to characterize the miRNA profile of synovial fibroblasts-derived small EVs (FS_OA_sEVs) and investigate their role in inflammation in chondrocytes. Chondrocytes were isolated from macroscopically preserved and lesioned OA cartilage (C_OAmin and C_OAmax) and synovial fibroblasts from OA synovium. Synovial fibroblasts-derived small EVs (FS_OA_sEVs) were characterized according to ISEV guidelines and used for miRNA profiling and bioinformatics analysis. miR-21-5p was identified as one of the most abundant, and its target genes, such as KLF6, were enriched in OA-related processes including inflammation. Treatment of C_OAmin chondrocytes with FS_OA_sEVs resulted in decreased expression of COL2A1 and ACAN and an increase in catabolic markers MMP-3 and MMP-13. Moreover, C-OAmin receiving FS_OA_sEVs exhibited increased levels of inflammatory markers and miR-21-5p expression, resembling chondrocytes’ phenotype from lesioned OA cartilage, whereas miR-21-5p inhibition reversed their expression of inflammatory markers and miR-21-5p. Compared to C_OA min, C_OAmax chondrocytes exhibited increased miR-21-5p and inflammatory markers expression and decreased KLF6 expression. miR-21-5p inhibition in C_OAmax led to KLF6 upregulation and suppression of inflammatory mediators, whereas co-treatment with siRNA against KLF6 negated this effect, confirming a potential direct regulatory relationship between miR-21-5p and KLF6. Our results provide novel insights into the FS_OA_sEV-mediated inflammation axis, highlighting FS_OA_sEV-derived miR-21-5p as a driver of OA progression via regulating inflammation in chondrocytes. Full article

Two novel strains, CB1-14^T and CB2-10, were isolated from the marine polychaetes Chaetopterus cautus from the Sea of Japan. Phylogenetic analysis based on the 16S rRNA sequences revealed that the two strains belong to the genus Vibrio, sharing 98.96% identity with Vibrio hangzhouensis CN 83^T. MLSA using five protein-coding genes (ftsZ, gyrA, gyrB, mreB, and rpoA) showed that CB1-14^T and CB2-10 are closely related to the members of the Mediterranei clade, namely Vibrio mediterranei CECT 621^T, Vibrio barjaei 3062^T, Vibrio thalassae CECT 8203^T, Vibrio hangzhouensis CGMCC 1.7062^T, Vibrio maritimus CAIM 1455^T, and Vibrio variabilis CAIM 1454^T. Based on both MLST neighbor-net phylogenetic network and phylogenomic tree results, they fell into the subclade formed by V. maritimus CAIM 1455^T and V. variabilis CAIM 1454^T. Both new strains CB1-14^T and CB2-10 showed the highest ANI/AAI values of 91.3%/92.7% with V. variabilis CAIM 1454^T and 90.3%/93.1% with V. maritimus CAIM 1455^T. The dDDH values between strain CB1-14^T and the members of the Mediterranei clade ranged from 20.9% to 45.7%. Major fatty acids were C_16:1ω9c, C_16:1ω7c, and C_18:1ω9c, followed by C_16:0 and C_18:1ω7c. The genome of CB1-14^T is 5,591,686 bp in size, with DNA G+C content of 46.1%. It consists of two circular chromosomes (3,497,892 and 1,804,652 bp) and one plasmid (241,015 bp) and comprises 4782 protein-coding genes and 10 rrn operons. The CB1-14^T and CB2-10 genomes were enriched in CAZyme-encoding genes of the following families: GH1, GH3, GH13, GH23, GH43, GH94, PL17, and CE4, indicating the potential to catabolize alginate, xylan, and chitin, common polysaccharides in marine ecosystems. Based on the combined phylogenomic analyses and phenotypic properties, a new species, Vibrio chaetopteri sp. nov., is proposed, with CB1-14^T = (KMM 8419^T = KCTC 92790^T) as the type strain. Full article

In countries with a long petroleum extraction and processing history, such as Romania, extensive soil areas are often polluted with petroleum and its derivatives, posing significant environmental and human health risks. This study explores the diesel biodegradation potential of two native bacterial consortia isolated from hydrocarbon-polluted soils, focusing on their phenotypic and molecular characteristics, growth kinetics, alkane hydroxylase activity, hydrolase production, and biosurfactant synthesis capabilities. The bacterial consortia, CoP1 and CoP2, were successfully obtained using the standard successive enrichment culture method from two soil samples collected from a region affected by petroleum pollution. The CoP1 and CoP2 consortia demonstrated efficient diesel-degrading capabilities, achieving 50.81−84.32% degradation when cultured in a minimal medium containing 1–10% (v/v) diesel as the sole carbon and energy source. This biodegradation potential was corroborated by their significant alkane hydroxylase activity and the detection of multiple catabolic genes in their genomes. The CoP1 consortium contains at least four catabolic genes (alkB, alkM, todM, ndoM) as well as rhamnosyltransferase 1 genes (rhlAB), while the CoP2 consortium contains only two catabolic genes (ndoM, C23DO). The RND transporter gene (HAE1) was present in both consortia. Secondary metabolites, such as glycolipid-type biosurfactants, as well as extracellular hydrolases (protease, amylase, cellulase, and lipase), were produced by both consortia. The CoP1 and CoP2 consortia demonstrate exceptional efficiency in diesel degradation and biosurfactant production, making them well suited for the bioremediation of soils contaminated with petroleum and its derivatives. Full article

In Escherichia coli cells, the main enzymes involved in pentose interconversion are ribose-5-phosphate isomerases RpiA and RpiB and ribulose-5-phosphate epimerase Rpe. The inactivation of rpiAB limits ribose-5-phosphate (R5P) synthesis via the oxidative branch of the pentose phosphate pathway (PPP) and unexpectedly results in antibiotic supersensitivity. This type of metabolism is accompanied by significant changes in the level of reducing equivalents of NADPH and glutathione, as well as a sharp drop in the ATP pool. However, this redox and energy imbalance does not lead to the activation of the soxRS oxidative stress defense system but the increased sensitivity to oxidants paraquat and H₂O₂. The deletion of rpiAB leads to a significant increase in the activity of transketalase (Tkt), a key enzyme of the nonoxidative branch of the PPP and increased sensitivity to ribose added in the growth medium. The phenotype of supersensitivity of rpiAB to antibiotics and ribose can be suppressed by activating the utilization of sedoheptulose-7-phosphate, which originates from R5P, to LPS synthesis or limitation of nucleoside catabolism by the inactivation of the DeoB enzyme, responsible for conversion of ribose-1-phospate to R5P. Our results indicate that the induction of unidirectional synthesis of R5P is the cause of supersensitivity to antibiotics in rpiAB mutant. Full article

Several soluble factors secreted by the stromal cells and cancer cells within the tumor microenvironment facilitate the progression and invasiveness of ovarian cancer. In ovarian cancer cells, lysophosphatidic acid (LPA) modulates the transcriptome profile and promotes cell invasiveness by the downregulation of autophagy. Here, we further elucidate this mechanism by focusing on the molecular and cellular events regulating autophagy. Transcriptomic and Western blotting analyses revealed NKX3-2, a transcriptional factor, to be among the genes hyperexpressed in LPA-stimulated ovarian cancer cells. Bioinformatic analyses revealed that in ovarian cancer patients, the expression of NKX3-2 positively correlates with genes involved in cell motility and migration, while it negatively correlates with macromolecular catabolic pathways. In various ovarian cancer cell lines, NKX3-2 silencing abrogated LPA-induced cell migration. Mechanistically, this effect is linked to the restoration of the HDAC6-mediated relocation of the lysosomes in the para-golgian area, and this results in an increase in autolysosome formation and the overall upregulation of autophagy. Silencing the expression of ATG7 or BECN1, two autophagy genes, rescued the migratory phenotype of the NKX3-2-silenced ovarian cancer cells. Taken together, these data reveal the mechanism by which the LPA-NKX3-2 axis promotes the invasiveness of ovarian cancer cells and supports the possibility of targeting NKX3-2 to reduce the migratory capacity of cancer cells in response to a permissive microenvironment. Full article

Background: The endogenous ecto-enzyme and exogenously administered alkaline phosphatase (ALP) have been evidenced to significantly attenuate inflammatory conditions, including Toll-like receptor 4 (TLR4)-related signaling and cytokine overexpression, barrier tissue dysfunction and oxidative stress, and metabolic syndrome and insulin resistance, in experimental models of colitis, liver failure, and renal and cardiac ischemia-reperfusion injury. This suggests multiple mechanisms of ALP anti-inflammatory action that remain to be fully elucidated. Methods: Recent studies have contributed to a deeper comprehension of the role played by ALP in immune metabolism. This review outlines the established effects of ALP on lipopolysaccharide (LPS)-induced inflammation, including the neutralization of LPS and the modulation of purinergic signaling. Results: The additional mechanisms of anti-inflammatory activity of ALP observed in different pathologies are proposed. Conclusions: The anti-inflammatory pathways of ALP may include a scavenger receptor (CD36)-mediated activation of β-oxidation and oxidative phosphorylation, caveolin-dependent endocytosis, and selective autophagy-dependent degradation. Full article

Transportation, an unavoidable process in livestock farming, causes metabolic disorders in the body, which then lead to endocrine disruption, being immunocompromised, and growth suppression. Lipid metabolism dysregulation is a critical phenotype induced by transportation. The liver is a vital organ in lipid metabolism, with a role in both lipid synthesis and lipolysis. However, the specific mechanisms by which transportation affects hepatic lipid metabolism remain unclear. This study employed rats as a model to investigate the effects of transportation on hepatic lipid metabolism. Rats subjected to transportation showed altered serum lipid profiles, including decreased serum triglyceride (TG), low-density lipoprotein cholesterol (VLDL-C), and non-esterified fatty acid (NEFA) immediately after transportation (IAT) and serum total cholesterol (TC) on day 3, and increasing serum TG, TC, and low-density lipoprotein cholesterol (LDL-C) on day 10. Meanwhile, fatty droplets in the liver were also reduced at IAT and increased on days 3 and 10. Notably, transportation also affected hepatic-lipid-metabolism-related enzyme activities and signaling pathways, such as increased AMP-activated protein kinase alpha (AMPKα) phosphorylation and modulations in key proteins and genes related to lipid metabolism, decreased hepatic acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) activities at IAT, and increased carnitine palmitoyl transferase 1 alpha (CPT-1α) at IAT and ACC and CPT-1α activities on days 3 and 10. Supplementation with alkaline mineral complex water (AMC) before and after transportation mitigated the adverse effects on hepatic lipid metabolism by modulating the AMPKα-SREBP-1c/PPARα pathway, enhancing lipid synthesis, and reducing the oxidative catabolism of fatty acids. AMC inhibited the transportation-induced activation of AMPKα and restored the balance of lipid-metabolism-related enzymes and pathways. These findings highlight AMC’s potential as a therapeutic intervention to alleviate transportation-induced lipid metabolism disorders, offering significant implications for improving animal welfare and reducing economic losses in livestock farming. Full article

Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation and inflammation. This study investigates the therapeutic potential of secretome derived from adipose tissue mesenchymal stem cells (ASCs) in mitigating inflammation and promoting cartilage repair in an in vitro model of OA. Our in vitro model comprised chondrocytes inflamed with TNF. To assess the therapeutic potential of secretome, inflamed chondrocytes were treated with it and concentrations of pro-inflammatory cytokines, metalloproteinases (MMPs) and extracellular matrix markers were measured. In addition, secretome-treated chondrocytes were subject to a microarray analysis to determine which genes were upregulated and which were downregulated. Treating TNF-inflamed chondrocytes with secretome in vitro inhibits the NF-κB pathway, thereby mediating anti-inflammatory and anti-catabolic effects. Additional protective effects of secretome on cartilage are revealed in the inhibition of hypertrophy markers such as RUNX2 and COL10A1, increased production of COL2A1 and ACAN and upregulation of SOX9. These findings suggest that ASC-derived secretome can effectively reduce inflammation, promote cartilage repair, and maintain chondrocyte phenotype. This study highlights the potential of ASC-derived secretome as a novel, non-cell-based therapeutic approach for OA, offering a promising alternative to current treatments by targeting inflammation and cartilage repair mechanisms. Full article

In this very personal hunt for the meaning of the bacterial cell cycle, the snark, I briefly revisit and update some of the mechanisms we and many others have proposed to regulate the bacterial cell cycle. These mechanisms, which include the dynamics of calcium, membranes, hyperstructures, and networks, are based on physical and physico-chemical concepts such as ion condensation, phase transition, crowding, liquid crystal immiscibility, collective vibrational modes, reptation, and water availability. I draw on ideas from subjects such as the ‘prebiotic ecology’ and phenotypic diversity to help with the hunt. Given the fundamental nature of the snark, I would expect that its capture would make sense of other parts of biology. The route, therefore, followed by the hunt has involved trying to answer questions like “why do cells replicate their DNA?”, “why is DNA replication semi-conservative?”, “why is DNA a double helix?”, “why do cells divide?”, “is cell division a spandrel?”, and “how are catabolism and anabolism balanced?”. Here, I propose some relatively unexplored, experimental approaches to testing snark-related hypotheses and, finally, I propose some possibly original ideas about DNA packing, about phase separations, and about computing with populations of virtual bacteria. Full article