bims-toxgon 2025-10-05 papers

bims-toxgon

Biomed News

on Toxoplasma gondii metabolism

Issue of 2025–10–05
thirty-two papers selected by
Lakesh Kumar, BITS Pilani

Plasma membrane recycling drives reservoir formation during Toxoplasma gondii intracellular replication.
Toxoplasma gondii alters gut microbiota and systemic metabolism in cats: A multi-omics approach.
Impact of equilibrative nucleoside transporters on Toxoplasma gondii infection and differentiation.
Immunological insights and vaccine advances against apicomplexan parasites: Emerging concepts and innovations.
Redox-dependent activity and thioredoxin interaction of cyclophilin TgCyp21 from toxoplasma gondii.
Characterization of the immune response to recombinant GRA-4 protein (rGRA-4) of Toxoplasma gondii in Balb/c strain mice.
Proteome changes during in vitro culture adaptation of Toxoplasma gondii archetypal II and III field isolates.
Human SerRS/SIRT2 complex structure reveals cross regulation between translation and NAD + metabolism.
Sirtuins in Parkinson's disease: Molecular mechanisms and pathophysiological roles.
Identification of Potent HDAC6 Inhibitors for Breast Cancer Through Multi-Stage In Silico Modeling.
Association of infection with Toxoplasma gondii and arthritis: Insights from a cross-sectional study and genetic epidemiology analysis.
Host-parasite interaction in latent cerebral toxoplasmosis: The role of cytokine response in a mouse model.
Hierarchical small molecule inhibition of MYST acetyltransferases.
The research progress of α-ketoglutarate in osteoarthritis.
The arabidopsis GyraseB3 contributes to transposon silencing by promoting histone deacetylation.
H3 acetylation triggers SWR1 recruitment to promote H2A.Z incorporation into chromatin and stimulate gene expression.
Role of Post-Translational Modifications in Virulence of Bacillus anthracis: A narrative review.
Mechanistic insights into post-translational modifications in hepatic fibrosis: pathogenic roles and therapeutic potentials.
ID-MS-Based Quantitative Analysis of Metabolites in Pichia pastoris: A Step-by-Step Protocol.
The epigenetic landscape of kinetoplastid parasites: From histone post-translational modifications to emerging therapeutic strategies.
HISTONE DEACETYLASE-1 is required for epigenome stability in Neurospora crassa.
Recent progress in histone post-translational modifications as regulator of metabolic diseases: A review.
Advances in the interaction between gut microbiota and post-translational modifications of proteins.
Phosphoinositide dynamics in virus-associated malignancies.
Lysosome-dependent nutrient scavenging underlies stress adaptation during epithelial-to-mesenchymal transition.
A comprehensive application of FiveFold for conformation ensemble-based protein structure prediction.
Deacetylation of ACLY Mediates RNA M6A-Modification of NOXA and Promotes Chemoresistance of Colorectal Cancer.
Metabolic adaptation to host acetate facilitates oxidative stress resistance and intracellular survival of Neisseria meningitidis in macrophages.
Evolution of parasitism-related traits in nematodes.
Redox Regulation of Cell Migration via Nischarin S-glutathionylation.
Lactucin enhances glucose uptake and glycolysis in C2C12 myotubes by activating AMPK signaling pathway.
Changes of cognitive functions and proinflammatory cytokines across the lifespan in latent Toxoplasma gondii infection.

PLoS Biol. 2025 Sep 30. 23(9): e3003415

Plasma membrane recycling drives reservoir formation during Toxoplasma gondii intracellular replication.

Julia von Knoerzer-Suckow, Eva-Helena Aden, Romuald Haase, Andreas Klingl, Ignasi Forné, Simon Gras.

During intracellular development, apicomplexan parasites reside within a parasitophorous vacuole largely derived from the host plasma membrane (PM) and rendered nonfusogenic with the host endolysosomal system. Yet, the parasite is capable of protein uptake from the host cell via endocytosis, which occurs via a conserved structure, the micropore. Recently the composition of the micropore was characterized and its stability was shown to depend on the presence of the kelch-domain protein K13 which is also central to malarial drug-resistance to artemisinin. Interestingly, depletion of K13 also resulted in an impressive accumulation of PM attached to or between individual parasites, suggesting that the micropore plays a critical role in PM homoeostasis. Here, we characterized the dynamics and recycling of the PM in Toxoplasma gondii. In intracellular parasites, the PM is shared between individual parasites and undergoes a cycle of endocytosis and exocytosis during replication, similar to what has been previously demonstrated for extracellular parasites. This cycle appears to depend on Rab5b and MyoF. Interestingly, in contrast to Plasmodium falciparum, Rab5b is dispensable for the lytic cycle of T. gondii. During replication, parasites establish an extracellular plasma membrane reservoir (PMR) prior to daughter cell formation. The PMR is a dynamic membranous structure that varies in size and position throughout replication and disappears after daughter cell budding. Perturbation of the endo-exocytic balance disrupts PMR formation, leading to increased number and size of PMRs and, ultimately, to a complete loss of membrane organization directly linking endocytosis to the regulation of PMR formation.

DOI: https://doi.org/10.1371/journal.pbio.3003415
Vet J. 2025 Sep 25. pii: S1090-0233(25)00159-5. [Epub ahead of print]314 106455

Toxoplasma gondii alters gut microbiota and systemic metabolism in cats: A multi-omics approach.

Ji-Xin Zhao, Xue-Yao Wang, Xuancheng Zhang, Lu-Yao Tang, Shi-Chen Xie, Yi-Han Lv, Zhi Zheng, Ying-Qian Gao, Jing Jiang, Xiao-Xuan Zhang, He Ma.

  Toxoplasma gondii (T. gondii) is an obligate intracellular parasite with a complex life cycle that culminates in cats-its only definitive host. While its immunological impact is well studied, how T. gondii shapes the feline gut microbiota and systemic metabolism remains largely unexplored. To investigate host-parasite-microbiome interactions, we performed a multi-omics study combining metagenomic sequencing and untargeted serum metabolomics in cats before and after T. gondii infection. Fecal samples were used to construct a comprehensive microbial gene catalog and assess functional shifts, while serum samples were analyzed via liquid chromatography-tandem mass spectrometry (LC-MS/MS) to capture systemic metabolic changes. Infection with T. gondii, particularly during its sexual replication phase, significantly disrupted gut microbial diversity, composition, and function. Functional annotation revealed downregulation of microbial genes involved in vitamin, cofactor, and energy metabolism, alongside upregulation of carbohydrate metabolism pathways. Concurrently, metabolomic profiling showed marked alterations in lipid profiles, amino acid pathways, and folate-mediated one-carbon metabolism. Integrated analysis uncovered strong correlations between specific microbial taxa-such as Bifidobacterium adolescentis and Ligilactobacillus animalis-and host metabolites, underscoring a tight link between microbial function and host metabolic responses to infection. To our knowledge, this is the first study to comprehensively map the microbiome and metabolic landscape of T. gondii infection in the feline host. Our findings reveal profound parasite-induced shifts in microbial function and systemic metabolism, offering new insights into the molecular interplay between host, parasite, and microbiota. These insights may inform future strategies for therapeutic modulation of host responses in toxoplasmosis.

Keywords:  Cats; Gut microbiome; Host–parasite interaction; Serum metabolomics; Toxoplasma gondii

DOI:  https://doi.org/10.1016/j.tvjl.2025.106455
mBio. 2025 Sep 30. e0220725

Impact of equilibrative nucleoside transporters on Toxoplasma gondii infection and differentiation.

Gabriel Messina, Amber Goerner, Charlotte Bennett, Euwen Brennan, Vern B Carruthers, Bruno Martorelli Di Genova.

  Toxoplasma gondii cannot synthesize purines de novo and must import them; however, the functional interplay among its four equilibrative nucleoside transporters (ENTs) homologs remains unclear. We systematically deconstructed this network by combining CRISPR-Cas9 knockouts with an auxin-inducible degron. Across all phenotypic assays, tachyzoite replication, nucleoside-analog sensitivity, alkaline-stress-induced differentiation, and murine cyst formation, the ΔTgENT2 strain was indistinguishable from the parental line, indicating that TgENT2 is dispensable under the conditions tested. In contrast, the double mutant ΔTgAT1ΔTgENT3 exhibited delayed bradyzoite differentiation in vitro and produced smaller brain cysts in vivo. This double deletion triggered approximately threefold transcriptional upregulation of TgENT1, whose product we partially localized to the plant-like vacuolar compartment (PLVAC). Conditional depletion of TgENT1 caused complete intracellular growth arrest, PLVAC swelling, and a purine-starvation-like transcriptomic program enriched for nucleoside phosphatases and cyclic-nucleotide phosphodiesterases. These findings reveal a compensatory salvage pathway in which the parasite reroutes purine acquisition through a vacuolar route when plasma-membrane import is compromised. Although this response sustains tachyzoite proliferation, it fails during the energetically demanding transition to bradyzoites, creating a metabolic bottleneck that impairs chronic infection. Our work reveals an adaptable yet ultimately limited purine-import network and identifies TgENT1, along with the vacuolar salvage axis it mediates.
IMPORTANCE: In this manuscript, we demonstrate that Toxoplasma gondii employs a flexible transporter network that redirects to a vacuolar salvage route when primary transporters are compromised. Disrupting this backup pathway disrupts parasite growth, exposing an Achilles' heel in purine homeostasis. Because nucleoside transporters are druggable, these findings suggest that the purine import machinery and TgENT1 may be potential targets for therapies against T. gondii infections.

Keywords:  Toxoplasma gondii; host-pathogen interactions; intracellular parasites; nutrient transport; parasitology

DOI:  https://doi.org/10.1128/mbio.02207-25
Microb Pathog. 2025 Sep 29. pii: S0882-4010(25)00799-5. [Epub ahead of print]209 108074

Immunological insights and vaccine advances against apicomplexan parasites: Emerging concepts and innovations.

Ayed Alshammari.

  The apicomplexan parasites are globally considered as the major cause of numerous infectious diseases in humans and animals. Apicomplexan parasites include Plasmodium, Toxoplasma gondii, Cryptosporidium, Eimeria and Babesia. The rise in the drug resistance have made the traditional control measures, such as chemotherapy and vector management, inadequate against them. These are the intracellular infectious agent and possess complex life cycles, antigenic variability, and immune evasion abilities. These different abilities hinder the development of vaccines against them. Hence, there is urgent need for development of effective vaccines by novel measures. However, notable progress has been made in past years due to the advancements in immunology, molecular biology, and biotechnology. Different types of vaccines including subunit vaccines have been developed and have demonstrated favorable efficiency. In the meantime, live-attenuated vaccines (LAV) continue to provide protection in animals. Apart from that, there are different innovations like CRISPR/Cas9 gene editing that have enabled the creation of genetically attenuated strains for T. gondii and Eimeria. These attenuated strains are used for the development of vaccines. Furthermore, mRNA vaccine technology, which was successfully utilized during the COVID-19 pandemic, is now being used against parasitic infections. It is now offering fast and rapid development along with vigorous cellular immunity. The use of nanoparticles and novel adjuvants such as TLR agonists and saponins has improved the stability and effectiveness of vaccines. Approaches like mucosal delivery, especially for enteric parasites such as Cryptosporidium and Eimeria, is achieving attention for their ability to provide the localized protection. In spite of these advancements some challenges still persist. Antigenic diversity, short-lived immunity, regulatory barriers, and limited funding need to be addressed. Some of the emerging technologies including systems vaccinology, reverse vaccinology, and vectored delivery platforms, are paving the way for more targeted and effective vaccination. There is need for concerted effort incorporating multidisciplinary research, One Health integration, and scalable manufacturing methodologies for effective translation of these scientific innovations into solutions. By harnessing these emerging technologies within a One Health framework, the next generation of vaccines has the potential to transform the management of apicomplexan diseases worldwide.

Keywords:  Apicomplexa; CRISPR; Toxoplasmosis; Vaccinology; mRNA vaccines

DOI:  https://doi.org/10.1016/j.micpath.2025.108074
Int J Biol Macromol. 2025 Sep 30. pii: S0141-8130(25)08576-9. [Epub ahead of print] 148019

Redox-dependent activity and thioredoxin interaction of cyclophilin TgCyp21 from toxoplasma gondii.

Filippo Favretto, Silvia Fruncillo, Eva Jiménez-Faraco, Nicola Masè, Paola Dominici, Uxía P de José, Inés G Muñoz, Juan A Hermoso, Alessandra Astegno.

  Cyclophilins (Cyps) are ubiquitous cytosolic proteins with peptidyl-prolyl cis-trans isomerase (PPIase) activity and the ability to bind the immunosuppressant cyclosporin A (CsA). The genome of Toxoplasma gondii, the parasite responsible for toxoplasmosis, encodes multiple putative Cyps, whose specific functions remain largely unexplored. Here, we characterize TgCyp21, a predicted Cyp from T. gondii. TgCyp21 displays PPIase activity and is inhibited by CsA in vitro. Importantly, its activity decreases markedly under oxidizing conditions but is partially restored by reducing agents, including dithiothreitol (DTT) and the parasite endogenous thioredoxin (TgTrx). TgCyp21 contains four cysteines, with Cys87 and Cys141 predicted to be spatially close based on structural modeling. Substitution of both residues significantly reduced PPIase activity, with Cys87 emerging as the main contributor to this loss. Structural modeling further indicates that Cys87 and Cys141 are suitably oriented to interact with the conserved active-site cysteines of TgTrx. This interaction is supported experimentally by mixed disulfide trapping, which identifies a stable disulfide-linked intermediate between TgCyp21 and TgTrx, consistent with a thiol-disulfide exchange mechanism. Small-angle X-ray scattering (SAXS) and nuclear magnetic resonance (NMR) spectroscopy further confirm the formation of the complex. Taken together, our data indicate that TgCyp21 behaves in vitro as a redox-responsive Cyp and a substrate for Trx, suggesting a potential involvement in Trx-mediated redox processes in T. gondii.

Keywords:  Cyclophilin; Cyclosporin a; Peptidyl-prolyl cis–trans isomerase; Redox regulation; Thioredoxin; Toxoplasma gondii

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.148019
Open Vet J. 2025 ;15(8): 3468-3476

Characterization of the immune response to recombinant GRA-4 protein (rGRA-4) of Toxoplasma gondii in Balb/c strain mice.

Muhammad Hanafiah, Nurliana, Muhammad Bahi, Fihiruddin, Febi Silvia Alfina.

   Background: Toxoplasma gondii is an obligate intracellular parasite capable of infecting several hosts, including humans and animals. Controlling toxoplasmosis remains challenging due to early diagnosis limitations and the lack of effective human vaccines. One strategic approach for diagnostic and vaccine development involves the use of recombinant proteins derived from T. gondii-specific antigens, such as dense granule (GRA) proteins. GRA-4, an excretion-secretion antigen, plays a critical role in the formation of parasitophorous vacuoles and modulation of host immune responses. This protein reportedly exhibits immunogenic potential, stimulating both humoral and cellular immune responses.
Aim: This study aimed to characterize the immune response to recombinant GRA-4 protein (rGRA-4) of T. gondii in Balb/c strain mice.
Methods: The samples used in this study included splenic organs from six 2-month-old male Balb/c strain mice to evaluate T and B cell proliferation. Recombinant GRA-4 protein was employed for transmembrane protein analysis using HMMTOP software, while SOPMA was used for protein structure analysis.
Result: The results of the study using B cell proliferation analysis with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) showed that the optical density (OD) value obtained was different in each treatment. Treatment with a combination of LPS and GRA-4 protein showed the highest results at a concentration of 10 µg/ml. The results of microscopic examination with 400× magnification showed that the number of T cells stained with MTT was greater in treatment group 2 (added PHA and GRA-4 protein (T lymphocyte proliferation) and treatment group 3 [added lipopolysaccharide (LPS) and GRA-4 protein (B lymphocyte proliferation) compared to treatment group 1 added Phytoheamagglutinin (PHA) (Control). The results of the microscopic examination with 400× magnification of B lymphocyte proliferation showed that after being stained with MTT, the results were almost the same as those in treatment 2. Exposure to a mixture of LPS with GRA-4 protein in Roswell Park Memorial Institute media showed that the number of B lymphocytes stained with MTT was more than the media that were only exposed to LPS.
Conclusion: The results of this study indicate that recombinant rGRA-4 protein has potential as a vaccine candidate to protect the host against T. gondii infection by inducing effective humoral and cellular immune responses.

Keywords:  Immune; Mice; Recombinant; Toxoplasma; rGRA4

DOI:  https://doi.org/10.5455/OVJ.2025.v15.i8.10
Front Cell Infect Microbiol. 2025 ;15 1633384

Proteome changes during in vitro culture adaptation of Toxoplasma gondii archetypal II and III field isolates.

Joachim Müller, Javier Regidor-Cerrillo, David Arranz-Solís, Sophie Braga-Lagache, Anne-Christine Uldry, Manfred Heller, Rafael Calero-Bernal, Andrew Hemphill, Luis Miguel Ortega-Mora.

   Introduction: Rapid in vitro culture adaptation of recently obtained Toxoplasma gondii isolates leading to deep changes in relevant phenotypic traits has been demonstrated earlier. Few reports exist on the molecular bases that govern this adaptation. Herein, we analyzed the T. gondii proteomes of different isolates at two timepoints during cell culture adaptation.
Methods: The differential proteomes of six recently obtained archetypal European T. gondii Type II (TgShSp1 (Genotype ToxoDB#3), TgShSp2 (#1), TgShSp3 (#3) and TgShSp16 (#3)) and Type III (TgShSp24 (#2) and TgPigSp1(#2)) isolates maintained at low (10-16) and high (50-53) passage numbers in Vero cells were determined by label free liquid chromatography-mass spectrometry.
Results: Among these isolates, 2.3% and 10.2% of proteins were differentially or constantly abundant when comparing low and high passage numbers. Constant proteins included components involved in essential cellular processes such as energy metabolism or protein synthesis, many of them identified as drug and vaccine targets. Interestingly, differentially abundant proteins were clearly linked to phenotypic changes associated to in vitro adaptation: loss of ability to spontaneously form cysts at high passages and decreased expression of cyst and bradyzoite markers (BAG1, Enolase 1, and SRS35A), while culture adaptation was associated with increased abundance of recognized virulence factors such as GRA15, GRA16, TEEGR and NSM.
Conclusion: Our results highlight the changes at the proteomic level that take place in recently obtained isolates after in vitro culture adaptation, an important feature that should be considered during T. gondii investigations.

Keywords:  Toxoplasma gondii; bradyzoite; culture adaptation; drug- vaccine targets; proteome; virulence factors

DOI:  https://doi.org/10.3389/fcimb.2025.1633384
bioRxiv. 2025 Sep 24. pii: 2025.09.23.677902. [Epub ahead of print]

Human SerRS/SIRT2 complex structure reveals cross regulation between translation and NAD + metabolism.

Qian Zhang, Huimin Zhang, Marscha Hirschi, Sheng Li, Gabriel C Lander, Jie Yang, Xiang-Lei Yang.

Life at the cellular level depends on effective coordination between diverse processes. Here we uncover a novel cross-regulation between metabolism and translation through a 3.2 Å cryo-EM structure of human cytosolic seryl-tRNA synthetase (SerRS) bound to sirtuin-2 (SIRT2), an NAD + -dependent deacetylase. This interaction, naturally triggered by the NAD + metabolite ADP-ribose (ADPR), resembles substrate binding and block SIRT2's active site. Interestingly, SerRS acetylation is not required for this interaction. SIRT2 binding sterically and allosterically impedes tRNA binding to SerRS, lowering charged tRNA Ser level and protein synthesis activity. Key interaction residues in both proteins emerged simultaneously in vertebrates, suggesting co-evolution for cross-regulation. Given ADPR's accumulation under stress, the ADPR-induced SerRS/SIRT2 interaction likely serves as a cell-protective response.

DOI: https://doi.org/10.1101/2025.09.23.677902
Ageing Res Rev. 2025 Sep 26. pii: S1568-1637(25)00248-X. [Epub ahead of print]112 102902

Sirtuins in Parkinson's disease: Molecular mechanisms and pathophysiological roles.

Xiang Li, Xuequn Luo, Xueqin Cao, Elizabeth Rosalind Thomas, Wenjun Wang, Xiaogang Zhou, Shiying Zhou, Anguo Wu, Ruixia Gao, Kezhi Liu, Jianming Wu.

  Parkinson's disease (PD) is a progressive neurodegenerative disorder that is associated with mitochondrial dysfunction, oxidative stress, neuroinflammation, and abnormal protein aggregation. The silent information regulator 2 (Sir2) family of proteins, known as sirtuins (SIRT1 - SIRT7), is nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases that regulate important signal transduction pathways in both prokaryotes and eukaryotes. An increasing number of studies revealed that sirtuins play diverse roles in cellular homeostasis, such as metabolic regulation, oxidative stress response, apoptosis, organelle protection, and gene stability. Intriguingly, growing evidence suggests that sirtuins may serve as pivotal molecular mediators in PD, yet a comprehensive synthesis of their roles in this disorder is lacking. Although the precise pathogenesis of PD remains unmapped, identifying common molecular nodes could offer effective therapeutic strategies. In this review, we present the first systematic integration of current knowledge on the distinct contributions of individual sirtuins to PD pathophysiology offering promising molecular targets for the treatment of PD. Unlike previous studies focusing on isolated aspects of sirtuin biology, our work uniquely consolidates the multifaceted mechanisms by which sirtuins modulate PD, offering a holistic perspective on their therapeutic potential. We underscore the transformative potential of sirtuin modulation, positioning a promising and unexplored frontier in neurodegenerative disease therapy. This work aims to provide new insights into potential sirtuin-targeted therapy of PD.

Keywords:  Deacetylases; Parkinson's disease; SIRT; Therapeutic strategies; α-syn

DOI:  https://doi.org/10.1016/j.arr.2025.102902
Bioinform Biol Insights. 2025 ;19 11779322251379037

Identification of Potent HDAC6 Inhibitors for Breast Cancer Through Multi-Stage In Silico Modeling.

Vaishali Pankaj, Inderjeet Bhogal, Sudeep Roy.

  Histone deacetylases (HDACs) are essential epigenetic regulators, with HDAC6 overexpression linked to estrogen receptor (ER) activity and breast cancer progression. While several HDAC6 inhibitors have been investigated, their clinical success remains limited due to toxicity and off-target effects, necessitating the discovery of novel, selective inhibitors. This study employs a multi-stage computational approach to identify potent HDAC6 inhibitors for breast cancer therapy. A large-scale virtual screening of 264 834 compounds was conducted, followed by molecular docking, molecular dynamics (MD) simulations (100 ns), molecular mechanics/generalized born surface area (MM/GBSA) binding free energy calculations, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions. The HDI-3 emerged as the most promising candidate among replicate simulations, exhibiting a substantially favorable MM/GBSA binding free energy of -130.67 kcal/mol-indicative of strong thermodynamic stability and stronger binding affinity compared to reference inhibitors Trichostatin A and Ricolinostat. Molecular dynamics simulations revealed that HDI-3 maintained structural stability, persistent key interactions with active site residues (ASP649, HIS651, ASP742), and low conformational fluctuations. The ADMET evaluation confirmed HDI-3's favorable pharmacokinetic properties, including optimal bioavailability, non-mutagenicity, and low hepatotoxicity. Essential dynamics and principal component analysis further validated its stable binding profile. While these findings highlight HDI-3 as a selective and pharmacologically viable HDAC6 inhibitor, it is important to acknowledge that the results are entirely computational. Therefore, experimental validation is essential to confirm the compound's efficacy and safety. This integrated computational pipeline provides an efficient strategy to accelerate targeted drug discovery, laying the groundwork for future experimental investigations.

Keywords:  ADMET; HDAC6 inhibitors; MD simulation; MM/GBSA; breast cancer; molecular docking; virtual screening

DOI:  https://doi.org/10.1177/11779322251379037
Microb Pathog. 2025 Oct 01. pii: S0882-4010(25)00811-3. [Epub ahead of print] 108086

Association of infection with Toxoplasma gondii and arthritis: Insights from a cross-sectional study and genetic epidemiology analysis.

Dan Zhu, Haining Li, Chu Zhang, Ying Zhou, Jin Yang, Changzhou Feng.

   BACKGROUND: Toxoplasma gondii (T. gondii), a ubiquitous protozoan infecting one-third of humanity, exhibits complex immunomodulatory properties. While experimental models suggest paradoxical roles in inflammation regulation, epidemiological data linking T. gondii to arthritis remain inconclusive, and the genetic causality unexplored. This multidisciplinary study integrates population epidemiology with genetic epidemiology to elucidate this relationship.
METHODS: Analyzing 17,029 U.S. adults from NHANES, we performed multivariable-adjusted logistic regression with complex survey weighting. Genetic correlations were assessed via linkage disequilibrium score regression (LDSC), complemented by bidirectional two-sample Mendelian randomization (MR) using GWAS data for three T. gondii serological markers (IgG, p22, sag1) and arthritis phenotypes.
RESULTS: T. gondii IgG seropositivity showed significant association with arthritis prevalence after multivariable adjustment (OR=1.19, 95% CI:1.03-1.38). Racial disparities were prominent, particularly in non-Hispanic whites across overall arthritis, rheumatoid arthritis (RA), and osteoarthritis (OA) (all Pinteraction<0.05). LDSC and forward MR revealed no genetic correlation or causal effect of T. gondii infection on arthritis phenotypes risk (all P>0.05). Reverse MR demonstrated reduced T. gondii sag1 IgG levels in RA (OR=0.92, 95% CI:0.87-0.98) and OA (OR=0.63, 95% CI:0.44-0.88), suggesting impaired anti-parasitic humoral immunity.
CONCLUSION: Our study reveals a complex duality: while chronic T. gondii exposure correlates with arthritis susceptibility in specific populations, the genetic evidence proposes a paradigm-shifting mechanism - autoimmune dysregulation in arthritis may compromise anti-parasitic antibody responses. This bidirectional relationship advances our understanding of infection-autoimmunity crosstalk, with critical implications for managing parasitic co-infections in rheumatological care.

Keywords:  Arthritis; Causality; Genetic correlation; Mendelian randomization (MR); Toxoplasma gondii

DOI:  https://doi.org/10.1016/j.micpath.2025.108086
Open Vet J. 2025 ;15(8): 3558-3570

Host-parasite interaction in latent cerebral toxoplasmosis: The role of cytokine response in a mouse model.

Tuğçe Anteplioğlu, Merve Bişkin Türkmen, Erva Eser, Damla Okatan, Oğuz Kul.

   Background: Toxoplasma gondii is a widespread intracellular protozoan that can cause chronic infection in immunocompetent hosts, leading to subclinical neuroinflammation. Understanding the immunopathogenesis of chronic cerebral toxoplasmosis requires well-characterized animal models.
Aim: This study aimed to evaluate infection severity, affected immune cell populations, and cytokine response in both early and late chronic phases of T. gondii infection.
Methods: A murine model was developed by infecting C57BL/6 mice with a sub-infective dose (104 tachyzoites) of the ME49 strain. Forty mice were used: 30 infected and 10 controls. Animals were sacrificed on days 30, 60, and 180 after infection. Brains were analyzed using histopathology, immunohistochemistry, and nested polymerase chain reaction (PCR).
Results: Histopathological changes, including gliosis, meningitis, vasculitis, and neuronal degeneration, were most prominent on days 30 and 60 and decreased by day 180. Immunohistochemistry revealed dynamic changes in immune cell populations (CD4+, CD8+, CD11b+, CD11c+, CD19+, and FOXP3+) and cytokine expression (TNF-α, IFN-γ, IL-1β, IL-4, IL-10, IL-12, and IL-18). A mixed pro- and anti-inflammatory response was observed, shifting toward immunoregulation at day 180, with increased FOXP3+ cells and anti-inflammatory cytokines. PCR confirmed T. gondii DNA in all infected groups.
Conclusion: This model shares several immunopathological features with chronic cerebral toxoplasmosis observed in immunocompetent humans, modeling aspects of the infection even in the absence of demonstrable tissue cysts. The immunological shift from pro-inflammatory to regulatory responses highlights the mechanisms of immune modulation and persistence. This study provides a useful platform to explore host-pathogen interactions and CNS immune dynamics in chronic cerebral toxoplasmosis.

Keywords:  Brain disease; Cytokine; Immunohistochemistry; Mice; Toxoplasma gondii

DOI:  https://doi.org/10.5455/OVJ.2025.v15.i8.18
bioRxiv. 2025 Apr 27. pii: 2025.04.25.650653. [Epub ahead of print]

Hierarchical small molecule inhibition of MYST acetyltransferases.

Xuemin Chen, Alexandra Castroverde, Minervo Perez, Ronald Holewinski, Kiall F Suazo, Rashmi Karki, Thorkell Andressen, Benjamin A Garcia, Jordan L Meier.

MYST lysine acetyltransferases (KATs) is a class of epigenetic enzymes critical for cellular function that constitute an emerging therapeutic target in cancer. Recently, several drug-like MYST inhibitors have been reported that show promise in a variety of preclinical models as well as in clinical trials of breast cancer. However, the comparative properties of these small molecules remains to be directly assessed. Here we apply an integrated profiling strategy to systematically define the potency and selectivity of drug-like MYST KAT inhibitors. First, we use optimized chemoproteomic profiling and histone acetylation biormarkers to study the industry-developed KAT inhibitor PF-9363. This reveals dose-dependent engagement of native KAT complexes, with hierarchical inhibition following the order KAT6A/B > KAT7 >> KAT8 > KAT5. Next, we demonstrate how PF-9363's ability to disrupt capture of MYST complex members in chemoproteomic experiments can be leveraged to identify new candidate members of these complexes, including the transcription factor FOXK2. Applying insights from these studies to WM-8014, WM-1119 and WM-3835, which have been extensively applied in the literature as MYST probes, highlights unexpected cross-inhibition and suggests a new framework for how these small molecules and biomarkers may be applied to differentiate KAT6A/B and KAT7-dependent phenotypes. Finally, we benchmark the activity of PF-9363 in the NCI-60 cell line screen, providing evidence that it can inhibit the growth of cell lines that are resistant to other epigenetic inhibitors by engaging the essential MYST enzyme KAT8 at high concentrations. Collectively, our studies indicate the potential for MYST KAT inhibitors to exhibit dose-dependent target engagement reminiscent of kinase inhibitors and specify assays and biomarkers for facile monitoring of selective and hierarchical effects.

DOI: https://doi.org/10.1101/2025.04.25.650653
Biochem Biophys Rep. 2025 Dec;44 102270

The research progress of α-ketoglutarate in osteoarthritis.

Fanghao Long, Junlin Xiang, Yangfan Tan, Jun Zhao, Chi Ma.

  α-Ketoglutarate (AKG) is a key intermediate in the tricarboxylic acid, (TCA) cycle. AKG is not only involved in cellular energy metabolism but also plays important roles in a variety of physiological and pathological processes such as antioxidant activity, anti-inflammatory effects, immune regulation, and maintenance of mitochondrial function, which have garnered widespread attention. Many experiments have shown that there is a certain correlation between AKG and OA. The purpose of this paper is to comprehensively review the literature to elucidate the mechanisms of AKG in alleviating osteoarthritis (OA), such as autophagy, gut microbiota, cellular senescence, and ferroptosis. We aim to provide theoretical references and evidence for the use of AKG in the prevention and treatment of OA.

Keywords:  Chondrocyte; Osteoarthritis; Tricaroxylic acid; α-Ketoglutarate

DOI:  https://doi.org/10.1016/j.bbrep.2025.102270
Nucleic Acids Res. 2025 Sep 23. pii: gkaf985. [Epub ahead of print]53(18):

The arabidopsis GyraseB3 contributes to transposon silencing by promoting histone deacetylation.

Isabelle Gy, Sébastien Beaubiat, Nicolas Bouché.

DNA methylation and histone modifications are key epigenetic marks controlling chromatin structure, gene expression, and transposable element (TE) activity. In plants, the histone demethylase INCREASE IN BONSAI METHYLATION1 (IBM1) prevents heterochromatic silencing marks from accumulating on actively transcribed genes. Through a genetic screen of mutants defective in IBM1 production, we identified suppressor mutations in genes essential for maintaining balanced genome-wide epigenetic states. The gyrb3 mutation partly reversed DNA hypermethylation in IBM1-deficient plants, revealing a novel role for GyrB3, a nuclear protein combining domains from cyanobacterial gyrases and ELM2/SANT proteins involved in histone acetylation. In gyrb3 mutants, TEs exhibit transcriptional activity, showing reduced DNA methylation and increased histone H3 acetylation, both of which are epigenetic marks associated with expression activation. GyrB3 physically interacts with histone deacetylases like HISTONE DEACETYLASE6 (HDA6), likely mediating their activities at TEs. The functional overlap between HDA6 and GyrB3 is further supported by the observation that, similar to gyrb3, a mutation in hda6 suppresses the Ibm2 phenotype. Our findings reinforce that histone deacetylation is essential for TE silencing and that loss of IBM1 in plants abolished the frontiers between genes and TEs, emphasizing its importance in maintaining epigenomic stability.

DOI: https://doi.org/10.1093/nar/gkaf985
Plant Physiol. 2025 Sep 30. pii: kiaf469. [Epub ahead of print]

H3 acetylation triggers SWR1 recruitment to promote H2A.Z incorporation into chromatin and stimulate gene expression.

Han Jiang, Mingming Zhao, Min Liu, Wenshuo Zhang, Junjie Xu, Thierry Pélissier, Olivier Mathieu, Israel Ausin, Yafei Wang.

Following DNA replication, the canonical H2A in eukaryotes is frequently replaced by histone variants, such as the conserved H2A.Z. Chromatin remodelers like the SWI/SNF-Related 1 (SWR1) complex facilitate this process, substituting the H2A histone with H2A.Z in an ATP-dependent manner. However, the precise mechanisms that recruit SWR1 to specific loci remain elusive. In this study, we investigate the role of H3 acetylation in mediating H2A.Z incorporation into chromatin to promote gene expression. Our results show that artificially induced hyperacetylation is associated with higher levels of H2A.Z and a decrease in H2A.W (HTA6 and HTA7). This phenomenon is also observed in genetic backgrounds that are defective in the histone deacetylases HISTONE DEACETYLASE 6 (HDA6) and HISTONE DEACETYLASE 9 (HDA9). Moreover, H2A.Z is required for the phenotypes observed in hda6-1 and hda9-1.

DOI: https://doi.org/10.1093/plphys/kiaf469
Res Microbiol. 2025 Sep 30. pii: S0923-2508(25)00079-8. [Epub ahead of print] 104344

Role of Post-Translational Modifications in Virulence of Bacillus anthracis: A narrative review.

Renu Baweja, Hema Rajput, Prateek Bhardwaj, Aakriti Gangwal, B S Balaji, Yogendra Singh.

  Bacillus anthracis, a rod-shaped, spore-forming bacterium, is the causative agent of anthrax. The life cycle of B. anthracis involves sporulation and germination processes that are precisely regulated by distinct sigma factors and associated proteins. Its pathogenicity is primarily attributed to a tripartite toxin consisting of lethal factor (LF), edema factor (EF) and protective antigen (PA), as well as an antiphagocytic capsule of Poly-γ-D-Glutamate. The virulence of B. anthracis is further regulated by various post-translational modifications (PTMs), including protein phosphorylation, acetylation, glycosylation, hydroxylation, and lipidation. These modifications play a key role in modulating bacterial virulence by influencing enzymatic activity and protein expression. This review summarizes the role of PTMs in the regulation of B. anthracis virulence. A deeper understanding of how these PTMs contribute to B. anthracis pathogenesis may offer new insights into novel enzyme targets, strategies to disrupt toxin production and the development of therapeutic approaches to combat anthrax infections.

Keywords:  Bacillus anthracis; Post-translational modifications; Two- Component System; Virulence

DOI:  https://doi.org/10.1016/j.resmic.2025.104344
J Transl Med. 2025 Oct 01. 23(1): 1036

Mechanistic insights into post-translational modifications in hepatic fibrosis: pathogenic roles and therapeutic potentials.

Xiwen Bai, Zhihan Liu, Xianbin Li, Ranran Sun, Zujiang Yu.

  Hepatic fibrosis, a critical progression in liver disease, has been widely studied. While the activation of stellate cells and the accumulation of extracellular matrix components are recognized as key mechanisms, additional research is necessary to uncover further complexities. Recent investigations underscore the pivotal role of post-translational modifications (PTMs) in hepatic fibrosis. This study explores nine PTMs-methylation, acetylation, SUMOylation, Neddylation, phosphorylation, crotonylation, glycosylation, lactylation, and ubiquitination-each implicated in the pathogenesis of hepatic fibrosis. Furthermore, six classes of drugs-ACC inhibitors, ASK1 inhibitors, Akt activators, FXR agonists, PTP1B inhibitors, and HDAC inhibitors-are reviewed for their therapeutic potential in targeting PTMs to treat hepatic fibrosis.

Keywords:  Extracellular matrix; Hepatic fibrosis; Post-translational modification; Stellate cell

DOI:  https://doi.org/10.1186/s12967-025-07037-6
Methods Mol Biol. 2026 ;2697 137-152

ID-MS-Based Quantitative Analysis of Metabolites in Pichia pastoris: A Step-by-Step Protocol.

Marc Carnicer, S Aljoscha Wahl, Reza Maleki Seifar, Joan Albiol, Walter van Gulik, Pau Ferrer.

  Quantitative metabolomics is based on a set of experimental approaches to accurately quantify intracellular metabolite concentrations. This allows us to characterize the response of a metabolic network (i.e., the metabolic phenotype) to an environmental or genetic perturbation. Here, we describe a four-step protocol adapted to the methylotrophic yeast Komagataella phaffii: (1) separation of the cells from the fermentation broth by cold filtration and addition of 13C-labeled cell extract, (2) a metabolic quenching step based on aqueous cold methanol, (3) a metabolite extraction method based on boiling ethanol, and (4) quantification by isotope dilution mass spectrometry (LC-IDMS/MS and/or GC-IDMS). This method allows us to quantify most metabolites of central carbon metabolism, including glycolytic, tricarboxylic acid cycle, and pentose phosphate pathway intermediates, as well as cofactors and free amino acids. This method has been validated for K. phaffii grown on glucose, as well as on a mixture of carbon substrates such as methanol in combination with glucose or glycerol.

Keywords:  13C-labeled internal standard; Extraction; Intracellular metabolites; Isotope dilution mass spectrometry; Komagataella phaffii; Metabolomics; Microbial metabolism; Pichia pastoris; Quenching

DOI:  https://doi.org/10.1007/978-1-0716-4779-0_8
Bioorg Med Chem. 2025 Sep 27. pii: S0968-0896(25)00318-9. [Epub ahead of print]131 118377

The epigenetic landscape of kinetoplastid parasites: From histone post-translational modifications to emerging therapeutic strategies.

Inès Jacquet, Romain Paoli-Lombardo, Patrice Vanelle, Nicolas Primas.

  Kinetoplastids are parasites which cause various neglected tropical diseases. A hallmark feature of their genomic composition is the presence of polycistronic transcription, a phenomenon that involves the transcription of multiple genes into a single mRNA molecule, along with unconventional modes of gene regulation. In these organisms, histone variants and post-translational modifications play pivotal roles in modulating chromatin structure and transcriptional activity. This review provides a comprehensive overview of histone variants and post-translational modifications identified across Leishmania spp., Trypanosoma cruzi, and Trypanosoma brucei, detailing both the diversity of modifications and their known functional roles. This review also focuses on the writers, erasers, and readers proteins, including available three-dimensional structural data, to better understand their contribution to chromatin regulation, cell cycle progression, and parasite adaptation. Concurrently, this review offers a synopsis of therapeutic endeavors that have targeted these pathways, emphasizing the outcomes of in silico, in vitro and in vivo studies. This comprehensive review underscores the potential of unraveling kinetoplastid epigenetic mechanisms as a promising avenue for developing innovative treatments against these major human pathogens.

Keywords:  Antikinetoplastid; Bromodomain; Epigenetics; Histone modifiers; Histone post-translational modifications; Inhibitors

DOI:  https://doi.org/10.1016/j.bmc.2025.118377
Proc Natl Acad Sci U S A. 2025 Oct 07. 122(40): e2503876122

HISTONE DEACETYLASE-1 is required for epigenome stability in Neurospora crassa.

Felicia Ebot-Ojong, Aileen R Ferraro, Rochelle E Yap, Farh Kaddar, Clayton Hull-Crew, Ashley W Scadden, Abigail M Deaven, Andrew D Klocko, Zachary A Lewis.

  Polycomb group (PcG) proteins form chromatin modifying complexes that stably repress lineage- or context-specific genes in animals, plants, and some fungi. Polycomb Repressive Complex 2 (PRC2) catalyzes trimethylation of lysine 27 on histone H3 (H3K27me3) to assemble repressive chromatin. In the model fungus Neurospora crassa, H3K27me3 deposition is regulated by the H3K36 methyltransferase ASH1 and components of constitutive heterochromatin including the H3K9me3-binding protein HETEROCHROMATIN PROTEIN 1 (HP1). Hypoacetylated histones are a defining feature of both constitutive heterochromatin and PcG-repressed chromatin, but how histone deacetylases (HDACs) contribute to normal H3K27me3 and transcriptional repression within PcG-repressed chromatin is poorly understood. We performed a genetic screen to identify HDACs required for repression of PRC2-methylated genes. In the absence of HISTONE DEACETYLASE-1 (HDA-1), PRC2-methylated genes were activated and H3K27me3 was depleted from typical PRC2-targeted regions. At constitutive heterochromatin, HDA-1 deficient cells displayed reduced H3K9me3, hyperacetylation, and aberrant enrichment of H3K27me3 and H3K36me3. CHROMODOMAIN PROTEIN-2 (CDP-2) is required to target HDA-1 to constitutive heterochromatin and is also required for normal H3K27me3 patterns. Patterns of aberrant H3K27me3 were distinct in isogenic ∆hda-1 strains, suggesting that loss of HDA-1 causes stochastic or progressive epigenome dysfunction. To test this, we constructed a new Δhda-1 strain and performed a laboratory "aging" experiment. Deletion of hda-1 led to progressive epigenome decay over hundreds of nuclear divisions. Together, our data indicate that HDA-1 is a critical regulator of epigenome stability in N. crassa.

Keywords:  H3K27me3; Polycomb Repressive Complex 2; constitutive heterochromatin; facultative heterochromatin; histone deacetylase

DOI:  https://doi.org/10.1073/pnas.2503876122
Int J Biol Macromol. 2025 Oct 01. pii: S0141-8130(25)08521-6. [Epub ahead of print] 147964

Recent progress in histone post-translational modifications as regulator of metabolic diseases: A review.

Aiqiang Zhu, Tong Ye, Minjia Tan, Junyu Xu.

  Histone post-translational modifications (PTMs) are epigenetic mechanisms that regulate protein activity, localization, and gene expression by altering chromatin states. Through individual or synergistic effects, PTMs dynamically modulate protein functions, contributing to metabolic homeostasis and disease pathogenesis. Recent advances in mass spectrometry (MS)-based proteomics, particularly liquid chromatography-tandem mass spectrometry (LC-MS/MS) platforms, have enabled systematic mapping of PTM dynamics. Building on these technological advancements, this review comprehensively classifies PTM types, elucidates their roles in disease-associated signaling pathways, and discusses cutting-edge detection methods. Furthermore, we highlight therapeutic strategies targeting PTMs, offering new insights into drug development for metabolic dysregulation. Integrating mechanistic insights with clinical applications, this work informs the rational development of future PTM-targeted interventions.

Keywords:  Detection methods; Epigenetics; Metabolic diseases; PTMs; Pharmacological interventions

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.147964
Microbiol Res. 2025 Sep 24. pii: S0944-5013(25)00308-8. [Epub ahead of print]302 128349

Advances in the interaction between gut microbiota and post-translational modifications of proteins.

Lingling Zhao, Hengqi He, Zhaohui Luo, Liwen Jin, Bo Xiao.

  Gut microbiota intricately regulate host cells through diverse mechanisms, with numerous pathways involving protein post-translational modifications (PTMs). This review comprehensively summarizes the impacts of the gut microbiota on various PTMs in host cells. It elaborates on how these modifications contribute to the development of host diseases, delving into mediating pathways, including changes in microbial metabolites, key enzymes, and the microenvironment. Conversely, it also explores how PTMs influence gut microbiota abundance. To overcome current research limitations, such as narrow perspectives and monotonous methods, novel strategies are proposed. Applying single-cell/spatial omics could reveal cell-type-specific and spatial PTM responses to microbial signals, while integrating AI algorithms with traditional experiments may predict PTM regulatory networks using microbial and host data. These strategies aim to expand research approaches and promote the clinical translation of findings in this field.

Keywords:  Gut microbiota; Host metabolism; Protein post-translational modification

DOI:  https://doi.org/10.1016/j.micres.2025.128349
Trends Cell Biol. 2025 Oct 01. pii: S0962-8924(25)00206-5. [Epub ahead of print]

Phosphoinositide dynamics in virus-associated malignancies.

Mingchuan Li, Wenbin Zhong, Emilio Hirsch, Daoguang Yan.

  Virus-associated cancers, which account for ~15-20% of the global cancer burden, arise from infections with human oncoviruses. These viruses drive malignant transformation through diverse mechanisms but share common oncogenic features, including reprogramming host membrane signaling and trafficking. Such processes are tightly regulated by phosphoinositides (PPIn), essential organizers of membrane dynamics and signal transduction implicated in cancer development and progression. Oncoviruses exploit host PPIn metabolism to facilitate their replication and persistence, often leading to its dysregulation. In turn, this disruption can activate oncogenic signaling pathways that promote malignant transformation. In this review, we summarize how oncoviruses manipulate PPIn metabolism to sustain their life cycle and drive long-term interactions with host cells, ultimately contributing to tumorigenesis.

Keywords:  cancer; kinase; lipid transport protein; phosphatase; phosphoinositide; virus-associated cancer

DOI:  https://doi.org/10.1016/j.tcb.2025.09.002
bioRxiv. 2025 Sep 23. pii: 2025.09.22.677807. [Epub ahead of print]

Lysosome-dependent nutrient scavenging underlies stress adaptation during epithelial-to-mesenchymal transition.

Michal J Nagiec, Paola M Cavaliere, Friederike Dundar, Derrick M Spencer, Nikolaos Koundouros, Joana B Nunes, Sejeong Shin, Sang-Oh Yoon, Julie Han, Andre Chavez, Olivia M Kester, Rabia Khan, Paul Zumbo, Eric E Gardner, Bobak Parang, Anders P Mutvei, John M Asara, Steven P Gygi, Doron Betel, Noah Dephoure, John Blenis.

Metastatic cancer cells invade tissue, overcome nutrient stress, and survive transit to distant sites. Many of the mechanisms that support these processes are incompatible with proliferation. This study defines cellular transition states in breast epithelial cells undergoing epithelial-mesenchymal transition (EMT) driven by ERK2 and TGF-β signaling. EMT triggers robust endolysosomal system upregulation and metabolic adaptations that balance proliferative and invasive states. Surprisingly, invasive cells rely on scavenging via lysosomes and macropinocytosis to acquire amino acids, rather than plasma membrane transport, even in nutrient-rich conditions. Macropinocytosis increases intracellular amino acid storage, promoting survival during amino acid deprivation. This metabolic shift depends on c-MYC downregulation, an early EMT event. Reintroducing c-MYC suppresses the metabolic switch, endolysosomal induction, macropinocytosis, and the proliferation-to-migration transition. These findings reveal how cells dynamically balance proliferation and invasion, offering insights into transition states difficult to capture in models of breast cancer metastasis.

DOI: https://doi.org/10.1101/2025.09.22.677807
Sci Rep. 2025 Sep 29. 15(1): 33498

A comprehensive application of FiveFold for conformation ensemble-based protein structure prediction.

Sarfaraz K Niazi, Jiaan Yang.

  The emergence of artificial intelligence in protein structure prediction has significantly advanced our understanding of protein folding. Yet, challenges remain in accurately modeling intrinsically disordered proteins (IDPs) and capturing conformational diversity essential for drug discovery. FiveFold is a novel ensemble method that combines predictions from five complementary algorithms (AlphaFold2, RoseTTAFold, OmegaFold, ESMFold, and EMBER3D) to improve our understanding of protein conformational landscapes, representing a significant advancement in structural biology. This review examines current applications of the methodology, analyzes its unique advantages in modeling IDPs, and explores its expanding potential in drug discovery. To demonstrate the utility of this method, we conducted computational modeling of alpha-synuclein as a model IDP system, proving it can better capture conformational diversity than traditional single-structure methods. We discuss future applications in structure-based drug design, allosteric drug discovery, protein-protein interaction inhibitors, and precision medicine. The framework's ability to generate multiple plausible conformations through its Protein Folding Shape Code (PFSC) and Protein Folding Variation Matrix (PFVM) addresses critical limitations in current structure prediction methodologies, enabling novel therapeutic intervention strategies targeting previously "undruggable" proteins.

Keywords:  Alpha-synuclein; Ensemble methods; FiveFold; Intrinsically disordered proteins; Protein structure prediction

DOI:  https://doi.org/10.1038/s41598-025-17022-0
Adv Sci (Weinh). 2025 Oct 02. e03323

Deacetylation of ACLY Mediates RNA M6A-Modification of NOXA and Promotes Chemoresistance of Colorectal Cancer.

Jun Wen, Mengqin Shen, Haitao Zhao, Liu Liu, Qian Hua, Xiaoping Zhao, Jianjun Liu, Haizhong Feng, Gang Huang.

  Chemoresistance is a major challenge for colorectal cancer (CRC) therapy and is a leading cause of cancer mortality, yet the underlying molecular mechanism remains unclear. ATP citrate lyase (ACLY), a rate-limiting enzyme of de novo lipid synthesis, plays an important role in tumor progression and chemotherapy. Here, It is demonstrated that deacetylation of ACLY is critical for chemoresistance in CRC. Through proteomic screening acetylated proteins in chemoresistant patient-derived cells, It is identified that ACLY is deacetylated at K978 site, which induces the relocation of ACLY to the nucleus and promotes its binding to RNA-binding protein 15 (RBM15). This facilitates N6-methyladenosine (m6A) methylation of NOXA (also known as PMAIP1, phorbol-12-myristate-13-acetate-induced protein 1) and decreases the stability of NOXA mRNA, resulting in chemoresistance. With the selective inhibitor Santacruzamate A, targeting the deacetylase histone deacetylase 2 (HDAC2) to inhibit the acetylation may enhance the sensitivity of chemoresistance. These findings provide new insights into the mechanism of ACLY deacetylation promoting chemoresistance and suggest a potential therapeutic strategy to mitigate the chemoresistant effects.

Keywords:  ACLY; acetylation; chemoresistance; colorectal cancer; m6A

DOI:  https://doi.org/10.1002/advs.202503323
Virulence. 2025 Dec;16(1): 2566242

Metabolic adaptation to host acetate facilitates oxidative stress resistance and intracellular survival of Neisseria meningitidis in macrophages.

Tiyasa Haldar, Divya Tripathi, Sunil D Saroj.

  Neisseria meningitidis encounters a dynamic nutrient landscape during host colonization, which necessitates its metabolic adaptation to different host metabolites such as acetate. Acetate, a short chain fatty acid (SCFA) within the host milieu, found to regulate host defense and inflammation during bacterial infection. In macrophage acetate gets converted into acetyl-CoA to provide energy via TCA cycle. Also, acetate is a crucial metabolic intermediate that takes part in lipid biosynthesis and protein acetylation. Acetate acts as an immunomodulator which improves the bactericidal effect of macrophage by activating the inflammasome. Therefore, to persist in nutrient limited conditions encountered in macrophages pathogens should resort to effective utilization of energy sources. We demonstrate that N. meningitidis can potentially utilize host acetate as a carbon source and regulate its virulence. The utilization of acetate enhanced the survival of N. meningitidis in H2O2 induced oxidative stress which can be correlated with the macrophage infection assay. Moreover, our investigation into underlying mechanism suggests that acetate exposure upregulates bacterial oxidative stress response by significantly increasing catalase and superoxide dismutase activity. We demonstrated that acetate metabolism also upregulated expression of nitric oxide detoxification genes fnr, narQ which mitigate reactive oxygen and nitrogen species produced in macrophages. Therefore, we conclude that bacterial utilization of physiologically relevant host acetate levels represents an important strategy to consume or detoxify macrophage-mediated oxidative stress, thereby facilitating bacterial survival.

Keywords:  Oxidative stress; acetate; carbon sources; nitric oxide detoxification; reactive oxygen species

DOI:  https://doi.org/10.1080/21505594.2025.2566242
bioRxiv. 2025 Sep 27. pii: 2025.09.26.678730. [Epub ahead of print]

Evolution of parasitism-related traits in nematodes.

Chieh-Hsiang Tan, Hillel T Schwartz, Nathan Y Rodak, Paul W Sternberg.

The abundant resources provided by the host provide an evolutionary rationale for parasitism and drive the metabolic and developmental divergence of parasitic and free-living animals. Two evolutionally distant nematode genera, Steinernema and Heterorhabditis , independently evolved an entomopathogenic lifestyle, in which they invade insects and kill them with the assistance of specifically associated symbiotic pathogenic bacteria. It had been generally assumed that the worm, being a bacterivore, feeds on its symbiotic bacteria, which rapidly reproduce while consuming the insect host. The evolutionary adaptations of entomopathogenic nematodes to a parasitic lifestyle developmentally, and the symbiotic relationships of entomopathogenicity, remain largely unknown. We developed an axenic culture medium that allows for robust and sustained growth of Steinernema hermaphroditum , allowing finite control of nutrients available to the nematodes. We found that, uniquely among nematodes tested, the hatchlings of S. hermaphroditum cannot endure in a nutrient-poor environment; this ability is impaired but still present in Heterorhabditis bacteriophora . Similarly, the ability to forage for food is completely lost in H. bacteriophora hatchlings and severely compromised in S. hermaphroditum . We reasoned that these traits were lost because they are unnecessary to obligate parasites that always hatch in a resource-rich host. We further found that Steinernema and, to a limited extent, Heterorhabditis nematodes can successfully invade, develop, and reproduce inside a living insect host independent of their symbiotic bacteria, apparently feeding on the hemolymph, and emerge carrying bacteria found within, explaining the evolutionary origins of entomopathogenic nematodes.
Highlights: A simple but robust axenic culturing method for the emerging model nematode Steinernema hermaphroditum and other invertebrate parasitic nematodes. Convergent evolution led to the loss of hatchling survival traits in entomopathogenic nematodes.Nematode adaptation to parasitism is associated with changes in modes of feeding.Entomopathogenic nematodes evolved from parasitoid ancestors.
Graphical abstract:

DOI: https://doi.org/10.1101/2025.09.26.678730
bioRxiv. 2025 Sep 26. pii: 2025.09.25.678565. [Epub ahead of print]

Redox Regulation of Cell Migration via Nischarin S-glutathionylation.

Madhu C Shivamadhu, Dhanushika S K Kukulage, Rayavarapu Padmavathi, Daniel Oppong, Faezeh Mashhadi Ramezani, Denaye N Eldershaw, Brett M Collins, Young-Hoon Ahn.

Reactive oxygen species (ROS) are central players in redox signaling, controlling all biological processes in human health. Many reports demonstrated that ROS play essential roles in regulating cell migration and invasion, while contributing to cancer progression and metastasis, potentially via inducing protein cysteine oxidations. Nevertheless, specific redox players involved in cell migration and invasion remain ill-defined. In this report, we found that Nischarin (NISCH), established as a tumor suppressor, is susceptible to S-glutathionylation, selectively at Cys185 located near its leucine-rich repeat (LRR) domains, which are implicated in protein-protein interactions with Rac1 and PAK1. We demonstrated that epithelial breast cancer cell lines, MCF7 and MDA-MB-231, expressing NISCH wild-type (WT), compared to its cysteine mutant (C185S), exhibit increased migration and invasion in response to oxidative stress, such as limited glucose. Mechanistically, NISCH S-glutathionylation reduced its binding to Rac1 and PAK1, without altering its binding to integrin α5. The dissociation of NISCH led to the activation of Rac1 and PAK1, resulting in the localization of Rac1 to the cell periphery, which facilitates lamellipodia formation. The activated PAK1 increased the phosphorylation of the LIMK1-cofilin axis, thereby further enhancing actin filament dynamics that promote cell migration. Based on the mechanistic analysis, we produced an engineered NISCH construct, composed of the N-terminal PX and LRR domains. We demonstrated that the engineered NISCH PX-LRR constructs, particularly one lacking the S-glutathionylation site (i.e., C185S), can suppress the migration, invasion, and colony formation of MDA-MB-231 cells, regardless of the presence of oxidative stress. Our data reports a new redox player in cell migration and invasion, while supporting the potential application of NISCH-derived protein-based therapeutics for breast cancer.

DOI: https://doi.org/10.1101/2025.09.25.678565
Nat Prod Res. 2025 Sep 30. 1-7

Lactucin enhances glucose uptake and glycolysis in C2C12 myotubes by activating AMPK signaling pathway.

Hao Zheng, Kaiwen Kang, Yujia Zhang, Ligen Lin, Lishe Gan.

  Lactucin is a sesquiterpenoid from the well-known traditional Chinese medicine Cichorium intybus L. The antidiabetic effect of lactucin and its underlying mechanism remain unclear. Using fluorescence-labelled glucose analogue, we found that lactucin dose-dependently increased glucose uptake through upregulating expression and membrane translocation of GLUT4 in C2C12 myotubes. These effects were mediated by AMP-activated protein kinase (AMPK) activation, which was abolished by the co-treatment of Compound C or Ampkα1 silencing. Furthermore, lactucin induced a controlled suppression of mitochondrial function, as evidenced by decreased mitochondrial membrane potential and ATP levels, thereby mimicking cellular energy stress to activate AMPK. The metabolic reprogramming subsequently enhanced glycolysis and reduced intracellular lipid accumulation in C2C12 myotubes. Taken together, lactucin induces a controlled mitochondrial suppression and mimics exercise-like energy stress, which in turn enhances glucose uptake in C2C12 myotubes. We firstly uncover the metabolic reprogramming effect of lactucin, suggesting its potential as an antidiabetic agent.

Keywords:  AMPK; Lactucin; glucose uptake; mitochondrial function; skeletal muscle

DOI:  https://doi.org/10.1080/14786419.2025.2567637
Brain Behav Immun Health. 2025 Nov;49 101105

Changes of cognitive functions and proinflammatory cytokines across the lifespan in latent Toxoplasma gondii infection.

Patrick D Gajewski, Peter Bröde, Maren Claus, Klaus Golka, Jan G Hengstler, Jörg Reinders, Carsten Watzl, Edmund Wascher, Stephan Getzmann.

   Background: Recent findings showed serious consequences of latent T. gondii infection on the central nervous system, leading to psychiatric, immunological and cognitive impairments. However, little is known about the temporal dynamics of the latent T. gondii infection in respect to immunological and cognitive changes across the adult life span. The present study aims at evaluating the course of cognitive changes across the adult life span in relation to latent T. gondii infection and the interplay with proinflammatory cytokines leading to chronic inflammation as a potential origin of the cognitive decline in infected adults.
Methods: In a double-blinded cross-sectional design, data of 218 seropositive and 475 seronegative adults aged between 20 and 88 years were compared regarding crucial cognitive domains: processing speed, working memory, immediate and delayed memory, sustained attention, and executive functions. In a subsample of up to 300 participants, concentrations of proinflammatory cytokines IL-6, IL-8, IL-18, and TNF-α were analyzed to evaluate their interaction with T. gondii, and to determine whether the cytokines interact in their effects on cognition across the lifespan.
Results: The results showed an interaction between age and T. gondii status, with a decline in cognitive performance in infected, relative to non-infected, older individuals, and the reversed pattern in young to middle-aged adults. Specifically, this pattern was evident in working memory, immediate and delayed recall, as well as switching ability. Age was associated with increased levels of proinflammatory cytokines, and reduced concentration of T. gondii antibodies. IL-6, IL-8 and TNF-α levels were negatively associated with T. gondii antibody level and cognitive performance. Finally, T. gondii interacted with IL-6, IL-8 and TNF-α, predicting superior performance in immediate and delayed memory tasks in younger adults with high levels of T. gondii IgG antibodies and cytokines, whereas T. gondii IgG antibody and cytokine levels played less of a role for these functions in older age.
Conclusion: The findings support a model of dynamically shifting effects of T. gondii and proinflammatory cytokines on the central nervous system and cognition with increasing age, suggesting positive effects of T. gondii infections in younger adults, and neuroinflammatory effects in older age presumably due to chronic inflammation. Given the high prevalence of latent toxoplasmosis in the general population and the growing population of older adults, these findings are of relevance for public health.
Trial registration: Clinicaltrials.gov NCT05155397.

Keywords:  Adult lifespan; Aging; Cognition; Cytokines; Executive functions; Learning and memory; Toxoplasma gondii

DOI:  https://doi.org/10.1016/j.bbih.2025.101105