bims-toxgon Biomed News
on Toxoplasma gondii metabolism
Issue of 2024–09–22
forty-six papers selected by
Lakesh Kumar, BITS Pilani
  1. A combination of four Toxoplasma gondii nuclear-targeted effectors protects against interferon gamma-driven human host cell death.
  2. The GPI sidechain of Toxoplasma gondii inhibits parasite pathogenesis.
  3. Toxoplasma FER1 is a versatile and dynamic mediator of differential microneme trafficking and microneme exocytosis.
  4. Plasmodium RON11 triggers biogenesis of the merozoite rhoptry pair and is essential for erythrocyte invasion.
  5. Inflammatory pathways of Toxoplasmagondii infection in pregnancy.
  6. In vitro anti-parasitic effect of the alkaloids harmaline and piperine on Toxoplasma gondii.
  7. The linking of toxoplasmosis and schizophrenia.
  8. SIRT1-FOXOs signaling pathway: A potential target for attenuating cardiomyopathy.
  9. Understanding the significance of oxygen tension on the biology of Plasmodium falciparum blood stages: From the human body to the laboratory.
  10. Dynamics of amylopectin granule accumulation during the course of the chronic Toxoplasma infection is linked to intra-cyst bradyzoite replication.
  11. Variant surface protein GP60 contributes to host infectivity of Cryptosporidium parvum.
  12. A new perspective on essential tremor: the potential etiologic role of Toxoplasma gondii and Toxocara spp.
  13. Overview of the PRMT6 modulators in cancer treatment: Current progress and emerged opportunity.
  14. Development of new pyrazoles as class I HDAC inhibitors: Synthesis, molecular modeling, and biological characterization in leukemia cells.
  15. Is SIRT3 and Mitochondria a Reliable Target for Parkinson's Disease and Aging? A Narrative Review.
  16. Role of histone deacetylases and their inhibitors in neurological diseases.
  17. FYVE1/FREE1 is involved in glutamine-responsive TORC1 activation in plants.
  18. Exploring Cohesin-Related Multiomics Information in the Web Browser.
  19. Identification and function characterization of NcAP2XII-4 in Neospora caninum.
  20. Occlusal disharmony promotes anxiety-like behaviours by suppressing Sirt1.
  21. Crossing epigenetic frontiers: the intersection of novel histone modifications and diseases.
  22. Suppression of neuronal AMPKβ2 isoform impairs recognition memory and synaptic plasticity.
  23. Dynamics and necessity of SIRT1 for maternal-zygotic transition.
  24. A novel dual-epigenetic inhibitor enhances recombinant monoclonal antibody expression in CHO cells.
  25. Autophagy3D: a comprehensive autophagy structure database.
  26. hsa_circ_0072309 Inhibits Oncogenesis in Hepatocellular Carcinoma by Epigenetic Activation of its Host Gene.
  27. Structural insight into the function of human peptidyl arginine deiminase 6.
  28. Coenzymes in a pre-enzymatic metabolism.
  29. Multifaceted roles of SUMO in DNA metabolism.
  30. Insects and microbes: best friends from the nursery.
  31. Emerging roles of lipid and metabolic sensing in the neuroendocrine control of body weight and reproduction.
  32. Dominant-negative KAI2d paralogs putatively attenuate strigolactone responses in root parasitic plants.
  33. EX527, a sirtuins 1 inhibitor, sensitizes T-cell leukemia to death receptor-mediated apoptosis by downregulating cellular FLICE inhibitory protein.
  34. The interplay between probiotics and host autophagy: mechanisms of action and emerging insights.
  35. Is ATP a signaling regulator for postharvest chilling tolerance in fruits?
  36. Pyruvate kinase modulators as a therapy target: an updated patent review 2018-2023.
  37. Untangling the complexity and impact of tau protein ubiquitination.
  38. Technologies for Decoding Cancer Metabolism with Spatial Resolution.
  39. Molecular mechanics studies of factors affecting overall rate in cascade reactions: Multi-enzyme colocalization and environment.
  40. Lysine acetylation regulates the subcellular localization and function of WRKY63.
  41. Unlocking the multifaceted molecular functions and diverse disease implications of lactylation.
  42. Sirtuin 1-mediated autophagy regulates testosterone synthesis in Leydig cells of piglets.
  43. The effect of nitrosative stress on histone H3 and H4 acetylation in Phytophthora infestans life cycle.
  44. Histone deacetylases: Regulation of vascular homeostasis via endothelial cells and vascular smooth muscle cells and the role in vascular pathogenesis.
  45. Computational drug discovery pipelines identify NAMPT as a therapeutic target in neuroendocrine prostate cancer.
  46. Histone deacetylase HDAC3 regulates ergosterol production for oxidative stress tolerance in the entomopathogenic and endophytic fungus Metarhizium robertsii.
  1. mBio. 2024 Sep 18. e0212424
    A combination of four Toxoplasma gondii nuclear-targeted effectors protects against interferon gamma-driven human host cell death.
    Brittany Henry, Aubrey J Phillips, L David Sibley, Alex Rosenberg.
      In both mice and humans, Type II interferon gamma (IFNγ) is crucial for the regulation of Toxoplasma gondii (T. gondii) infection, during acute or chronic phases. To thwart this defense, T. gondii secretes protein effectors hindering the host's immune response. For example, T. gondii relies on the MYR translocon complex to deploy soluble dense granule effectors (GRAs) into the host cell cytosol or nucleus. Recent genome-wide loss-of-function screens in IFNγ-primed primary human fibroblasts identified MYR translocon components as crucial for parasite resistance against IFNγ-driven vacuole clearance. However, these screens did not pinpoint specific MYR-dependent GRA proteins responsible for IFNγ signaling blockade, suggesting potential functional redundancy. Our study reveals that T. gondii depends on the MYR translocon complex to prevent parasite premature egress and host cell death in human cells stimulated with IFNγ post-infection, a unique phenotype observed in various human cell lines but not in murine cells. Intriguingly, inhibiting parasite egress did not prevent host cell death, indicating this mechanism is distinct from those described previously. Genome-wide loss-of-function screens uncovered TgIST, GRA16, GRA24, and GRA28 as effectors necessary for a complete block of IFNγ response. GRA24 and GRA28 directly influenced IFNγ-driven transcription, GRA24's action depended on its interaction with p38 MAPK, while GRA28 disrupted histone acetyltransferase activity of CBP/p300. Given the intricate nature of the immune response to T. gondii, it appears that the parasite has evolved equally elaborate mechanisms to subvert IFNγ signaling, extending beyond direct interference with the JAK/STAT1 pathway, to encompass other signaling pathways as well.IMPORTANCEToxoplasma gondii, an intracellular parasite, affects nearly one-third of the global human population, posing significant risks for immunocompromised patients and infants infected in utero. In murine models, the core mechanisms of IFNγ-mediated immunity against T. gondii are consistently preserved, showcasing a remarkable conservation of immune defense mechanisms. In humans, the recognized restriction mechanisms vary among cell types, lacking a universally applicable mechanism. This difference underscores a significant variation in the genes employed by T. gondii to shield itself against the IFNγ response in human vs murine cells. Here, we identified a specific combination of four parasite-secreted effectors deployed into the host cell nucleus, disrupting IFNγ signaling. This disruption is crucial in preventing premature egress of the parasite and host cell death. Notably, this phenotype is exclusive to human cells, highlighting the intricate and unique mechanisms T. gondii employs to modulate host responses in the human cellular environment.
    Keywords:  CRISPR screen; dense granule proteins; host-pathogen interactions; innate immunity; interferon gamma; intracellular parasite; secretory proteins
    DOI:  https://doi.org/10.1128/mbio.02124-24
  2. mBio. 2024 Sep 20. e0052724
    The GPI sidechain of Toxoplasma gondii inhibits parasite pathogenesis.
    Julia A Alvarez, Elisabet Gas-Pascual, Sahil Malhi, Juan C Sánchez-Arcila, Ferdinand Ngale Njume, Hanke van der Wel, Yanlin Zhao, Laura García-López, Gabriella Ceron, Jasmine Posada, Scott P Souza, George S Yap, Christopher M West, Kirk D C Jensen.
      Glycosylphosphatidylinositols (GPIs) are highly conserved anchors for eukaryotic cell surface proteins. The apicomplexan parasite, Toxoplasma gondii, is a widespread intracellular parasite of warm-blooded animals whose plasma membrane is covered with GPI-anchored proteins, and free GPIs called GIPLs. While the glycan portion is conserved, species differ in sidechains added to the triple mannose core. The functional significance of the Glcα1,4GalNAcβ1- sidechain reported in Toxoplasma gondii has remained largely unknown without understanding its biosynthesis. Here we identify and disrupt two glycosyltransferase genes and confirm their respective roles by serology and mass spectrometry. Parasites lacking the sidechain on account of deletion of the first glycosyltransferase, PIGJ, exhibit increased virulence during primary and secondary infections, suggesting it is an important pathogenesis factor. Cytokine responses, antibody recognition of GPI-anchored SAGs, and complement binding to PIGJ mutants are intact. By contrast, the scavenger receptor CD36 shows enhanced binding to PIGJ mutants, potentially explaining a subtle tropism for macrophages detected early in infection. Galectin-3, which binds GIPLs, exhibits an enhancement of binding to PIGJ mutants, and the protection of galectin-3 knockout mice from lethality suggests that Δpigj parasite virulence in this context is sidechain dependent. Parasite numbers are not affected by Δpigj early in the infection in wild-type mice, suggesting a breakdown of tolerance. However, increased tissue cysts in the brains of mice infected with Δpigj parasites indicate an advantage over wild-type strains. Thus, the GPI sidechain of T. gondii plays a crucial and diverse role in regulating disease outcomes in the infected host.IMPORTANCEThe functional significance of sidechain modifications to the glycosylphosphatidylinositol (GPI) anchor in parasites has yet to be determined because the glycosyltransferases responsible for these modifications have not been identified. Here we present identification and characterization of both Toxoplasmsa gondii GPI sidechain-modifying glycosyltransferases. Removal of the glycosyltransferase that adds the first GalNAc to the sidechain results in parasites without a sidechain on the GPI, and increased host susceptibility to infection. Loss of the second glycosyltransferase results in a sidechain with GalNAc alone, and no glucose added, and has negligible effect on disease outcomes. This indicates GPI sidechains are fundamental to host-parasite interactions.
    Keywords:  CD36; GIPL; GPI; GPI sidechain; PIGE; PIGJ; Toxoplasma gondii; galectin-3; macrophages; mass spectrometry; pathogenesis; surface antigens
    DOI:  https://doi.org/10.1128/mbio.00527-24
  3. Sci Rep. 2024 09 18. 14(1): 21819
    Toxoplasma FER1 is a versatile and dynamic mediator of differential microneme trafficking and microneme exocytosis.
    Daniel N A Tagoe, Adeline Ribeiro E Silva, Allison A Drozda, Isabelle Coppens, Bradley I Coleman, Marc-Jan Gubbels.
      Toxoplasma gondii is a polarized cell concentrating several secretory organelles at the apical pole. The secretory micronemes come in two sub-populations differentiated by dependence on Rab5A/C in their biogenesis. Calcium-dependent exocytosis of micronemes occurs at the very apical tip and is critical for parasite egress from its host cell, adhesion and invasion of the next cell. Ferlins represent a protein family with roles in exocytosis containing multiple Ca2+-sensing C2 domains. We determined that T. gondii's ferlin 1 (FER1) localized dynamically to the parasite's secretory pathway. FER1 function was dissected by dominant negative overexpression strategies. We demonstrated that FER1 traffics microneme organelles along the following trajectories: (1) Along the cortex to the apical end; (2) To the apical tip for fusion with the plasma membrane; (3) Differential microneme sub-population traffic, and that FER1 could putatively be responsible for microneme protein trafficking. (4) From the trans-Golgi-endosomal network to the subpellicular cortex; (5) Retrograde transport allowing microneme recycling from mother to daughter. Finally, FER1 overexpression triggers a microneme exocytosis burst, supporting the notion that the radially organized micronemes at the apical tip comprise a readily-releasable microneme pool. In summary, FER1 is pivotal for dynamic microneme trafficking, acts differently on the two microneme subpopulations, and acts on the plasma membrane fusion step during microneme exocytosis.
    Keywords:   Toxoplasma ; Exocytosis; Ferlin; Microneme; Trafficking
    DOI:  https://doi.org/10.1038/s41598-024-72628-0
  4. PLoS Biol. 2024 Sep 18. 22(9): e3002801
    Plasmodium RON11 triggers biogenesis of the merozoite rhoptry pair and is essential for erythrocyte invasion.
    David Anaguano, Opeoluwa Adewale-Fasoro, Grace W Vick, Sean Yanik, James Blauwkamp, Manuel A Fierro, Sabrina Absalon, Prakash Srinivasan, Vasant Muralidharan.
      Malaria is a global and deadly human disease caused by the apicomplexan parasites of the genus Plasmodium. Parasite proliferation within human red blood cells (RBCs) is associated with the clinical manifestations of the disease. This asexual expansion within human RBCs begins with the invasion of RBCs by P. falciparum, which is mediated by the secretion of effectors from 2 specialized club-shaped secretory organelles in merozoite-stage parasites known as rhoptries. We investigated the function of the Rhoptry Neck Protein 11 (RON11), which contains 7 transmembrane domains and calcium-binding EF-hand domains. We generated conditional mutants of the P. falciparum RON11. Knockdown of RON11 inhibits parasite growth by preventing merozoite invasion. The loss of RON11 did not lead to any defects in processing of rhoptry proteins but instead led to a decrease in the amount of rhoptry proteins. We utilized ultrastructure expansion microscopy (U-ExM) to determine the effect of RON11 knockdown on rhoptry biogenesis. Surprisingly, in the absence of RON11, fully developed merozoites had only 1 rhoptry each. The single rhoptry in RON11-deficient merozoites were morphologically typical with a bulb and a neck oriented into the apical polar ring. Moreover, rhoptry proteins are trafficked accurately to the single rhoptry in RON11-deficient parasites. These data show that in the absence of RON11, the first rhoptry is generated during schizogony but upon the start of cytokinesis, the second rhoptry never forms. Interestingly, these single-rhoptry merozoites were able to attach to host RBCs but are unable to invade RBCs. Instead, RON11-deficient merozoites continue to engage with RBC for prolonged periods eventually resulting in echinocytosis, a result of secreting the contents from the single rhoptry into the RBC. Together, our data show that RON11 triggers the de novo biogenesis of the second rhoptry and functions in RBC invasion.
    DOI:  https://doi.org/10.1371/journal.pbio.3002801
  5. Travel Med Infect Dis. 2024 Sep 16. pii: S1477-8939(24)00077-2. [Epub ahead of print]62 102760
    Inflammatory pathways of Toxoplasmagondii infection in pregnancy.
    Reyhaneh Moghaddami, Mahdi Mahdipour, Ehsan Ahmadpour.
      Toxoplasma gondii (T. gondii), an obligate intracellular parasite, is considered as an opportunistic infection and causes toxoplasmosis in humans and animals. Congenital toxoplasmosis can influence pregnancy and cause mild to severe consequences for the fetal and neonatal. During early T. gondii infection, neutrophils as the most abundant white blood cells provide a front line of defense mechanism against infection. The activated dendritic cells are then responsible for initiating an inflammatory response via T-helper 1 (Th1) cells. As part of its robust immune response, the infected host cells produce interferon (IFN-γ). IFN-γ inhibits T. gondii replication and promotes its transformation from an active form to tissue cysts. Although anti- T. gondii antibodies play an important role in infection control, T-helper 2 (Th2) immune response, can facilitate the growth and proliferation of T. gondii in the host cell. In pregnant women infected with T. gondii, the expression of cytokines may vary and in response diverse outcomes are expected. Cytokine profiles serve as valuable indicators for estimating the patho-immunological effects of T. gondii infection. This demonstrates the intricate relationship between pro-inflammatory and anti-inflammatory cytokines, as well as their influence on the various pregnancy outcomes in T. gondii infection.
    Keywords:  Congenital infection; Gestation; Immune responses; Inflammation; Toxoplasmosis
    DOI:  https://doi.org/10.1016/j.tmaid.2024.102760
  6. Rev Bras Parasitol Vet. 2024 ;pii: S1984-29612024000300805. [Epub ahead of print]33(3): e001824
    In vitro anti-parasitic effect of the alkaloids harmaline and piperine on Toxoplasma gondii.
    Daniele Silva Souza Carreira, Carolina Emy Sato, Waléria Borges da Silva, Thereza Cristina Borio Dos Santos Calmon de Bittencourt, Silvia Lima Costa, Rosângela Soares Uzêda.
      Toxoplasma gondii is a coccidian protozoan of zoonotic importance that causes toxoplasmosis. Although the current treatments for toxoplasmosis may be associated with adverse effects and limited efficacy for different biological forms of the parasite, evidence suggests that alkaloid molecules such as harmaline and piperine exhibit antiparasitic effects against protozoa parasites. This investigation aimed to evaluate the in vitro effect of harmaline and piperine against T. gondii tachyzoites in infected Vero cell cultures. After 24 hours of host cell infection, the cultures were treated with harmaline or piperine (0.49 to 15.63 µg/mL). Negative and positive controls were RPMI/DMSO (0.1%) and sulfadiazine (200 µg/mL). Harmaline significantly reduced parasite multiplication by 20% compared to the negative control, while piperine decreased between 55.56% and 88.89% in a dose-dependent manner. According to an intracellular parasite proportion scale, it was observed that the Vero cells with low or moderate parasitic proliferation were more prevalent after the alkaloid treatment. The study demonstrated that the alkaloids had antiparasitic effects on T. gondii, with piperine being the most effective. Additional studies must be carried out to clarify other aspects of the action of the alkaloids on parasites.
    DOI:  https://doi.org/10.1590/S1984-29612024053
  7. Folia Parasitol (Praha). 2024 Sep 10. pii: 2024.017. [Epub ahead of print]71
    The linking of toxoplasmosis and schizophrenia.
    Edwin Fuller Torrey.
      Toxoplasmosis is caused by Toxoplasma gondii (Nicolle et Manceaux, 1908), a coccidian protist (Apicomplexa). It has a strong predilection for infecting the central nervous system. Researchers have therefore investigated its association with several neurological and psychiatric disorders, including Alzheimer's disease, attention-deficit hyperactivity disorder, autism, bipolar disorder, cerebral palsy, depression, Guillain-Barre syndrome, multiple sclerosis, obsessive compulsive disorder, Parkinson's disease, personality disorders, and schizophrenia. Among these disorders the strongest evidence for a role of T. gondii exists for psychosis in general and schizophrenia in particular. This paper reviews the origins of this association, briefly summarises the current evidence in support, and discusses future research strategies.
    Keywords:  Cats; brain cysts; epidemiology
    DOI:  https://doi.org/10.14411/fp.2024.016
  8. Cell Signal. 2024 Sep 12. pii: S0898-6568(24)00377-2. [Epub ahead of print]124 111409
    SIRT1-FOXOs signaling pathway: A potential target for attenuating cardiomyopathy.
    Changxu Lu, Can Gao, Jinwen Wei, Dan Dong, Mingli Sun.
      Cardiomyopathy constitutes a global health burden. It refers to myocardial injury that causes alterations in cardiac structure and function, ultimately leading to heart failure. Currently, there is no definitive treatment for cardiomyopathy. This is because existing treatments primarily focus on drug interventions to attenuate symptoms rather than addressing the underlying causes of the disease. Notably, the cardiomyocyte loss is one of the key risk factors for cardiomyopathy. This loss can occur through various mechanisms such as metabolic disturbances, cardiac stress (e.g., oxidative stress), apoptosis as well as cell death resulting from disorders in autophagic flux, etc. Sirtuins (SIRTs) are categorized as class III histone deacetylases, with their enzyme activity primarily reliant on the substrate nicotinamide adenine dinucleotide (NAD (+)). Among them, Sirtuin 1 (SIRT1) is the most intensively studied in the cardiovascular system. Forkhead O transcription factors (FOXOs) are the downstream effectors of SIRT1. Several reports have shown that SIRT1 can form a signaling pathway with FOXOs in myocardial tissue, and this pathway plays a key regulatory role in cell loss. Thus, this review describes the basic mechanism of SIRT1-FOXOs in inhibiting cardiomyocyte loss and its favorable role in cardiomyopathy. Additionally, we summarized the SIRT1-FOXOs related regulation factor and prospects the SIRT1-FOXOs potential clinical application, which provide reference for the development of cardiomyopathy treatment.
    Keywords:  Cardiomyocytes loss; Cardiomyopathy; Deacetylation; Myocardial injury; PTMs; SIRT1-FOXOs
    DOI:  https://doi.org/10.1016/j.cellsig.2024.111409
  9. PLoS Pathog. 2024 Sep;20(9): e1012514
    Understanding the significance of oxygen tension on the biology of Plasmodium falciparum blood stages: From the human body to the laboratory.
    Dinah S Nahid, Kevin A Coffey, Amy K Bei, Regina Joice Cordy.
      Plasmodium falciparum undergoes sequestration within deep tissues of the human body, spanning multiple organ systems with differing oxygen (O2) concentrations. The parasite is exposed to an even greater range of O2 concentrations as it transitions from the human to the mosquito host, suggesting a high level of plasticity as it navigates these different environments. In this review, we explore factors that may contribute to the parasite's response to different environmental O2 concentrations, recognizing that there are likely multiple pieces to this puzzle. We first review O2-sensing mechanisms, which exist in other apicomplexans such as Toxoplasma gondii and consider whether similar systems could exist in Plasmodium. Next, we review morphological and functional changes in P. falciparum's mitochondrion during the asexual-to-sexual stage transition and discuss how these changes overlap with the parasite's access to O2. We then delve into reactive oxygen species (ROS) as ROS production is influenced by O2 availability and oxidative stress impacts Plasmodium intraerythrocytic development. Lastly, given that the primary role of the red blood cell (RBC) is to deliver O2 throughout the body, we discuss how changes in the oxygenation status of hemoglobin, the RBC's O2-carrying protein and key nutrient for Plasmodium, could also potentially impact the parasite's growth during intraerythrocytic development. This review also highlights studies that have investigated P. falciparum biology under varying O2 concentrations and covers technical aspects related to P. falciparum cultivation in the lab, focusing on sources of technical variation that could alter the amount of dissolved O2 encountered by cells during in vitro experiments. Lastly, we discuss how culture systems can better replicate in vivo heterogeneity with respect to O2 gradients, propose ideas for further research in this area, and consider translational implications related to O2 and malaria.
    DOI:  https://doi.org/10.1371/journal.ppat.1012514
  10. bioRxiv. 2024 Sep 02. pii: 2024.09.02.610794. [Epub ahead of print]
    Dynamics of amylopectin granule accumulation during the course of the chronic Toxoplasma infection is linked to intra-cyst bradyzoite replication.
    Aashutosh Tripathi, Ryan W Donkin, Joy S Miracle, Robert D Murphy, Abhijit Patwardhan, Anthony P Sinai.
      The contribution of amylopectin granules (AG), comprised of a branched chain storage homopolymer of glucose, to the maintenance and progression of the chronic Toxoplasma gondii infection has remained undefined. Here we describe the role of AG in the physiology of encysted bradyzoites by using a custom developed imaging-based application AmyloQuant that permitted quantification of relative levels of AG within in vivo derived tissue cysts during the initiation and maturation of the chronic infection. Our findings establish that AG are dynamic entities, exhibiting considerable heterogeneity among tissue cysts at all post infection time points examined. Quantification of relative AG levels within tissue cysts exposes a previously unrecognized temporal cycle defined by distinct phases of AG accumulation and utilization over the first 6 weeks of the chronic phase. This AG cycle is temporally coordinated with overall bradyzoite mitochondrial activity implicating amylopectin in the maintenance and progression of the chronic infection. In addition, the staging of AG accumulation and it rapid utilization within encysted bradyzoites was associated with a burst of coordinated replication. As such our findings suggest that AG levels within individual bradyzoites, and across bradyzoites within tissue cysts may represent a key component in the licensing of bradyzoite replication, intimately linking stored metabolic potential to the course of the chronic infection. This extends the impact of AG beyond the previously assigned role that focused exclusively on parasite transmission. These findings force a fundamental reassessment of the chronic Toxoplasma infection, highlighting the critical need to address the temporal evolution of this crucial stage in the parasite life cycle.
    DOI:  https://doi.org/10.1101/2024.09.02.610794
  11. Commun Biol. 2024 Sep 19. 7(1): 1175
    Variant surface protein GP60 contributes to host infectivity of Cryptosporidium parvum.
    Muxiao Li, Fuxian Yang, Tianyi Hou, Xiaoqing Gong, Na Li, L David Sibley, Yaoyu Feng, Lihua Xiao, Yaqiong Guo.
      Biological studies of the determinants of Cryptosporidium infectivity are lacking despite the fact that cryptosporidiosis is a major public health problem. Recently, the 60-kDa glycoprotein (GP60) has received attention because of its high sequence polymorphism and association with host infectivity of isolates and protection against reinfection. However, studies of GP60 function have been hampered by its heavy O-linked glycosylation. Here, we used advanced genetic tools to investigate the processing, fate, and function of GP60. Endogenous gene tagging showed that the GP60 cleavage products, GP40 and GP15, are both highly expressed on the surface of sporozoites, merozoites and male gametes. During invasion, GP40 translocates to the apical end of the zoites and remains detectable at the parasite-host interface. Deletion of the signal peptide, GPI anchor, and GP15 sequences affects the membrane localization of GP40. Deletion of the GP60 gene significantly reduces parasite growth and severity of infection, and replacement of the GP60 gene with sequence from an avirulent isolate reduces the pathogenicity of a highly infective isolate. These results have revealed dynamic changes in GP60 expression during parasite development. They further suggest that GP60 is a key protein mediating host infectivity and pathogenicity.
    DOI:  https://doi.org/10.1038/s42003-024-06885-0
  12. Int J Environ Health Res. 2024 Sep 17. 1-8
    A new perspective on essential tremor: the potential etiologic role of Toxoplasma gondii and Toxocara spp.
    Tuncay Celik, Erman Altunisik, Turkan Mutlu Yar, Tuba Gul, Yeliz Kasko Arici, Ulku Karaman.
      Our aim was to examine the relationship between Toxoplasma gondii (T. gondii) and Toxocara infection and patients with essential tremor (ET). This study comprised a total of 174 participants, consisting of 99 patients with ET and 75 healthy controls. The presence of anti-T. gondii IgG and anti-Toxocara IgG antibodies was investigated using ELISA. The relationship between the severity of the disease and the seropositivity of T. gondii and Toxocara were examined. The seropositivity rate for anti-T. gondii IgG antibodies among patients and control groups were 43.4% and 12%, respectively (odds ratio [OR]: 5.63; 95% CI: 2.53-12.56). The patient group exhibited a higher seroprevalence of anti-Toxocara IgG antibodies (32.3%) compared with the control group (13.3%; OR: 3.10; 95% CI: 1.41-6.83; p = 0.004). This study suggests that T. gondii and Toxocara infections can contribute to the pathogenic mechanisms underlying ET and could be risk factors for ET.
    Keywords:  Essential tremor; Toxocara spp.; Toxoplasma gondii; enzyme-linked immunosorbent assay (ELISA); neurologic disorder
    DOI:  https://doi.org/10.1080/09603123.2024.2404480
  13. Eur J Med Chem. 2024 Sep 12. pii: S0223-5234(24)00738-4. [Epub ahead of print]279 116857
    Overview of the PRMT6 modulators in cancer treatment: Current progress and emerged opportunity.
    Jinjin Peng, Bin Ni, Deping Li, Binbin Cheng, Renze Yang.
      Protein Arginine Methyltransferase 6 (PRMT6) is a Type I PRMT enzyme that plays a role in the epigenetic regulation of gene expression by methylating histone and non-histone proteins. It is also involved in various cellular processes, including alternative splicing, DNA repair, and cell signaling. Furthermore, PRMT6 exerts multiple effects on cellular processes such as growth, migration, invasion, apoptosis, and drug resistance in various cancers, positioning it as a promising target for anti-tumor therapeutics. In this review, we initially provide an overview of the structure and biological functions of PRMT6, along with its association with cancer. Subsequently, we focus on recent progress in the design and development of modulators targeting PRMT6. This includes a comprehensive review of PRMT6 inhibitors (isoform-selective and non-selective), dual-target inhibitors based on PRMT6, PRMT6 covalent inhibitors, and PRMT6-targeting hydrophobic tagging (HyT) degraders, from the perspectives of rational design, pharmacodynamics, pharmacokinetics, and the clinical status of these modulators. Finally, we also provided the challenges and prospective directions for PRMT6 targeting drug discovery in cancer therapy.
    Keywords:  Challenges; Degraders; Inhibitors; Modulators; Protein arginine methyltransferase 6
    DOI:  https://doi.org/10.1016/j.ejmech.2024.116857
  14. Arch Pharm (Weinheim). 2024 Sep 18. e2400437
    Development of new pyrazoles as class I HDAC inhibitors: Synthesis, molecular modeling, and biological characterization in leukemia cells.
    Francesco Berluti, Fady Baselious, Sven Hagemann, Sebastian Hilscher, Matthias Schmidt, Stefan Hüttelmaier, Mike Schutkowski, Wolfgang Sippl, Hany S Ibrahim.
      Class I histone deacetylases (HDACs) are considered promising targets in current cancer research. To obtain subtype-selective and potent HDAC inhibitors, we used the aminobenzamide scaffold as the zinc-binding group and prepared new derivatives with a pyrazole ring as the linking group. The synthesized compounds were analyzed in vitro using an enzymatic assay against HDAC1, -2, and -3. Compounds 12b, 15b, and 15i were found to be potent HDAC1 inhibitors, also in comparison to the reference compounds entinostat and tacedinaline, with IC50 values of 0.93, 0.22, and 0.68 μM, respectively. The best compounds were measured for their cellular effect and target engagement in acute myeloid leukemia (AML) cells. In addition, we studied the interaction of the compounds with HDAC subtypes using docking and molecular dynamic simulations. In summary, we have developed a new chemotype of HDAC1 inhibitors that can be used for further structure-based optimization.
    Keywords:  aminobenzamide; class I HDAC; molecular docking; pyrazoles; tacedinaline
    DOI:  https://doi.org/10.1002/ardp.202400437
  15. Mol Neurobiol. 2024 Sep 17.
    Is SIRT3 and Mitochondria a Reliable Target for Parkinson's Disease and Aging? A Narrative Review.
    Amarjith Thiyyar Kandy, Jagdish Chand, Mohammad Zubair Baba, Gomathy Subramanian.
      Aging is a complicated degenerative process that has been thoroughly researched in a variety of taxa, including mammals, worms, yeast, and flies. One important controller of organismal lifetime is the conserved deacetylase protein known as silencing information regulator 2 (SIR2). It has been demonstrated that overexpressing SIR2 lengthens the life span in worms, flies, and yeast, demonstrating its function in enhancing longevity. SIRT3 is a member of the sirtuin protein family, identified as a major regulator of longevity and aging. Sirtuin 3 (SIRT3), a possible mitochondrial tumor suppressor, has been explicitly linked to the control of cellular reactive oxygen species (ROS) levels, the Warburg effect, and carcinogenesis. SIRT3 plays a significant part in neurodegenerative illnesses such as Parkinson's and Alzheimer's disease by decreasing the oxidative stress in mitochondria and reducing the ROS levels. Furthermore, SIRT3 has been linked to metabolic and cardiovascular disorders, indicating its wider role in the pathophysiology of disease and possible therapeutic applications.
    Keywords:  Aging; Mitochondria; Neurodegeneration; Parkinson’s disease; ROS; SIRT3
    DOI:  https://doi.org/10.1007/s12035-024-04486-w
  16. Pharmacol Res. 2024 Sep 12. pii: S1043-6618(24)00355-4. [Epub ahead of print]208 107410
    Role of histone deacetylases and their inhibitors in neurological diseases.
    Li-Ying Zhang, Sen-Yu Zhang, Ri Wen, Tie-Ning Zhang, Ni Yang.
      Histone deacetylases (HDACs) are zinc-dependent deacetylases that remove acetyl groups from lysine residues of histones or form protein complexes with other proteins for transcriptional repression, changing chromatin structure tightness, and inhibiting gene expression. Recent in vivo and in vitro studies have amply demonstrated the critical role of HDACs in the cell biology of the nervous system during both physiological and pathological processes and have provided new insights into the conduct of research on neurological disease targets. In addition, in vitro and in vivo studies on HDAC inhibitors show promise for the treatment of various diseases. This review summarizes the regulatory mechanisms of HDAC and the important role of its downstream targets in nervous system diseases, and summarizes the therapeutic mechanisms and efficacy of HDAC inhibitors in various nervous system diseases. Additionally, the current pharmacological situation, problems, and developmental prospects of HDAC inhibitors are described. A better understanding of the pathogenic mechanisms of HDACs in the nervous system may reveal new targets for therapeutic interventions in diseases and help to relieve healthcare pressure through preventive measures.
    Keywords:  4-phenylbutyric acid (PBA) (Pubchem CID:4775); 5-Cinnamic acid (CNA)(Pubchem CID:444539); Alzheimer’s disease; Belinostat (Pubchem CID:6918638); Benzamide(Pubchem CID:2331); Chidamide(Pubchem CID:9800555); Entinostat(Pubchem CID:4261); Givinostat/Duvyzat(Pubchem CID:9804992); Histone deacetylase; Histone deacetylase inhibitors; Huntington’s disease; LMK235(Pubchem CID:71520717); MC1568(Pubchem CID:11381449); Neurological disease; Panobinostat(Pubchem CID:6918837); Panobinostat(Pubchem CID:6918837).; Parkinson’s disease; Romidepsin(Pubchem CID:5352062); Sodium butyrate(Pubchem CID:5222465); Sodium phenylbutyrate(Pubchem CID:5258); Trichostatin A(Pubchem CID:444732); Ursodeoxycholic acid taurine(AMX0035)(Pubchem CID:129316491); Valproic acid(Pubchem CID:3121); Venlafaxine(Pubchem CID:5656); Vorinostat(Pubchem CID:5311)
    DOI:  https://doi.org/10.1016/j.phrs.2024.107410
  17. iScience. 2024 Sep 20. 27(9): 110814
    FYVE1/FREE1 is involved in glutamine-responsive TORC1 activation in plants.
    Mirai Tanigawa, Tatsuya Maeda, Erika Isono.
      Target of rapamycin complex 1 (TORC1) integrates nutrient availability, growth factors, and stress signals to regulate cellular metabolism according to its environment. Similar to mammals, amino acids have been shown to activate TORC1 in plants. However, as the Rag complex that controls amino acid-responsive TORC1 activation mechanisms in many eukaryotes is not conserved in plants, the amino acid-sensing mechanisms upstream of TORC1 in plants remain unknown. In this study, we report that Arabidopsis FYVE1/FREE1 is involved in glutamine-induced TORC1 activation, independent of its previously reported function in ESCRT-dependent processes. FYVE1/FREE1 has a domain structure similar to that of the yeast glutamine sensor Pib2 that directly activates TORC1. Similar to Pib2, FYVE1/FREE1 interacts with TORC1 in response to glutamine. Furthermore, overexpression of a FYVE1/FREE1 variant lacking the presumptive TORC1 activation motif hindered the glutamine-responsive activation of TORC1. Overall, these observations suggest that FYVE1/FREE1 acts as an intracellular amino acid sensor that triggers TORC1 activation in plants.
    Keywords:  Biological sciences; Molecular biology; Plant biology;
    DOI:  https://doi.org/10.1016/j.isci.2024.110814
  18. Methods Mol Biol. 2025 ;2856 445-453
    Exploring Cohesin-Related Multiomics Information in the Web Browser.
    Jiankang Wang.
      Cohesin is a protein complex that plays a key role in regulating chromosome structure and gene expression. While next-generation sequencing technologies have provided extensive information on various aspects of cohesin, integrating and exploring the vast datasets associated with cohesin are not straightforward. CohesinDB ( https://cohesindb.iqb.u-tokyo.ac.jp ) offers a web-based interface for browsing, searching, analyzing, visualizing, and downloading comprehensive multiomics cohesin information in human cells. In this protocol, we introduce how to utilize CohesinDB to facilitate research on transcriptional regulation and chromatin organization.
    Keywords:  Chromatin structure; Cohesin; Database; Multiomics; Transcriptional regulation
    DOI:  https://doi.org/10.1007/978-1-0716-4136-1_26
  19. Parasit Vectors. 2024 Sep 14. 17(1): 392
    Identification and function characterization of NcAP2XII-4 in Neospora caninum.
    Huizhu Nan, Xin Lu, Chao Zhang, Xin Yang, Zhu Ying, Lei Ma.
       BACKGROUND: Neospora caninum is a protozoan parasite in the Apicomplexa controlled by complex signaling pathways. Transcriptional control, an important way to regulate gene expression, has been almost absent in the N. caninum life process. However, to date, research on the transcriptional regulation of the AP2 family factors in N. caninum has been extremely limited. A prior study demonstrated that removing rhoptry protein 5 (ROP5), a significant virulence factor, resulted in abnormal expression levels of predicted NcAP2XII-4 in N. caninum, suggesting that the factor may regulate the function of ROP5. This study aimed to identify NcAP2XII-4 and its function in transcriptional regulation.
    METHODS: The NcAP2XII-4 gene was identified by analyzing the N. caninum genome. A polyclonal antibody against the protein was prepared and purified, and its expression and localization in the parasite were detected using western blot (WB) and immunofluorescence assay (IFA). The ΔNcAP2XII-4 strain was constructed from the Nc1 strain using CRISPR/Cas9 to study its effect on the growth and development of N. caninum, and DAP-Seq and electrophoretic mobility shift assay (EMSA) were used to verify the transcriptional regulatory functions of the gene.
    RESULTS: Bioinformatic analysis showed that NcAP2XII-4 consists of 11,976 bp and encodes 3991 amino acids, with a predicted molecular mass of 410 kDa. The protein has two AP2 domains, 1207aa-1251aa and 3453aa-3500aa, and is predicted to be located in the nucleus. The results of PCR, WB, and IFA were in accordance with the bioinformatics analysis. ΔNcAP2XII-4 was successfully constructed, but the strain could not be released and ultimately succumbed within parasitophorous vacuoles (PVs). Plaque assays demonstrated that parasites lacking this gene could not form plaques. One motif was successfully identified using DAP-Seq technique. Two prokaryotic expression vectors containing the AP2 domain of NcAP2XII-4 were successfully constructed, and two prokaryotic expression proteins, AP2-D1 and AP2-D2, and ROP5 biotinylated probes were prepared. Using EMSA, NcAP2XII-4 was shown to regulate ROP5 transcription by binding to its promoter.
    CONCLUSIONS: NcAP2XII-4 is an essential gene in N. caninum. This study provides a foundation for further research on transcriptional regulation in N. caninum and identifies a new candidate factor for the development of vaccines against N. caninum.
    Keywords:  DAP-Seq; NcAP2XII-4; Neospora caninum; Transcription factor
    DOI:  https://doi.org/10.1186/s13071-024-06477-1
  20. Clin Oral Investig. 2024 Sep 14. 28(10): 526
    Occlusal disharmony promotes anxiety-like behaviours by suppressing Sirt1.
    Ling Wu, Sihui Zhang, Mi Zhang, Yanjing Ou, Jiang Chen.
       BACKGROUND: Previous studies have indicated that occlusal disharmony (OD) can promote anxiety-like behaviours. However, the specific molecules involved in the development of anxiety-like behaviours and their underlying mechanisms remain unknown.
    METHODS: OD was produced by anterior crossbite of female mice. We measured the anxiety levels of mice in each group and screened the hippocampal mRNA expression profiles of mice in the control group and OD group. The role of target mRNA in OD-induced anxiety-like behaviours was evaluated and we preliminarily explored the possible downstream pathways.
    RESULTS: The results suggested that OD can induce and promote anxiety-like behaviours with/without chronic unpredictable mild stress. We found that Sirt1 was significantly downregulated within the hippocampus in OD mice. In addition, the downregulation of Sirt1 within the hippocampus in OD and control mice promoted anxiety-like behaviours, increased acetylated histone H3 expression and decreased Dnah12 transcription levels. In contrast, in OD mice subjected to an injection of resveratrol, there was a remission of anxiety-like behaviours and an upregulation of Sirt1 in the hippocampus, the effects of which were accompanied by decreased acetylated histone H3 expression and increased Dnah12 transcription levels.
    CONCLUSIONS: OD leads to increased sensitivity to chronic stress in mice, resulting in anxiety-like behaviours. During this process, Sirt1 acts as an effective factor in the regulation of OD-induced anxiety-like behaviours.
    CLINICAL RELEVANCE: OD, as a stressor, could induce anxiety-like behaviours. It investigates the impact of OD (a stressor) on the molecular genetic of the pathophysiology of major neuropsychiatric disorders.
    Keywords:  Acetylated histone H3; Anxiety-like behaviour; Chronic stress; Occlusal disharmony; Sirt1
    DOI:  https://doi.org/10.1007/s00784-024-05918-6
  21. Signal Transduct Target Ther. 2024 Sep 16. 9(1): 232
    Crossing epigenetic frontiers: the intersection of novel histone modifications and diseases.
    Weiyi Yao, Xinting Hu, Xin Wang.
      Histone post-translational modifications (HPTMs), as one of the core mechanisms of epigenetic regulation, are garnering increasing attention due to their close association with the onset and progression of diseases and their potential as targeted therapeutic agents. Advances in high-throughput molecular tools and the abundance of bioinformatics data have led to the discovery of novel HPTMs which similarly affect gene expression, metabolism, and chromatin structure. Furthermore, a growing body of research has demonstrated that novel histone modifications also play crucial roles in the development and progression of various diseases, including various cancers, cardiovascular diseases, infectious diseases, psychiatric disorders, and reproductive system diseases. This review defines nine novel histone modifications: lactylation, citrullination, crotonylation, succinylation, SUMOylation, propionylation, butyrylation, 2-hydroxyisobutyrylation, and 2-hydroxybutyrylation. It comprehensively introduces the modification processes of these nine novel HPTMs, their roles in transcription, replication, DNA repair and recombination, metabolism, and chromatin structure, as well as their involvement in promoting the occurrence and development of various diseases and their clinical applications as therapeutic targets and potential biomarkers. Moreover, this review provides a detailed overview of novel HPTM inhibitors targeting various targets and their emerging strategies in the treatment of multiple diseases while offering insights into their future development prospects and challenges. Additionally, we briefly introduce novel epigenetic research techniques and their applications in the field of novel HPTM research.
    DOI:  https://doi.org/10.1038/s41392-024-01918-w
  22. Neurobiol Dis. 2024 Sep 13. pii: S0969-9961(24)00264-X. [Epub ahead of print]201 106664
    Suppression of neuronal AMPKβ2 isoform impairs recognition memory and synaptic plasticity.
    Nathaniel A Swift, Qian Yang, Hannah M Jester, Xueyan Zhou, Adam Manuel, Bruce E Kemp, Gregory R Steinberg, Tao Ma.
      AMP-activated protein kinase (AMPK) is an αβγ heterotrimer protein kinase that functions as a molecular sensor to maintain energy homeostasis. Accumulating evidence suggests a role of AMPK signaling in the regulation of synaptic plasticity and cognitive function; however, isoform-specific roles of AMPK in the central nervous system (CNS) remain elusive. Regulation of the AMPK activities has focused on the manipulation of the α or γ subunit. Meanwhile, accumulating evidence indicates that the β subunit is critical for sensing nutrients such as fatty acids and glycogen to control AMPK activity. Here, we generated transgenic mice with conditional suppression of either AMPKβ1 or β2 in neurons and characterized potential isoform-specific roles of AMPKβ in cognitive function and underlying mechanisms. We found that AMPKβ2 (but not β1) suppression resulted in impaired recognition memory, reduced hippocampal synaptic plasticity, and altered structure of hippocampal postsynaptic densities and dendritic spines. Our study implicates a role for the AMPKβ2 isoform in the regulation of synaptic and cognitive function.
    Keywords:  AMPK; Isoform; LTP; Memory; Mouse model; Synaptic plasticity
    DOI:  https://doi.org/10.1016/j.nbd.2024.106664
  23. Sci Rep. 2024 09 16. 14(1): 21598
    Dynamics and necessity of SIRT1 for maternal-zygotic transition.
    Jan Nevoral, David Drutovic, Michaela Vaskovicova, Michal Benc, Frantisek Liska, Iveta Valentova, Sara Stachovicova, Jan Kubovciak, Jirina Havrankova, Miki Shavit, Ladan Monsef, Maria Iniesta-Cuerda, Tereza Zalmanova, Petr Hosek, Frantisek Strejcek, Milena Kralickova, Jaroslav Petr.
      Dynamic changes in maternal‒zygotic transition (MZT) require complex regulation of zygote formation, maternal transcript decay, embryonic genome activation (EGA), and cell cycle progression. Although these changes are well described, some key regulatory factors are still elusive. Sirtuin-1 (SIRT1), an NAD+-dependent histone deacetylase, is a versatile driver of MZT via its epigenetic and nonepigenetic substrates. This study focused on the dynamics of SIRT1 in early embryos and its contribution to MZT. A conditional SIRT1-deficient knockout mouse model was used, accompanied by porcine and human embryos. Embryos across mammalian species showed the prominent localization of SIRT1 in the nucleus throughout early embryonic development. Accordingly, SIRT1 interacts with histone H4 on lysine K16 (H4K16) in both mouse and human blastocysts. While maternal SIRT1 is dispensable for MZT, at least one allele of embryonic Sirt1 is required for early embryonic development around the time of EGA. This role of SIRT1 is surprisingly mediated via a transcription-independent mode of action.
    Keywords:  Embryo; Embryonic genome activation; Epigenetics; Histone deacetylase; Oocyte, zygote
    DOI:  https://doi.org/10.1038/s41598-024-72595-6
  24. Appl Microbiol Biotechnol. 2024 Sep 18. 108(1): 467
    A novel dual-epigenetic inhibitor enhances recombinant monoclonal antibody expression in CHO cells.
    Ming-Ming Han, Hai-Tong Wang, Hui-Jie Zhang, Jiang-Tao Lu, Jia-Liang Guo, Le-Le Qiu, Xi Zhang, Xiao-Yin Wang, Tian-Yun Wang, Yan-Long Jia.
      Epigenetic regulation plays a central role in the regulation of a number of cellular processes such as proliferation, differentiation, cell cycle, and apoptosis. In particular, small molecule epigenetic modulators are key elements that can effectively influence gene expression by precisely regulating the epigenetic state of cells. To identify useful small-molecule regulators that enhance the expression of recombinant proteins in Chinese hamster ovary (CHO) cells, we examined a novel dual-HDAC/LSD1 inhibitor I-4 as a supplement for recombinant CHO cells. Treatment with 2 μM I-4 was most effective in increasing monoclonal antibody production. Despite cell cycle arrest at the G1/G0 phase, which inhibits cell growth, the addition of the inhibitor at 2 µM to monoclonal antibody-expressing CHO cell cultures resulted in a 1.94-fold increase in the maximal monoclonal antibody titer and a 2.43-fold increase in specific monoclonal antibody production. In addition, I-4 significantly increased the messenger RNA levels of the monoclonal antibody and histone H3 acetylation and methylation levels. We also investigated the effect on HDAC-related isoforms and found that interference with the HDAC5 gene increased the monoclonal antibody titer by 1.64-fold. The results of this work provide an effective method of using epigenetic regulatory strategies to enhance the expression of recombinant proteins in CHO cells. KEY POINTS: • HDAC/LSD1 dual-target small molecule inhibitor can increase the expression level of recombinant monoclonal antibodies in CHO cells. • By affecting the acetylation and methylation levels of histones in CHO cells and downregulating HDAC5, the production of recombinant monoclonal antibodies increased. • It provides an effective pathway for applying epigenetic regulation strategies to enhance the expression of recombinant proteins.
    Keywords:  Acetylation modification; CHO cells; Epigenetic regulation; Recombinant protein expression; Small molecule additives
    DOI:  https://doi.org/10.1007/s00253-024-13302-3
  25. Database (Oxford). 2024 Sep 19. pii: baae088. [Epub ahead of print]2024
    Autophagy3D: a comprehensive autophagy structure database.
    Neha, Jesu Castin, Saman Fatihi, Deepanshi Gahlot, Akanksha Arun, Lipi Thukral.
      Autophagy pathway plays a central role in cellular degradation. The proteins involved in the core autophagy process are mostly localised on membranes or interact indirectly with lipid-associated proteins. Therefore, progress in structure determination of 'core autophagy proteins' remained relatively limited. Recent paradigm shift in structural biology that includes cutting-edge cryo-EM technology and robust AI-based Alphafold2 predicted models has significantly increased data points in biology. Here, we developed Autophagy3D, a web-based resource that provides an efficient way to access data associated with 40 core human autophagic proteins (80322 structures), their protein-protein interactors and ortholog structures from various species. Autophagy3D also offers detailed visualizations of protein structures, and, hence deriving direct biological insights. The database significantly enhances access to information as full datasets are available for download. The Autophagy3D can be publicly accessed via https://autophagy3d.igib.res.in. Database URL: https://autophagy3d.igib.res.in.
    DOI:  https://doi.org/10.1093/database/baae088
  26. Cell Biochem Biophys. 2024 Sep 16.
    hsa_circ_0072309 Inhibits Oncogenesis in Hepatocellular Carcinoma by Epigenetic Activation of its Host Gene.
    Tao Wang, Yanan Du, Haiyang Song, Jiewei Sun, Wenjin Jiang, Zhiying Xu.
      Recently, numerous studies have revealed the participation of circular RNAs (circRNAs) in cancer progression. Likewise, this research focused on circRNAs in hepatocellular carcinoma (HCC). A lowly expressed circRNA hsa_circ_0072309 in HCC was screened by analyzing the circRNA microarray GSE242797 and GSE216115 and identified in clinical specimens and cells. Subsequently, CCK-8, colony formation, and transwell assays were performed. The results revealed that hsa_circ_0072309 overexpression suppressed HCC cell proliferation, migration, invasion, and sorafenib resistance, whereas its suppression showed opposite results. Mechanistic investigation found an interaction between hsa_circ_0072309 and its host gene leukemia inhibitory factor receptor (LIFR) in HCC. We found that LIFR overexpression promoted the hsa_circ_0072309 formation. In turn, hsa_circ_0072309 recruited the E1A binding protein p300 to promote the enrichment of H3K27 acetylation (H3K27ac) in the LIFR enhancer, thus transcriptionally promoting LIFR expression. To conclude, we revealed a hsa_circ_0072309/LIFR regulatory loop in HCC, which may provide a potential target for HCC treatment.
    Keywords:  LIFR; hepatocellular carcinoma; histone acetylation; hsa_circ_007230
    DOI:  https://doi.org/10.1007/s12013-024-01330-9
  27. Comput Struct Biotechnol J. 2024 Dec;23 3258-3269
    Structural insight into the function of human peptidyl arginine deiminase 6.
    Jack P C Williams, Stephane Mouilleron, Rolando Hernandez Trapero, M Teresa Bertran, Joseph A Marsh, Louise J Walport.
      Peptidyl arginine deiminase 6 (PADI6 or PAD6) is vital for early embryonic development in mice and humans, yet its function remains elusive. PADI6 is less conserved than other PADIs and it is currently unknown whether it has a catalytic function. Here we show that human PADI6 dimerises like hPADIs 2-4, however, does not bind Ca2+ and is inactive in in vitro assays against standard PADI substrates. By determining the crystal structure of hPADI6, we show that hPADI6 is structured in the absence of Ca2+ where hPADI2 and hPADI4 are not, and the Ca-binding sites are not conserved. Moreover, we show that whilst the key catalytic aspartic acid and histidine residues are structurally conserved, the cysteine is displaced far from the active site centre and the hPADI6 active site pocket appears closed through a unique evolved mechanism in hPADI6, not present in the other PADIs. Taken together, these findings provide insight into how the function of hPADI6 may differ from the other PADIs based on its structure and provides a resource for characterising the damaging effect of clinically significant PADI6 variants.
    Keywords:  Citrullination; Infertility; Peptidyl arginine deiminase; Protein folding; Protein mutation damage prediction; X-Ray crystallography
    DOI:  https://doi.org/10.1016/j.csbj.2024.08.019
  28. Sci Adv. 2024 Sep 20. 10(38): eadr5357
    Coenzymes in a pre-enzymatic metabolism.
    Quentin Dherbassy, Robert J Mayer, Joseph Moran.
      Experiments now support theoretical suggestions that coenzymes mediated key metabolic reactions before the emergence of enzymes. Three coenzymes believed essential to the core metabolism of the last universal common ancestor to extant life (pyridoxal phosphate, adenosine diphosphate, and nicotinamide adenine dinucleotide) were recently found to be active in their corresponding metabolic reactions in the absence of enzymes. These findings suggest an earlier contribution of coenzymes to abiogenesis, ultimately yielding insights into the prebiotic origins of metabolism.
    DOI:  https://doi.org/10.1126/sciadv.adr5357
  29. Nucleus. 2024 Dec;15(1): 2398450
    Multifaceted roles of SUMO in DNA metabolism.
    Yee Mon Thu.
      Sumoylation, a process in which SUMO (small ubiquitin like modifier) is conjugated to target proteins, emerges as a post-translational modification that mediates protein-protein interactions, protein complex assembly, and localization of target proteins. The coordinated actions of SUMO ligases, proteases, and SUMO-targeted ubiquitin ligases determine the net result of sumoylation. It is well established that sumoylation can somewhat promiscuously target proteins in groups as well as selectively target individual proteins. Through changing protein dynamics, sumoylation orchestrates multi-step processes in chromatin biology. Sumoylation influences various steps of mitosis, DNA replication, DNA damage repair, and pathways protecting chromosome integrity. This review highlights examples of SUMO-regulated nuclear processes to provide mechanistic views of sumoylation in DNA metabolism.
    Keywords:  Chromatin regulation; DNA damage; SUMO; genome instability; post-translational modification
    DOI:  https://doi.org/10.1080/19491034.2024.2398450
  30. Curr Opin Insect Sci. 2024 Sep 16. pii: S2214-5745(24)00112-3. [Epub ahead of print] 101270
    Insects and microbes: best friends from the nursery.
    Estelle Chabanol, Mathilde Gendrin.
      Insects host microbes and interact with them throughout their life cycle. This microbiota is an important, if not essential partner, participating in many aspects of insect physiology. Recent omics studies have contributed to considerable advances in the current understanding of the molecular implications of microbiota during insect development. In this review, we present an overview of the current knowledge about the mechanisms underlying interactions between developing insects and their microbial companions. The microbiota is implicated in nutrition, both via compensating for metabolic pathways lacking in the host and via regulating host metabolism. Furthermore, the microbiota plays a protective role, enhancing the insect's tolerance to, or resistance against, various environmental stresses.
    DOI:  https://doi.org/10.1016/j.cois.2024.101270
  31. Front Endocrinol (Lausanne). 2024 ;15 1454874
    Emerging roles of lipid and metabolic sensing in the neuroendocrine control of body weight and reproduction.
    Elvira Rodríguez-Vázquez, Álvaro Aranda-Torrecillas, María López-Sancho, Juan M Castellano, Manuel Tena-Sempere.
      The hypothalamus lies at the intersection of brain and hormonal mechanisms governing essential bodily functions, including metabolic/body weight homeostasis and reproduction. While metabolism and fertility are precisely regulated by independent neuroendocrine axes, these are tightly connected, as reflection of the bidirectional interplay between the energy status of the organisms and their capacity to reproduce; a connection with important pathophysiological implications in disorders affecting these two crucial systems. Beyond the well-characterized roles of key hormones (e.g., leptin, insulin, ghrelin) and neuropeptides (e.g., melanocortins, kisspeptins) in the integral control of metabolism and reproduction, mounting evidence has pointed out a relevant function of cell energy sensors and lipid sensing mechanisms in the hypothalamic control of metabolism, with prominent roles also for metabolic sensors, such as mTOR, AMPK and SIRT1, in the nutritional regulation of key aspects of reproduction, such as pubertal maturation. We provide herein a synoptic overview of these novel regulatory pathways, with a particular focus on their putative function in the metabolic control of puberty, and delineate new avenues for further exploration of the intricate mechanisms whereby metabolism and reproduction are tightly connected.
    Keywords:  AMPK; Kiss1; ceramides; fatty acids; lipid sensing; mTOR; reproduction; sirtuins
    DOI:  https://doi.org/10.3389/fendo.2024.1454874
  32. Plant Cell Physiol. 2024 Sep 13. pii: pcae106. [Epub ahead of print]
    Dominant-negative KAI2d paralogs putatively attenuate strigolactone responses in root parasitic plants.
    Alexandra R F White, Annalise Kane, Satoshi Ogawa, Ken Shirasu, David C Nelson.
      Many root parasitic plants in the Orobanchaceae use host-derived strigolactones as germination cues. This adaptation facilitates attachment to a host and is particularly important for the success of obligate parasitic weeds that cause substantial crop losses globally. Parasite seeds sense strigolactones through "divergent" KARRIKIN INSENSITIVE2 (KAI2d)/HYPOSENSITIVE TO LIGHT (HTL) α/β-hydrolases that have undergone substantial duplication and diversification in Orobanchaceae genomes. After germination, chemotropic growth of parasite roots toward a strigolactone source also occurs in some species. We investigated which of the seven KAI2d genes found in a facultative hemiparasite, Phtheirospermum japonicum, may enable chemotropic responses to strigolactones. To do so, we developed a triple mutant Nbd14a,b kai2i line of Nicotiana benthamiana in which strigolactone-induced degradation of SMAX1, an immediate downstream target of KAI2 signaling, is disrupted. In combination with a transiently expressed, ratiometric reporter of SMAX1 protein abundance, this mutant forms a system for the functional analysis of parasite KAI2d proteins in a plant cellular context. Using this system, we unexpectedly found three PjKAI2d proteins that do not trigger SMAX1 degradation in the presence of strigolactones. Instead, these PjKAI2d inhibit the perception of low strigolactone concentrations by strigolactone-responsive PjKAI2d in a dominant-negative manner that depends upon an active catalytic triad. Similar dominant-negative KAI2d paralogs were identified in an obligate hemiparasitic weed, Striga hermonthica. These proteins suggest a mechanism for attenuating strigolactone signaling in parasites, which might be used to enhance the perception of shallow strigolactone gradients during root growth toward a host or to restrict germination responses to specific strigolactones.
    Keywords:   Nicotiana benthamiana ; chemotropism; feedback inhibition; parasitism; signaling
    DOI:  https://doi.org/10.1093/pcp/pcae106
  33. Cancer Biol Ther. 2024 Dec 31. 25(1): 2402588
    EX527, a sirtuins 1 inhibitor, sensitizes T-cell leukemia to death receptor-mediated apoptosis by downregulating cellular FLICE inhibitory protein.
    Rongqi Guo, Yihui Wei, Yating Du, Luyue Liu, Haoqi Zhang, Ruiying Ren, Ruili Sun, Tingting Zhang, Xiwen Xiong, Lijun Zhao, Hongfei Wang, Xiaofang Guo, Xiaofei Zhu.
      Death receptor-mediated extrinsic apoptosis system had been developed as a promising therapeutic strategy in clinical oncology, such as TRAIL therapy. However, multiple studies have demonstrated that TRAIL resistance is the biggest problem for disappointing clinical trials despite preclinical success. Targeting cellular FLICE inhibitory protein (cFLIP) is one strategy of combinatorial therapies to overcome resistance to DR-mediated apoptosis due to its negative regulator of extrinsic apoptosis. E × 527 (Selisistat) is a specific inhibitor of SIRT1 activity with safe and well tolerance in clinical trials. Here, we show that E × 527 could strengthen significantly activation of rhFasL-mediated apoptotic signaling pathway and increased apoptotic rate of T leukemia cells with high expression of cFLIP. Mechanically, Inhibition of SIRT1 by E × 527 increased polyubiquitination level of cFLIP via increasing acetylation of Ku70, which could promote proteosomal degradation of cFLIP protein. It implied that combinatorial therapies of E × 527 plus TRAIL may have a potential as a novel clinical application for TRAIL-resistant hematologic malignancies.
    Keywords:  EX527; T leukemia; apoptosis; cellular flice-inhibitory protein; sirtuins 1
    DOI:  https://doi.org/10.1080/15384047.2024.2402588
  34. Autophagy. 2024 Sep 18.
    The interplay between probiotics and host autophagy: mechanisms of action and emerging insights.
    Zahra Sadeghloo, Ali Nabavi-Rad, Mohammad Reza Zali, Daniel J Klionsky, Abbas Yadegar.
      Autophagy, a lysosome-dependent protein degradation mechanism, is a highly conserved catabolic process seen in all eukaryotes. This cell protection system, which is present in all tissues and functions at a basic level, can be up- or downregulated in response to various stresses. A disruption in the natural route of the autophagy process is frequently followed by an interruption in the inherent operation of the body's cells and organs. Probiotics are live bacteria that protect the host through various mechanisms. One of the processes through which probiotics exert their beneficial effects on various cells and tissues is autophagy. Autophagy can assist in maintaining host homeostasis by stimulating the immune system and affecting numerous physiological and pathological responses. In this review, we particularly focus on autophagy impairments occurring in several human illnesses and investigate how probiotics affect the autophagy process under various circumstances.
    Keywords:  Autophagy; cancer; infectious diseases; neurological diseases; obesity; postbiotics; prebiotics; probiotics
    DOI:  https://doi.org/10.1080/15548627.2024.2403277
  35. Hortic Res. 2024 Sep;11(9): uhae204
    Is ATP a signaling regulator for postharvest chilling tolerance in fruits?
    Hansika Sati, Harinder Singh Oberoi, Sunil Pareek.
      Low-temperature storage is used to extend the shelf life of fruits, but prolonged storage at temperatures below tolerable levels may cause postharvest chilling injury (PCI) in sensitive commodities. This review aims to highlight adenosine triphosphate (ATP) activation and the interplay of extracellular ATP (eATP) and intracellular ATP (iATP) in fruits and to find out its significance in mitigating PCI. Various pathways, such as the Embden-Meyerhof-Parnas pathway, the tricarboxylic acid cycle, the pentose phosphate pathway, the γ-aminobutyric acid shunt pathway, and the cytochrome pathway, are studied critically to elucidate their role in continuous ATP supply and maintaining the membrane fluidity and integrity. This review summarizes the treatments helpful in modulating energy metabolism in fruit. Additionally, this work provides insights into the energy status in attenuating chilling tolerance. Moreover, it states the potential of nicotinamide adenine dinucleotide in mitigating PCI. Furthermore, it discusses the role of eATP and its receptor DORN1 in mitigating chilling stress.
    DOI:  https://doi.org/10.1093/hr/uhae204
  36. Expert Opin Ther Pat. 2024 Sep 20. 1-10
    Pyruvate kinase modulators as a therapy target: an updated patent review 2018-2023.
    Sevki Adem, Azhar Rasul, Saba Riaz, Ayesha Sadiqa, Matloob Ahmad, Muhammad Shahid Nazir, Mudassir Hassan.
       INTRODUCTION: Cancer cells adopt a glycolytic phenotype to fulfill their energy needs in unfavorable conditions. In metabolic rewiring, cancer cells upregulate the expression of glycolytic pathway regulators including glucose transporter 1, hexokinase 2, and PKM2 (pyruvate kinase) into its M2 splice form. Among these regulators, PKM2 plays a major role in metabolic reprogramming and is overexpressed in various diseases, including cancer. Dimerization of PKM2 causes the generation of synthetic precursors from glycolytic intermediates, which are essential for cellular growth and cancer cell proliferation.
    COVERED AREAS: This article is focused on examining recent patents (2018-2023) on PKM2 activators, inhibitors and their biological and synthesis properties by using the advanced search service of the European Patent Office (EPO). Moreover, other databases including PubMed, Google Scholar and Elsevier were also examined for scientific data. On basis of their chemical structures, PKM2 activators and inhibitors are classified into pyrazole, pyrolidine-pyrazole, phenol, benzoxazine, isoselenazolo-pyridinium, phthalazine, and propiolylamide derivatives.
    EXPERT OPINION: Activating PKM2 reduces proliferation and development of cells by reducing the quantity of biomolecules needed for cell formation. PKM2 activators and inhibitors are highly effective in treating many cancer pathogens. It is important to find new, more potent and selective molecules for PKM2 activation and inhibition.
    Keywords:  PKM2; activator; cancer; inhibitors; modulators; phenol; phthalazine; pyrazole
    DOI:  https://doi.org/10.1080/13543776.2024.2403616
  37. Chembiochem. 2024 Sep 18. e202400566
    Untangling the complexity and impact of tau protein ubiquitination.
    Daniele Trivellato, Francesca Munari, Michael Assfalg, Stefano Capaldi, Mariapina D'Onofrio.
      The microtubule-associated protein tau is an intrinsically disordered protein highly expressed in neuronal axons. In healthy neurons, tau regulates microtubule dynamics and neurite outgrowth. However, pathological conditions can trigger aberrant tau aggregation into insoluble filaments, a hallmark of neurodegenerative disorders known as tauopathies. Tau undergoes diverse posttranslational modifications (PTMs), suggesting complex regulation and potentially varied functions. Among PTMs, the role and mechanisms of ubiquitination in physiology and disease have remained enigmatic. The past three decades have witnessed the emergence of key studies on tau protein ubiquitination. In this concept, we discuss how these investigations have begun to shed light on the ubiquitination patterns of physiological and pathological tau, the responsible enzymatic machinery, and the influence of ubiquitination on tau aggregation. We also provide an overview of the semi-synthetic methods that have enabled in vitro investigations of conformational transitions of tau induced by ubiquitin modification. Finally, we discuss future perspectives in the field necessary to elucidate the molecular mechanisms of tau ubiquitination and clearance.
    Keywords:  Fibrils; Neurodegeneration; Post-translational modifications; Tau protein; Ubiquitination
    DOI:  https://doi.org/10.1002/cbic.202400566
  38. Cold Spring Harb Perspect Med. 2024 Sep 16. pii: a041553. [Epub ahead of print]
    Technologies for Decoding Cancer Metabolism with Spatial Resolution.
    Walter W Chen, Michael E Pacold, David M Sabatini, Naama Kanarek.
      It is increasingly appreciated that cancer cells adapt their metabolic pathways to support rapid growth and proliferation as well as survival, often even under the poor nutrient conditions that characterize some tumors. Cancer cells can also rewire their metabolism to circumvent chemotherapeutics that inhibit core metabolic pathways, such as nucleotide synthesis. A critical approach to the study of cancer metabolism is metabolite profiling (metabolomics), the set of technologies, usually based on mass spectrometry, that allow for the detection and quantification of metabolites in cancer cells and their environments. Metabolomics is a burgeoning field, driven by technological innovations in mass spectrometers, as well as novel approaches to isolate cells, subcellular compartments, and rare fluids, such as the interstitial fluid of tumors. Here, we discuss three emerging metabolomic technologies: spatial metabolomics, single-cell metabolomics, and organellar metabolomics. The use of these technologies along with more established profiling methods, like single-cell transcriptomics and proteomics, is likely to underlie new discoveries and questions in cancer research.
    DOI:  https://doi.org/10.1101/cshperspect.a041553
  39. Protein Sci. 2024 Oct;33(10): e5175
    Molecular mechanics studies of factors affecting overall rate in cascade reactions: Multi-enzyme colocalization and environment.
    Shivansh Kaushik, Ta I Hung, Chia-En A Chang.
      Millions of years of evolution have optimized many biosynthetic pathways by use of multi-step catalysis. In addition, multi-step metabolic pathways are commonly found in and on membrane-bound organelles in eukaryotic biochemistry. The fundamental mechanisms that facilitate these reaction processes provide strategies to bioengineer metabolic pathways in synthetic chemistry. Using Brownian dynamics simulations, here we modeled intermediate substrate transportation of colocalized yeast-ester biosynthesis enzymes on the membrane. The substrate acetate ion traveled from the pocket of aldehyde dehydrogenase to its target enzyme acetyl-CoA synthetase, then the substrate acetyl CoA diffused from Acs1 to the active site of the next enzyme, alcohol-O-acetyltransferase. Arranging two enzymes with the smallest inter-enzyme distance of 60 Å had the fastest average substrate association time as compared with anchoring enzymes with larger inter-enzyme distances. When the off-target side reactions were turned on, most substrates were lost, which suggests that native localization is necessary for efficient final product synthesis. We also evaluated the effects of intermolecular interactions, local substrate concentrations, and membrane environment to bring mechanistic insights into the colocalization pathways. The computation work demonstrates that creating spatially organized multi-enzymes on membranes can be an effective strategy to increase final product synthesis in bioengineering systems.
    Keywords:  GeomBD3; enzyme‐substrate binding; molecular modeling; molecular recognition; multienzyme nanostructures; substrate channeling
    DOI:  https://doi.org/10.1002/pro.5175
  40. Plant Physiol. 2024 Sep 17. pii: kiae492. [Epub ahead of print]
    Lysine acetylation regulates the subcellular localization and function of WRKY63.
    Yuan-Hsin Shih, Fu-Yu Hung, Pei-Yu Lin, Jian-Sheng Chen, Yi-Sheng Cheng, Songguang Yang, Keqiang Wu.
      
    DOI:  https://doi.org/10.1093/plphys/kiae492
  41. Biol Rev Camb Philos Soc. 2024 Sep 16.
    Unlocking the multifaceted molecular functions and diverse disease implications of lactylation.
    Fengyang Jing, Jianyun Zhang, Heyu Zhang, Tiejun Li.
      In recent years, a significant breakthrough has emerged in biology, the identification of lactylation, a novel post-translational process. This intriguing modification is not limited to a specific class of proteins but occurs across a diverse range, including histones, signalling molecules, enzymes, and substrates. It can exert a broad regulatory role in various diseases, ranging from developmental anomalies and neurodegenerative disorders to inflammation and cancer. Thus, it presents exciting opportunities for exploring innovative treatment approaches. As a result, there has been a recent surge of research interest, leading to a deeper understanding of the molecular mechanisms and regulatory functions underlying lactylation within physiological and pathological processes. Here, we review the detection and molecular mechanisms of lactylation, from biological functions to disease effects, providing a systematic overview of the mechanisms and functions of this post-translational modification.
    Keywords:  cellular metabolism; epigenetics; lactylation modification; molecular mechanism; targeted therapy
    DOI:  https://doi.org/10.1111/brv.13135
  42. Theriogenology. 2024 Sep 14. pii: S0093-691X(24)00379-0. [Epub ahead of print]230 130-141
    Sirtuin 1-mediated autophagy regulates testosterone synthesis in Leydig cells of piglets.
    Yanyan Zhang, Lingyun Yu, Yijing He, Chengyin Liu, Mahmoud M Abouelfetouh, Shiqiang Ju, Zhenlei Zhou, Qiao Li.
      Testosterone is secreted by Leydig cells (LCs), which play an important physiological role in preserving male secondary sex characteristics, protecting male reproductive function, and establishing the blood-testis barrier. Studies have shown that autophagy is particularly active in LCs; however, its involvement in testosterone synthesis in porcine LCs has not been fully explored. Therefore, this experiment aimed to investigate the influence of autophagy on testosterone secretion in porcine LCs and its potential regulatory mechanism. Our results demonstrated that both testicular autophagy and serum testosterone levels increased in piglets during postnatal development from 4 to 18 weeks. In addition, autophagy was found to degrade the Na+/H+ exchange regulatory factor 2 (NHERF2), leading to the up-regulation of scavenger receptor class B type 1 (SRB1). This process resulted in increased cholesterol intake and enhanced testosterone production. The observable level of sirtuin 1 (SIRT1) was directly proportional to the level of autophagy. In vitro investigations have shown that SIRT1 can affect the level of autophagy, cholesterol uptake as well as testosterone release. In conclusion, testosterone synthesis during pig development is regulated by SIRT1. SIRT1 mediates the degradation of NHERF2 through autophagy, thereby weakening its negative regulatory effect on the high-density lipoprotein receptor SRB1 in Leydig cells. This process increases cholesterol uptake and enhances testosterone synthesis.
    Keywords:  Autophagy; NHERF2; Porcine; SIRT1; SRB1; Testosterone
    DOI:  https://doi.org/10.1016/j.theriogenology.2024.09.010
  43. Plant Physiol Biochem. 2024 Sep 14. pii: S0981-9428(24)00797-6. [Epub ahead of print]216 109129
    The effect of nitrosative stress on histone H3 and H4 acetylation in Phytophthora infestans life cycle.
    Yufeng Guan, Joanna Gajewska, Ewa Sobieszczuk-Nowicka, Jolanta Floryszak-Wieczorek, Sjon Hartman, Magdalena Arasimowicz-Jelonek.
      The oomycete Phytophthora infestans is one of the most destructive phytopathogens globally. It has a proven ability to adapt to changing environments rapidly; however, molecular mechanisms responsible for host invasion and adaptation to new environmental conditions still need to be explored. The study aims to understand the epigenetic mechanisms exploited by P. infestans in response to nitrosative stress conditions created by the (micro)environment and the host plant. To characterize reactive nitrogen species (RNS)-dependent acetylation profiles in avirulent/virulent (avr/vr) P. infestans, a transient gene expression, ChIP and immunoblot analyses, and nitric oxide (NO) emission by chemiluminescence were used in combination with the pharmacological approach. Nitrosative stress increased total H3/H4 acetylation and some histone acetylation marks, mainly in sporulating hyphae of diverse (avr/vr) isolates and during potato colonization. These results correlated with transcriptional up-regulation of acetyltransferases PifHAC3 and PifHAM1, catalyzing H3K56 and H4K16 acetylation, respectively. NO or peroxynitrite-mediated changes were also associated with H3K56 and H4K16 mark deposition on the critical pathogenicity-related gene promoters (CesA1, CesA2, CesA3, sPLD-like1, Hmp1, and Avr3a) elevating their expression. Our study highlights RNS-dependent transcriptional reprogramming via histone acetylation of essential gene expression in the sporulating and biotrophic phases of plant colonization by P. infestans as a tool promoting its evolutionary plasticity.
    Keywords:  Epigenetic mechanisms; Histone acetylation; Nitric oxide; Nitrosative stress; Oomycete phytopathogen; Peroxynitrite; Potato
    DOI:  https://doi.org/10.1016/j.plaphy.2024.109129
  44. Genes Dis. 2024 Nov;11(6): 101216
    Histone deacetylases: Regulation of vascular homeostasis via endothelial cells and vascular smooth muscle cells and the role in vascular pathogenesis.
    Hanyi Yang, Kai Guo, Peng Ding, Jiayi Ning, Yimeng Zhang, Yuanyong Wang, Zhaoyang Wang, Guanglin Liu, Changjian Shao, Minghong Pan, Zhiqiang Ma, Xiaolong Yan, Jing Han.
      Histone deacetylases (HDACs) are proteases that play a key role in chromosome structural modification and gene expression regulation, and the involvement of HDACs in cancer, the nervous system, and the metabolic and immune system has been well reviewed. Our understanding of the function of HDACs in the vascular system has recently progressed, and a significant variety of HDAC inhibitors have been shown to be effective in the treatment of vascular diseases. However, few reviews have focused on the role of HDACs in the vascular system. In this study, the role of HDACs in the regulation of the vascular system mainly involving endothelial cells and vascular smooth muscle cells was discussed based on recent updates, and the role of HDACs in different vascular pathogenesis was summarized as well. Furthermore, the therapeutic effects and prospects of HDAC inhibitors were also addressed in this review.
    Keywords:  Deacetylation; Endothelial cells; Histone deacetylase; Vascular disease; Vascular smooth muscle cells
    DOI:  https://doi.org/10.1016/j.gendis.2024.101216
  45. Clin Transl Sci. 2024 Sep;17(9): e70030
    Computational drug discovery pipelines identify NAMPT as a therapeutic target in neuroendocrine prostate cancer.
    Weijie Zhang, Adam Lee, Lauren Lee, Scott M Dehm, R Stephanie Huang.
      Neuroendocrine prostate cancer (NEPC) is an aggressive advanced subtype of prostate cancer that exhibits poor prognosis and broad resistance to therapies. Currently, few treatment options are available, highlighting a need for new therapeutics to help curb the high mortality rates of this disease. We designed a comprehensive drug discovery pipeline that quickly generates drug candidates ready to be tested. Our method estimated patient response to various therapeutics in three independent prostate cancer patient cohorts and selected robust candidate drugs showing high predicted potency in NEPC tumors. Using this pipeline, we nominated NAMPT as a molecular target to effectively treat NEPC tumors. Our in vitro experiments validated the efficacy of NAMPT inhibitors in NEPC cells. Compared with adenocarcinoma LNCaP cells, NAMPT inhibitors induced significantly higher growth inhibition in the NEPC cell line model NCI-H660. Moreover, to further assist clinical development, we implemented a causal feature selection method to detect biomarkers indicative of sensitivity to NAMPT inhibitors. Gene expression modifications of selected biomarkers resulted in changes in sensitivity to NAMPT inhibitors consistent with expectations in NEPC cells. Validation of these markers in an independent prostate cancer patient dataset supported their use to inform clinical efficacy. Our findings pave the way for new treatments to combat pervasive drug resistance and reduce mortality. Furthermore, this research highlights the use of drug sensitivity-related biomarkers to understand mechanisms and potentially indicate clinical efficacy.
    DOI:  https://doi.org/10.1111/cts.70030
  46. mSystems. 2024 Sep 17. e0095324
    Histone deacetylase HDAC3 regulates ergosterol production for oxidative stress tolerance in the entomopathogenic and endophytic fungus Metarhizium robertsii.
    Shuxing Liu, Xinmiao Wang, Xingyuan Tang, Weiguo Fang.
      Oxidative stress is encountered by fungi in almost all niches, resulting in fungal degeneration or even death. Fungal tolerance to oxidative stress has been extensively studied, but the current understanding of the mechanisms regulating oxidative stress tolerance in fungi remains limited. The entomopathogenic and endophytic fungus Metarhizium robertsii encounters oxidative stress when it infects insects and develops a symbiotic relationship with plants, and we found that host reactive oxygen species (ROSs) greatly limited fungal growth in both insects and plants. We identified a histone H3 deacetylase (HDAC3) that catalyzed the deacetylation of lysine 56 of histone H3. Deleting Hdac3 significantly reduced the tolerance of M. robertsii to oxidative stress from insects and plants, thereby decreasing fungal ability to colonize the insect hemocoel and plant roots. HDAC3 achieved this by regulating the expression of three genes in the ergosterol biosynthesis pathway, which includes the lanosterol synthase gene Las1. The deletion of Hdac3 or Las1 reduced the ergosterol content and impaired cell membrane integrity. This resulted in an increase in ROS accumulation in fungal cells that were thus more sensitive to oxidative stress. We further showed that HDAC3 regulated the expression of the three ergosterol biosynthesis genes in an indirect manner. Our work significantly advances insights into the epigenetic regulation of oxidative stress tolerance and the interactions between M. robertsii and its plant and insect hosts.IMPORTANCEOxidative stress is a common challenge encountered by fungi that have evolved sophisticated mechanisms underlying tolerance to this stress. Although fungal tolerance to oxidative stress has been extensively investigated, the current understanding of the mechanisms for fungi to regulate oxidative stress tolerance remains limited. In the model entomopathogenic and plant symbiotic fungus Metarhizium robertsii, we found that the histone H3 deacetylase HDAC3 regulates the production of ergosterol, an essential cell membrane component. This maintains the cell membrane integrity to resist the oxidative stress derived from the insect and plant hosts for successful infection of insects and development of symbiotic associates with plants. Our work provides significant insights into the regulation of oxidative stress tolerance in M. robertsii and its interactions with insects and plants.
    Keywords:  Metarhizium; entomopathogenic fungi; epigenetic; ergosterol; histone deacetylase; oxidative stress; pathogenicity; plant symbiotic fungi; symbiosis
    DOI:  https://doi.org/10.1128/msystems.00953-24
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