bims-toxgon 2024-04-14 papers

bims-toxgon

Biomed News

on Toxoplasma gondii metabolism

Issue of 2024–04–14
twenty papers selected by
Lakesh Kumar, BITS Pilani

Properties and predicted functions of large genes and proteins of apicomplexan parasites.
Metabolic plasticity, essentiality and therapeutic potential of ribose-5-phosphate synthesis in Toxoplasma gondii.
The Crk4-Cyc4 complex regulates G2/M transition in Toxoplasma gondii.
Corrigendum to "Past and present seroprevalence and disease burden estimates of Toxoplasma gondii infections in Germany: An appreciation of the role of serodiagnostics" [Int. J. Med. Microbiol. 313 (2023) 151592].
Histone code: a common language and multiple dialects to meet the different developmental requirements of apicomplexan parasites.
Ubiquitinome Analysis Uncovers Alterations in Synaptic Proteins and Glucose Metabolism Enzymes in the Hippocampi of Adolescent Mice Following Cold Exposure.
Alterations in gut microbiota contribute to cognitive deficits induced by chronic infection of Toxoplasma gondii.
HAT and HDAC: Enzyme with Contradictory Action in Neurodegenerative Diseases.
ATG7(2) Interacts With Metabolic Proteins and Regulates Central Energy Metabolism.
Proxies introduce bias in decoding TORC1 activity.
Cellular Energy Sensor Sirt1 Augments Mapk Signaling to Promote Hypoxia/Reoxygenation-Induced Catch-up Growth in Zebrafish Embryo.
AMP-activated protein kinase can be allosterically activated by ADP but AMP remains the key activating ligand.
Glutaminase deficiency in rod photoreceptors disrupts nonessential amino acid levels to activate the integrated stress response and induce rapid degeneration.
Carbon dioxide shapes parasite-host interactions in a human-infective nematode.
Crebinostat facilitates memory formation.
Discovery and characterization of novel ATP citrate lyase inhibitors from Acanthopanax senticosus (Rupr. & Maxim.) Harms.
A Novel Liver Cancer-Selective Histone Deacetylase Inhibitor Is Effective Against Hepatocellular Carcinoma and Induces Durable Responses with Immunotherapy.
[Seroprevalence of the specific antibody against Toxoplasma gondii among patients with hematological diseases].
The SP1/SIRT1/ACLY signaling axis mediates fatty acid oxidation in renal ischemia-reperfusion-induced renal fibrosis.
Design and Evaluation of Nanoscale Materials with Programmed Responsivity towards Epigenetic Enzymes.

NAR Genom Bioinform. 2024 Jun;6(2): lqae032

Properties and predicted functions of large genes and proteins of apicomplexan parasites.

Tiffany Fang, Amir Mohseni, Stefano Lonardi, Choukri Ben Mamoun.

Evolutionary constraints greatly favor compact genomes that efficiently encode proteins. However, several eukaryotic organisms, including apicomplexan parasites such as Toxoplasma gondii, Plasmodium falciparum and Babesia duncani, the causative agents of toxoplasmosis, malaria and babesiosis, respectively, encode very large proteins, exceeding 20 times their average protein size. Although these large proteins represent <1% of the total protein pool and are generally expressed at low levels, their persistence throughout evolution raises important questions about their functions and possible evolutionary pressures to maintain them. In this study, we examined the trends in gene and protein size, function and expression patterns within seven apicomplexan pathogens. Our analysis revealed that certain large proteins in apicomplexan parasites harbor domains potentially important for functions such as antigenic variation, erythrocyte invasion and immune evasion. However, these domains are not limited to or strictly conserved within large proteins. While some of these proteins are predicted to engage in conventional metabolic pathways within these parasites, others fulfill specialized functions for pathogen-host interactions, nutrient acquisition and overall survival.

DOI: https://doi.org/10.1093/nargab/lqae032
Nat Commun. 2024 Apr 08. 15(1): 2999

Metabolic plasticity, essentiality and therapeutic potential of ribose-5-phosphate synthesis in Toxoplasma gondii.

Xuefang Guo, Nuo Ji, Qinghong Guo, Mengting Wang, Huiyu Du, Jiajia Pan, Lihua Xiao, Nishith Gupta, Yaoyu Feng, Ningbo Xia.

Ribose-5-phosphate (R5P) is a precursor for nucleic acid biogenesis; however, the importance and homeostasis of R5P in the intracellular parasite Toxoplasma gondii remain enigmatic. Here, we show that the cytoplasmic sedoheptulose-1,7-bisphosphatase (SBPase) is dispensable. Still, its co-deletion with transaldolase (TAL) impairs the double mutant's growth and increases 13C-glucose-derived flux into pentose sugars via the transketolase (TKT) enzyme. Deletion of the latter protein affects the parasite's fitness but is not lethal and is correlated with an increased carbon flux via the oxidative pentose phosphate pathway. Further, loss of TKT leads to a decline in 13C incorporation into glycolysis and the TCA cycle, resulting in a decrease in ATP levels and the inability of phosphoribosyl-pyrophosphate synthetase (PRPS) to convert R5P into 5'-phosphoribosyl-pyrophosphate and thereby contribute to the production of AMP and IMP. Likewise, PRPS is essential for the lytic cycle. Not least, we show that RuPE-mediated metabolic compensation is imperative for the survival of the ΔsbpaseΔtal strain. In conclusion, we demonstrate that multiple routes can flexibly supply R5P to enable parasite growth and identify catalysis by TKT and PRPS as critical enzymatic steps. Our work provides novel biological and therapeutic insights into the network design principles of intracellular parasitism in a clinically-relevant pathogen.

DOI: https://doi.org/10.1038/s41467-024-47097-8
EMBO J. 2024 Apr 10.

The Crk4-Cyc4 complex regulates G2/M transition in Toxoplasma gondii.

Lauren M Hawkins, Chengqi Wang, Dale Chaput, Mrinalini Batra, Clem Marsilia, Danya Awshah, Elena S Suvorova.

  A versatile division of apicomplexan parasites and a dearth of conserved regulators have hindered the progress of apicomplexan cell cycle studies. While most apicomplexans divide in a multinuclear fashion, Toxoplasma gondii tachyzoites divide in the traditional binary mode. We previously identified five Toxoplasma CDK-related kinases (Crk). Here, we investigated TgCrk4 and its cyclin partner TgCyc4. We demonstrated that TgCrk4 regulates conventional G2 phase processes, such as repression of chromosome rereplication and centrosome reduplication, and acts upstream of the spindle assembly checkpoint. The spatial TgCyc4 dynamics supported the TgCrk4-TgCyc4 complex role in the coordination of chromosome and centrosome cycles. We also identified a dominant TgCrk4-TgCyc4 complex interactor, TgiRD1 protein, related to DNA replication licensing factor CDT1 but played no role in licensing DNA replication in the G1 phase. Our results showed that TgiRD1 also plays a role in controlling chromosome and centrosome reduplication. Global phosphoproteome analyses identified TgCrk4 substrates, including TgORC4, TgCdc20, TgGCP2, and TgPP2ACA. Importantly, the phylogenetic and structural studies suggest the Crk4-Cyc4 complex is limited to a minor group of the binary dividing apicomplexans.

Keywords:   Toxoplasma gondii ; Apicomplexa; CDK; Cell Cycle; G2/M Checkpoint

DOI:  https://doi.org/10.1038/s44318-024-00095-4
Int J Med Microbiol. 2024 Apr 06. pii: S1438-4221(24)00022-5. [Epub ahead of print] 151618

Corrigendum to "Past and present seroprevalence and disease burden estimates of Toxoplasma gondii infections in Germany: An appreciation of the role of serodiagnostics" [Int. J. Med. Microbiol. 313 (2023) 151592].

Frank Seeber.

DOI: https://doi.org/10.1016/j.ijmm.2024.151618
Curr Opin Microbiol. 2024 Apr 05. pii: S1369-5274(24)00048-1. [Epub ahead of print]79 102472

Histone code: a common language and multiple dialects to meet the different developmental requirements of apicomplexan parasites.

Victoria Jeffers.

Apicomplexan parasites have complex life cycles, often requiring transmission between two different hosts, facing periods of dormancy within the host or in the environment to maximize chances of transmission. To support survival in these different conditions, tightly regulated and correctly timed gene expression is critical. The modification of histones and nucleosome composition makes a significant contribution to this regulation, and as eukaryotes, the fundamental mechanisms underlying this process in apicomplexans are similar to those in model eukaryotic organisms. However, single-celled intracellular parasites face unique challenges, and regulation of gene expression at the epigenetic level provides tight control for responses that must often be rapid and robust. Here, we discuss the recent advances in understanding the dynamics of histone modifications across Apicomplexan life cycles and the molecular mechanisms that underlie epigenetic regulation of gene expression to promote parasite life cycle progression, dormancy, and transmission.

DOI: https://doi.org/10.1016/j.mib.2024.102472
Cells. 2024 Mar 25. pii: 570. [Epub ahead of print]13(7):

Ubiquitinome Analysis Uncovers Alterations in Synaptic Proteins and Glucose Metabolism Enzymes in the Hippocampi of Adolescent Mice Following Cold Exposure.

Xin-Yue Li, Xin Yin, Jing-Jing Lu, Qian-Ru Li, Wan-Qun Xing, Qi Han, Hong Ji, Shi-Ze Li, Huan-Min Yang, Jing-Ru Guo, Zhi-Quan Wang, Bin Xu.

  Cold exposure exerts negative effects on hippocampal nerve development in adolescent mice, but the underlying mechanisms are not fully understood. Given that ubiquitination is essential for neurodevelopmental processes, we attempted to investigate the effects of cold exposure on the hippocampus from the perspective of ubiquitination. By conducting a ubiquitinome analysis, we found that cold exposure caused changes in the ubiquitination levels of a variety of synaptic-associated proteins. We validated changes in postsynaptic density-95 (PSD-95) ubiquitination levels by immunoprecipitation, revealing reductions in both the K48 and K63 polyubiquitination levels of PSD-95. Golgi staining further demonstrated that cold exposure decreased the dendritic-spine density in the CA1 and CA3 regions of the hippocampus. Additionally, bioinformatics analysis revealed that differentially ubiquitinated proteins were enriched in the glycolytic, hypoxia-inducible factor-1 (HIF-1), and 5'-monophosphate (AMP)-activated protein kinase (AMPK) pathways. Protein expression analysis confirmed that cold exposure activated the mammalian target of rapamycin (mTOR)/HIF-1α pathway. We also observed suppression of pyruvate kinase M2 (PKM2) protein levels and the pyruvate kinase (PK) activity induced by cold exposure. Regarding oxidative phosphorylation, a dramatic decrease in mitochondrial respiratory-complex I activity was observed, along with reduced gene expression of the key subunits NADH: ubiquinone oxidoreductase core subunit V1 (Ndufv1) and Ndufv2. In summary, cold exposure negatively affects hippocampal neurodevelopment and causes abnormalities in energy homeostasis within the hippocampus.

Keywords:  PSD-95; cold exposure; glucose metabolism; hippocampus; ubiquitinome

DOI:  https://doi.org/10.3390/cells13070570
Brain Behav Immun. 2024 Apr 10. pii: S0889-1591(24)00353-2. [Epub ahead of print]

Alterations in gut microbiota contribute to cognitive deficits induced by chronic infection of Toxoplasma gondii.

Xiaoying Yang, Yuying Zhou, Shimin Tan, Xiaokang Tian, Xianran Meng, Yiling Li, Beibei Zhou, Guihua Zhao, Xing Ge, Cheng He, Wanpeng Cheng, Yumei Zhang, Kuiyang Zheng, Kun Yin, Yinghua Yu, Wei Pan.

  Chronic infection with Toxoplasma gondii (T. gondii) emerges as a risk factor for neurodegenerative diseases in animals and humans. However, the underlying mechanisms are largely unknown. We aimed to investigate whether gut microbiota and its metabolites play a role in T. gondii-induced cognitive deficits. We found that T. gondii infection induced cognitive deficits in mice, which was characterized by synaptic ultrastructure impairment and neuroinflammation in the hippocampus. Moreover, the infection led to gut microbiota dysbiosis, barrier integrity impairment, and inflammation in the colon. Interestingly, broad-spectrum antibiotic ablation of gut microbiota attenuated the adverse effects of the parasitic infection on the cognitive function in mice; cognitive deficits and hippocampal pathological changes were transferred from the infected mice to control mice by fecal microbiota transplantation. In addition, the abundance of butyrate-producing bacteria and the production of serum butyrate were decreased in infected mice. Interestingly, dietary supplementation of butyrate ameliorated T. gondii-induced cognitive impairment in mice. Notably, compared to the healthy controls, the decreased butyrate production was negatively correlated with the levels of anti-T. gondii IgG antibody in the serum of human subjects. Overall, this study demonstrates that gut microbiota is a key regulator of T. gondii-induced cognitive impairment.

Keywords:  Butyrate; Cognitive decline; Gut microbiota; Neuroinflammation; Toxoplasma gondii

DOI:  https://doi.org/10.1016/j.bbi.2024.04.008
Mol Neurobiol. 2024 Apr 08.

HAT and HDAC: Enzyme with Contradictory Action in Neurodegenerative Diseases.

Richa Singh, Aaina Singh Rathore, Hagera Dilnashin, Priyanka Kumari Keshri, Nitesh Kumar Gupta, Singh Ankit Satya Prakash, Walia Zahra, Shekhar Singh, Surya Pratap Singh.

  In view of the increasing risk of neurodegenerative diseases, epigenetics plays a fundamental role in the field of neuroscience. Several modifications have been studied including DNA methylation, histone acetylation, histone phosphorylation, etc. Histone acetylation and deacetylation regulate gene expression, and the regular activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs) provides regulatory stages for gene expression and cell cycle. Imbalanced homeostasis in these enzymes causes a detrimental effect on neurophysiological function. Intriguingly, epigenetic remodelling via histone acetylation in certain brain areas has been found to play a key role in the neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. It has been demonstrated that a number of HATs have a role in crucial brain processes such regulating neuronal plasticity and memory formation. The most recent therapeutic methods involve the use of small molecules known as histone deacetylase (HDAC) inhibitors that antagonize HDAC activity thereby increase acetylation levels in order to prevent the loss of HAT function in neurodegenerative disorders. The target specificity of the HDAC inhibitors now in use raises concerns about their applicability, despite the fact that this strategy has demonstrated promising therapeutic outcomes. The aim of this review is to summarize the cross-linking between histone modification and its regulation in the pathogenesis of neurological disorders. Furthermore, these findings also support the notion of new pharmacotherapies that target particular areas of the brain using histone deacetylase inhibitors.

Keywords:  Alzheimer’s disease; Epigenetics; Histone acetyltransferase; Histone decetyltransferase; Huntington’s disease; Neurodegeneration; Parkinson’s disease; c-AMP response binding element

DOI:  https://doi.org/10.1007/s12035-024-04115-6
Traffic. 2024 Apr;25(4): e12933

ATG7(2) Interacts With Metabolic Proteins and Regulates Central Energy Metabolism.

Kevin Ostacolo, Adrián López García de Lomana, Clémence Larat, Valgerdur Hjaltalin, Kristrun Yr Holm, Sigríður S Hlynsdóttir, Margaret Soucheray, Linda Sooman, Ottar Rolfsson, Nevan J Krogan, Eirikur Steingrimsson, Danielle L Swaney, Margret H Ogmundsdottir.

  Macroautophagy/autophagy is an essential catabolic process that targets a wide variety of cellular components including proteins, organelles, and pathogens. ATG7, a protein involved in the autophagy process, plays a crucial role in maintaining cellular homeostasis and can contribute to the development of diseases such as cancer. ATG7 initiates autophagy by facilitating the lipidation of the ATG8 proteins in the growing autophagosome membrane. The noncanonical isoform ATG7(2) is unable to perform ATG8 lipidation; however, its cellular regulation and function are unknown. Here, we uncovered a distinct regulation and function of ATG7(2) in contrast with ATG7(1), the canonical isoform. First, affinity-purification mass spectrometry analysis revealed that ATG7(2) establishes direct protein-protein interactions (PPIs) with metabolic proteins, whereas ATG7(1) primarily interacts with autophagy machinery proteins. Furthermore, we identified that ATG7(2) mediates a decrease in metabolic activity, highlighting a novel splice-dependent function of this important autophagy protein. Then, we found a divergent expression pattern of ATG7(1) and ATG7(2) across human tissues. Conclusively, our work uncovers the divergent patterns of expression, protein interactions, and function of ATG7(2) in contrast to ATG7(1). These findings suggest a molecular switch between main catabolic processes through isoform-dependent expression of a key autophagy gene.

Keywords:  ATG7; ATG7(2); GTEx; PPI; autophagy; glycolysis; isoforms; lipidation; mitochondrial activity

DOI:  https://doi.org/10.1111/tra.12933
MicroPubl Biol. 2024 ;2024

Proxies introduce bias in decoding TORC1 activity.

Marco Caligaris, Claudio De Virgilio.

The eukaryotic TORC1 kinase integrates and links nutritional, energy, and hormonal signals to cell growth and homeostasis, and its deregulation is associated with human diseases including neurodegeneration, cancer, and metabolic syndrome. Quantification of TORC1 activities in various genetic settings and defined physiological conditions generally relies on the assessment of the phosphorylation level of residues in TORC1 targets. Here we show that two commonly used TORC1 effectors in yeast, namely Sch9 and Rps6, exhibit distinct phosphorylation patterns in response to rapamycin treatment or changes in nitrogen availability, indicating that the choice of TORC1 proxies introduces a bias in decoding TORC1 activity.

DOI: https://doi.org/10.17912/micropub.biology.001170
Zoolog Sci. 2024 Feb;41(1): 21-31

Cellular Energy Sensor Sirt1 Augments Mapk Signaling to Promote Hypoxia/Reoxygenation-Induced Catch-up Growth in Zebrafish Embryo.

Oki Hayasaka, Mukaze Shibukawa, Hiroyasu Kamei.

  Animal growth is blunted in adverse environments where catabolic metabolism dominates; however, when the adversity disappears, stunted animals rapidly catch up to age-equivalent body size. This phenomenon is called catch-up growth, which we observe in various animals. Since growth retardation and catch-up growth are sequential processes, catabolism or stress response molecules may remain active, especially immediately after growth resumes. Sirtuins (Sirt1-7) deacetylate target proteins in a nicotinamide adenine dinucleotide-dependent manner, and these enzymes govern diverse alleys of cellular functions. Here, we investigated the roles of Sirt1 and its close paralog Sirt2 in the hypoxia/reoxygenation-induced catch-up growth model using zebrafish embryos. Temporal blockade of Sirt1/2 significantly reduced the growth rate of the embryos in reoxygenation, but it was not evident in constant normoxia. Subsequent gene knockdown and chemical inhibition experiments demonstrated that Sirt1, but not Sirt2, was required for the catchup growth. Inhibition of Sirt1 significantly reduced the activity of mitogen-activated kinase (Mapk) of embryos in the reoxygenation condition. In addition, co-inhibition of Sirt1- and Igf-signaling did not further reduce the body growth or Mapk activation compared to those of the Igf-signaling-alone-inhibited embryos. Furthermore, in the reoxygenation condition, Sirt1- or Igf-signaling inhibition similarly blunted Mapk activity, especially in anterior tissues and trunk muscle, where the sirt1 expression was evident in the catching-up embryos. These results suggest that the catch-up growth requires Sirt1 action to activate the somatotropic Mapk pathway, likely by modifying the Igf-signaling.

Keywords:  catch-up growth; embryonic growth; hypoxia; insulin-like growth factor (Igf/IGF); mitogen-activated protein kinase (Mapk); re-oxygenation; sirtuin; zebrafish

DOI:  https://doi.org/10.2108/zs230059
Biochem J. 2024 Apr 09. pii: BCJ20240082. [Epub ahead of print]

AMP-activated protein kinase can be allosterically activated by ADP but AMP remains the key activating ligand.

Simon A Hawley, Fiona M Russell, D Grahame Hardie.

  The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status. When activated by increases in ADP:ATP and/or AMP:ATP ratios (signalling energy deficit), AMPK acts to restore energy balance. Binding of AMP to one or more of three CBS repeats (CBS1, CBS3, CBS4) on the AMPK-γ subunit activates the kinase complex by three complementary mechanisms: (i) promoting α-subunit Thr172 phosphorylation by the upstream kinase LKB1; (ii) protecting against Thr172 dephosphorylation; (iii) allosteric activation. Surprisingly, binding of ADP has been reported to mimic the first two effects, but not the third. We now show that at physiologically relevant concentrations of Mg.ATP2- (above those used in the standard assay) ADP binding does cause allosteric activation. However, ADP causes only a modest activation because (unlike AMP), at concentrations just above those where activation becomes evident, ADP starts to cause competitive inhibition at the catalytic site. Our results cast doubt on the physiological relevance of the effects of ADP and suggest that AMP is the primary activator in vivo. We have also made mutations to hydrophobic residues involved in binding adenine nucleotides at each of the three γ subunit CBS repeats of the human α2β2γ1 complex and examined their effects on regulation by AMP and ADP. Mutation of the CBS3 site has the largest effects on all three mechanisms of AMP activation, especially at lower ATP concentrations, while mutation of CBS4 reduces the sensitivity to AMP. All three sites appear to be required for allosteric activation by ADP.

Keywords:  ADP; AMP; AMPK; CBS repeats; LKB1; adenine nucleotides

DOI:  https://doi.org/10.1042/BCJ20240082
bioRxiv. 2024 Mar 27. pii: 2024.03.26.582525. [Epub ahead of print]

Glutaminase deficiency in rod photoreceptors disrupts nonessential amino acid levels to activate the integrated stress response and induce rapid degeneration.

Moloy T Goswami, Eric Weh, Shubha Subramanya, Katherine M Weh, Hima Bindu Durumutla, Heather Hager, Nicholas Miller, Sraboni Chaudhury, Anthony Andren, Peter Sajjakulnukit, Cagri G Besirli, Costas A Lyssiotis, Thomas J Wubben.

The bioenergetic demand of photoreceptors rivals that of cancer cells, and numerous metabolic similarities exist between these cells. Glutamine (Gln) anaplerosis via the tricarboxylic acid (TCA) cycle provides biosynthetic intermediates and is a hallmark of cancer metabolism. In this process, Gln is first converted to glutamate via glutaminase (GLS), which is a crucial pathway in many cancer cells. To date, no study has been undertaken to examine the role of Gln metabolism in vivo in photoreceptors. Here, mice lacking GLS in rod photoreceptors were generated. Animals lacking GLS experienced rapid photoreceptor degeneration with concomitant functional loss. Gln has multiple roles in metabolism including redox balance, biosynthesis of nucleotides and amino acids, and supplementing the TCA cycle. Few alterations were noted in redox balance. Unlabeled targeted metabolomics demonstrated few changes in glycolytic and TCA cycle intermediates, which corresponded with a lack of significant changes in mitochondrial function. GLS deficiency in rod photoreceptors did decrease the fractional labelling of TCA cycle intermediates when provided uniformly labeled 13 C-Gln in vivo . However, supplementation with alpha-ketoglutarate provided only marginal rescue of photoreceptor degeneration. Nonessential amino acids, glutamate and aspartate, were decreased in the retina of mice lacking GLS in rod photoreceptors. In accordance with this amino acid deprivation, the integrated stress response (ISR) was found to be activated with decreased global protein synthesis. Importantly, supplementation with asparagine delayed photoreceptor degeneration to a greater degree than alpha-ketoglutarate. These data show that GLS-mediated Gln catabolism is essential for rod photoreceptor amino acid biosynthesis, function, and survival.
Significance Statement: Glucose has been central in the study of photoreceptor cell metabolism. Recently, it was shown that fuel sources besides glucose can meet the metabolic needs of photoreceptors. Glutamine (Gln) is the most abundant circulating amino acid and has many biosynthetic and bioenergetic roles in cells. Glutaminolysis is the process by which Gln is metabolized into tricarboxylic acid cycle intermediates to provide biosynthetic precursors. Here, Gln is first converted to glutamate via the enzyme glutaminase (GLS). This research demonstrates that deletion of GLS in rod photoreceptors alters retinal metabolism, activates the integrated stress response (ISR), and results in rapid photoreceptor degeneration. As such, Gln is a critical fuel source that supports photoreceptor cell biomass, redox balance, and survival.

DOI: https://doi.org/10.1101/2024.03.26.582525
bioRxiv. 2024 Mar 31. pii: 2024.03.28.587273. [Epub ahead of print]

Carbon dioxide shapes parasite-host interactions in a human-infective nematode.

Navonil Banerjee, Spencer S Gang, Michelle L Castelletto, Felicitas Ruiz, Elissa A Hallem.

  Skin-penetrating nematodes infect nearly one billion people worldwide. The developmentally arrested infective larvae (iL3s) seek out hosts, invade hosts via skin penetration, and resume development inside the host in a process called activation. Activated infective larvae (iL3as) traverse the host body, ending up as parasitic adults in the small intestine. Skin-penetrating nematodes respond to many chemosensory cues, but how chemosensation contributes to host seeking, intra-host development, and intra-host navigation - three crucial steps of the parasite-host interaction - remains poorly understood. Here, we investigate the role of carbon dioxide (CO2) in promoting parasite-host interactions in the human-infective threadworm Strongyloides stercoralis. We show that S. stercoralis exhibits life-stage-specific preferences for CO2: iL3s are repelled, non-infective larvae and adults are neutral, and iL3as are attracted. CO2 repulsion in iL3s may prime them for host seeking by stimulating dispersal from host feces, while CO2 attraction in iL3as may direct worms toward high-CO2 areas of the body such as the lungs and intestine. We also identify sensory neurons that detect CO2; these neurons are depolarized by CO2 in iL3s and iL3as. In addition, we demonstrate that the receptor guanylate cyclase Ss-GCY-9 is expressed specifically in CO2-sensing neurons and is required for CO2-evoked behavior. Ss-GCY-9 also promotes activation, indicating that a single receptor can mediate both behavioral and physiological responses to CO2. Our results illuminate chemosensory mechanisms that shape the interaction between parasitic nematodes and their human hosts and may aid in the design of novel anthelmintics that target the CO2-sensing pathway.

Keywords:  BAG neurons; GCY-9; Strongyloides stercoralis; activation; carbon dioxide response; chemotaxis; host seeking; parasitic helminth; parasitic nematode

DOI:  https://doi.org/10.1101/2024.03.28.587273
Biochem Biophys Res Commun. 2024 Apr 04. pii: S0006-291X(24)00408-X. [Epub ahead of print]710 149872

Crebinostat facilitates memory formation.

Deepti Dama, Shiv K Sharma.

  Protein modifications importantly contribute to memory formation. Protein acetylation is a post-translational modification of proteins that regulates memory formation. Acetylation level is determined by the relative activities of acetylases and deacetylases. Crebinostat is a histone deacetylase inhibitor. Here we show that in an object recognition task, crebinostat facilitates memory formation by a weak training. Further, this compound enhances acetylation of α-tubulin, and reduces the level of histone deacetylase 6, an α-tubulin deacetylase. The results suggest that enhanced acetylation of α-tubulin by crebinostat contributes to its facilitatory effect on memory formation.

Keywords:  Acetylation; HDAC6; Memory; Object recognition task; α-tubulin

DOI:  https://doi.org/10.1016/j.bbrc.2024.149872
Fitoterapia. 2024 Apr 09. pii: S0367-326X(24)00139-4. [Epub ahead of print]175 105956

Discovery and characterization of novel ATP citrate lyase inhibitors from Acanthopanax senticosus (Rupr. & Maxim.) Harms.

Pan Wang, Xiujie Guo, Tao Hou, Fengbin Luo, Miao Li, Xiaoyu Wang, Jie Zhang, Jixia Wang, Chaoran Wang, Xinmiao Liang.

  ATP citrate lyase (ACLY) is a key enzyme in glucolipid metabolism, and abnormally high expression of ACLY occurs in many diseases, including cancers, dyslipidemia and cardiovascular diseases. ACLY inhibitors are prospective treatments for these diseases. However, the scaffolds of ACLY inhibitors are insufficient with weak activity. The discovery of inhibitors with structural novelty and high activity continues to be a research hotpot. Acanthopanax senticosus (Rupr. & Maxim.) Harms is used for cardiovascular disease treatment, from which no ACLY inhibitors have ever been found. In this work, we discovered three novel ACLY inhibitors, and the most potent one was isochlorogenic acid C (ICC) with an IC50 value of 0.14 ± 0.04 μM. We found dicaffeoylquinic acids with ortho-dihydroxyphenyl groups were important features for inhibition by studying ten phenolic acids. We further investigated interactions between the highly active compound ICC and ACLY. Thermal shift assay revealed that ICC could directly bind to ACLY and improve its stability in the heating process. Enzymatic kinetic studies indicated ICC was a noncompetitive inhibitor of ACLY. Our work discovered novel ACLY inhibitors, provided valuable structure-activity patterns and deepened knowledge on the interactions between this targe tand its inhibitors.

Keywords:  ACLY inhibitor; Acanthopanax senticosus (Rupr. & maxim.) harms; Natural products; Structure–activity relationship

DOI:  https://doi.org/10.1016/j.fitote.2024.105956
bioRxiv. 2024 Mar 28. pii: 2024.03.27.587062. [Epub ahead of print]

A Novel Liver Cancer-Selective Histone Deacetylase Inhibitor Is Effective Against Hepatocellular Carcinoma and Induces Durable Responses with Immunotherapy.

Bocheng Wu, Subhasish Tapadar, Zhiping Ruan, Carrie Q Sun, Rebecca S Arnold, Jeremiah O Olugbami, Alexis Johnston, Uche Arunsi, David A Gaul, John A Petros, Tatsuya Kobayashi, Dan G Duda, Adegboyega K Oyelere.

Hepatocellular cancer (HCC) progression is facilitated by gene-silencing chromatin histone hypoacetylation due to histone deacetylases (HDACs) activation. However, inhibiting HDACs - an effective treatment for lymphomas - has shown limited success in solid tumors. We report the discovery of a class of HDAC inhibitors (HDACi) that demonstrates exquisite selective cytotoxicity against human HCC cells. The lead compound STR-V-53 ( 3 ) showed favorable safety profile in mice and robustly suppressed tumor growth in orthotopic xenograft models of HCC. When combined with the anti-HCC drug sorafenib, STR-V-53 showed greater in vivo efficacy. Moreover, STR-V-53 combined with anti-PD1 therapy increased the CD8 + to regulatory T-cell (Treg) ratio and survival in an orthotopic HCC model in immunocompetent mice. This combination therapy resulted in durable responses in 40% of the mice. Collectively, our data demonstrate that the novel HDACi STR-V-53 is an effective anti-HCC agent that can induce profound responses when combined with standard immunotherapy.

DOI: https://doi.org/10.1101/2024.03.27.587062
Zhongguo Xue Xi Chong Bing Fang Zhi Za Zhi. 2023 Dec 25. 36(1): 83-86

[Seroprevalence of the specific antibody against Toxoplasma gondii among patients with hematological diseases].

D Gan, J Fan, J Zeng, J Lin, X Chen.

   OBJECTIVE: To investigate the seroprevalence of Toxoplasma gondii infections among patients with hematological diseases, so as to provide insights into improving the prognosis and quality of life among patients with hematological diseases.
METHODS: A total of 240 patients with hematological diseases (including 170 patients with hematological tumors and 70 patients with non-tumor hematological diseases) admitted to The Affiliated Hospital of Putian University during the period from January 1, 2021 through October 10, 2023 and 500 healthy volunteers in the hospital during the same period were enrolled. Subjects' demographics and serum samples were collected, and serum specific IgG and IgM antibodies against T. gondii were detected using the chemiluminescence assay, with any of a positive IgG or IgM antibody defined as a positive T. gondii infection. The seroprevalence of specific IgG and IgM antibodies against T. gondii was compared between patients with hematological diseases and healthy volunteers.
RESULTS: The mean age (F = 2.034, P > 0.05) and gender distribution (χ2 = 0.462, P > 0.05) were comparable among patients with hematological tumors, patients with non-tumor hematological diseases and healthy volunteers, and there was no significant difference in the proportion of history of cat or dog contacts between patients with hematological diseases and healthy volunteers (χ2 = 0, P > 0.05). The seroprevalence of anti-T. gondii antibody was significantly higher among patients with hematological diseases than among healthy volunteers (15.8% vs. 0.6%; χ2 = 71.902, P < 0.01), and there was a significant difference in the seroprevalence of anti-T. gondii antibody among patients with hematological tumors (18.2%), patients with non-tumor hematological diseases (10.0%) and healthy volunteers (χ2 = 78.327, P < 0.01). The seroprevalence of anti-T. gondii antibody was significantly higher among patients with hematological tumors and non-tumor hematological diseases than among healthy volunteers (both P values < 0.05), while no significant difference was seen in the seroprevalence of anti-T. gondii antibody between patients with hematological tumors and non-tumor hematological diseases (P > 0.05). In addition, the proportion of history of cat or dog contacts was significantly higher among patients with hematological diseases that were positive for serum anti-T. gondii anti-body than among those negative for serum anti-T. gondii antibody (21.1% vs. 5.4%; χ2 = 8.653, P < 0.05).
CONCLUSIONS: There is a high seroprevalene rate of T. gondii infections among hematological diseases, which is significantly greater than that among healthy volunteers.

Keywords:  Hematological disease; Seroprevalence; Toxoplasma gondii

DOI:  https://doi.org/10.16250/j.32.1374.2023197
Int Immunopharmacol. 2024 Apr 11. pii: S1567-5769(24)00520-4. [Epub ahead of print]132 112002

The SP1/SIRT1/ACLY signaling axis mediates fatty acid oxidation in renal ischemia-reperfusion-induced renal fibrosis.

Huailiang Wu, Liyan Wang, Peng Kang, Xiangjun Zhou, Wei Li, Zhongyuan Xia.

   BACKGROUND: Renal ischemia-reperfusion is the primary cause of acute kidney injury (AKI). Clinically, most patients who experience ischemia-reperfusion injury eventually progress gradually to renal fibrosis and chronic kidney disease (CKD). However, the underlying mechanism for AKI to CKD transition remain absent. Our study demonstrated that the downregulation of sirtuin 1 (Sirt1)-mediated fatty acid oxidation (FAO) facilitates IRI-induced renal fibrosis.
METHODS: The IRI animal model was established, and ribonucleic acid (RNA) sequencing was used to explore potential differentially expressed genes (DEGs) and pathways. The SIRT1 knockout mice were generated, and a recombinant adeno-associated virus that overexpresses SIRT1 was injected into mice to explore the function of SIRT1 in renal fibrosis induced by renal IRI. In vitro, hypoxia/reoxygenation (H/R) was used to establish the classical model of renal IRI and overexpression or knockdown of SIRT1 to investigate the SIRT1 function through lentiviral plasmids. The underlying molecular mechanism was explored through RNA sequencing, bioinformatics analysis, and chromatin immunoprecipitation assay.
RESULTS: RNA sequencing analysis and western blot demonstrated that the expression of SIRT1 was significantly decreased in IRI mice. Overexpression of SIRT1 improved renal function and reduced lipid deposition and renal fibrosis. On the contrary, knockout of SIRT1 aggravated kidney injury and renal fibrosis. RNA sequencing, bioinformatics analysis, and chromatin immunoprecipitation assay mechanistically revealed that SIRT1 impairs the acetylation of histone H3K27 on the promoter region of ACLY, thereby impeding FAO activity and promoting renal fibrosis. Additionally, SP1 regulated FAO by directly modulating SIRT1 expression.
CONCLUSION: Our findings highlight that downregulation of SIRT1-modulated FAO facilitated by the SP1/SIRT1/ACLY axis in the kidney increases IRI, suggesting SIRT1 to be a potential therapeutic target for renal fibrosis induced by renal IRI.

Keywords:  Fatty acid oxidation; Histone acetylation; Renal fibrosis; Renal ischemic-reperfusion injury; SIRT1

DOI:  https://doi.org/10.1016/j.intimp.2024.112002
bioRxiv. 2024 Mar 27. pii: 2024.03.26.585429. [Epub ahead of print]

Design and Evaluation of Nanoscale Materials with Programmed Responsivity towards Epigenetic Enzymes.

Priyanka Ray, Abbas Sedigh, Matthew Confeld, Lina Alhalhooly, Kweeni Iduoku, Gerardo M Casanola-Martin, Hai Pham-The, Bakhtiyor Rasulev, Yongki Choi, Zhongyu Yang, Sanku Mallik, Mohiuddin Quadir.

Self-assembled materials capable of modulating their assembly properties in response to specific enzymes play a pivotal role in advancing 'intelligent' encapsulation platforms for biotechnological applications. Here, we introduce a previously unreported class of synthetic nanomaterials that programmatically interact with histone deacetylase (HDAC) as the triggering stimulus for disassembly. These nanomaterials consist of co-polypeptides comprising poly (acetyl L-lysine) and poly(ethylene glycol) blocks. Under neutral pH conditions, they self-assemble into particles. However, their stability is compromised upon exposure to HDACs, depending on enzyme concentration and exposure time. Our investigation, utilizing HDAC8 as the model enzyme, revealed that the primary mechanism behind disassembly involves a decrease in amphiphilicity within the block copolymer due to the deacetylation of lysine residues within the particles' hydrophobic domains. To elucidate the response mechanism, we encapsulated a fluorescent dye within these nanoparticles. Upon incubation with HDAC, the nanoparticle structure collapsed, leading to controlled release of the dye over time. Notably, this release was not triggered by denatured HDAC8, other proteolytic enzymes like trypsin, or the co-presence of HDAC8 and its inhibitor. We further demonstrated the biocompatibility and cellular effects of these materials and conducted a comprehensive computational study to unveil the possible interaction mechanism between enzymes and particles. By drawing parallels to the mechanism of naturally occurring histone proteins, this research represents a pioneering step toward developing functional materials capable of harnessing the activity of epigenetic enzymes such as HDACs.

DOI: https://doi.org/10.1101/2024.03.26.585429