bims-toxgon 2023-07-30 papers

bims-toxgon

Biomed News

on Toxoplasma gondii metabolism

Issue of 2023‒07‒30
seventeen papers selected by
Lakesh Kumar
BITS Pilani

ROP16 of Toxoplasma gondii Inhibits Innate Immunity by Triggering cGAS-STING Pathway Inactivity through the Polyubiquitination of STING.
Co-Immunization with DNA Vaccines Expressing SABP1 and SAG1 Proteins Effectively Enhanced Mice Resistance to Toxoplasma gondii Acute Infection.
Genome-wide CRISPR screen identifies genes synthetically lethal with GRA17, a nutrient channel encoding gene in Toxoplasma.
Dynamic RNA profiles in the small intestinal epithelia of cats after Toxoplasma gondii infection.
Protective efficacy of Toxoplasma gondii GRA12 or GRA7 recombinant proteins encapsulated in PLGA nanoparticles against acute Toxoplasma gondii infection in mice.
Quantitative Risk Assessment of Oocyst Versus Bradyzoite Foodborne Transmission of Toxoplasma gondii in Brazil.
Global analysis of putative phospholipases in Plasmodium falciparum reveals an essential role of the phosphoinositide-specific phospholipase C in parasite maturation.
Gene editing of putative cAMP and Ca 2+ -regulated proteins using an efficient cloning-free CRISPR/Cas9 system in Trypanosoma cruzi.
Chemoproteomics Yields a Selective Molecular Host for Acetyl-CoA.
Glucose Inhibits Yeast AMPK (Snf1) by Three Independent Mechanisms.
Toxoplasma gondii Investigation of Home-Reared Pigs through Real-Time PCR and Digital Droplet PCR: A Very Low Prevalence.
Seroprevalence of Toxoplasma gondii and associated risk factors for infection in the Netherlands: third cross-sectional national study.
Sirtuin family in autoimmune diseases.
Discovery of Novel SIRT1/2 Inhibitors with Effective Cytotoxicity against Human Leukemia Cells.
Application of Ligand- and Structure-Based Prediction Models for the Design of Alkylhydrazide-Based HDAC3 Inhibitors as Novel Anti-Cancer Compounds.
Role of SIRT2 in intestinal barrier under cold exposure.
SIRT1 and SIRT6: The role in aging-related diseases.

Cells. 2023 Jul 15. pii: 1862. [Epub ahead of print]12(14):

ROP16 of Toxoplasma gondii Inhibits Innate Immunity by Triggering cGAS-STING Pathway Inactivity through the Polyubiquitination of STING.

Qi-Wang Jin, Ting Yu, Ming Pan, Yi-Min Fan, Si-Yang Huang.

  cGAS-STING signaling is a major pathway in inducing type Ⅰ IFN, which plays a crucial role in the defense against T. gondii infection. In contrast, T. gondii develops multiple strategies to counteract the host defense, causing serious diseases in a wide range of hosts. Here, we demonstrate that T. gondii rhoptry protein 16 (ROP16) dampens type I interferon signaling via the inhibition of the cGAS (cyclic GMP-AMP synthase) pathway through the polyubiquitination of STING. Mechanistically, ROP16 interacts with STING through the SignalP domain and inhibits the K63-linked ubiquitination of STING in an NLS (nuclear localization signal)-domain-dependent manner. Consequently, knocking out the ROP16 in PRU tachyzoites promotes the STING-mediated production of type I IFNs and limits the replication of T. gondii. Together, these findings describe a distinct pathway where T. gondii exploits the ubiquitination of STING to evade host anti-parasite immunity, revealing new insights into the interaction between the host and parasites.

Keywords:  ROP16; Toxoplasma gondii; cGAS-STING pathway; immune escape

DOI:  https://doi.org/10.3390/cells12141862
Vaccines (Basel). 2023 Jul 02. pii: 1190. [Epub ahead of print]11(7):

Co-Immunization with DNA Vaccines Expressing SABP1 and SAG1 Proteins Effectively Enhanced Mice Resistance to Toxoplasma gondii Acute Infection.

Xiaoyu Sang, Xiang Li, Ran Chen, Ying Feng, Ting He, Xiaohan Zhang, Saeed El-Ashram, Ebtsam Al-Olayan, Na Yang.

  Toxoplasma gondii (T. gondii) has many intermediate hosts, obligately invades nucleated cells, and seriously threatens human and animal health due to a lack of effective drugs and vaccines. Sialic acid-binding protein 1 (SABP1) is a novel invasion-related protein that, like surface antigen 1 (SAG1), is found on the plasma membrane of T. gondii. To investigate the immunogenicity and protective efficacy of DNA vaccines expressing SABP1 and SAG1 proteins against T. gondii acute infection, the recombinant plasmids pVAX1-SABP1 and pVAX1-SAG1 were produced and administered intramuscularly in Balb/c mice. Serum antibody levels and subtypes, lymphocyte proliferation, and cytokines were used to assess immunized mice's humoral and cellular immune responses. Furthermore, the ability of DNA vaccines to protect mice against T. gondii RH tachyzoites was tested. Immunized mice exhibited substantially higher IgG levels, with IgG2a titers higher than IgG1. When the immune group mice's splenocytes were stimulated with T. gondii lysate antigen, Th1-type cytokines (IL-12p70, IFN-γ, and IL-2) and Th2-type cytokine (IL-4) increased significantly. The combined DNA vaccine significantly increased the immunized mouse survival compared to the control group, with an average death time extended by 4.33 ± 0.6 days (p < 0.0001). These findings show that DNA vaccines based on the SABP1 and SAG1 genes induced robust humoral and cellular immunity in mice, effectively protecting against acute toxoplasmosis and potentially serving as a viable option for vaccination to prevent T. gondii infection.

Keywords:  DNA vaccine; SABP1; SAG1; Toxoplasma gondii; co-immunization

DOI:  https://doi.org/10.3390/vaccines11071190
PLoS Pathog. 2023 Jul 27. 19(7): e1011543

Genome-wide CRISPR screen identifies genes synthetically lethal with GRA17, a nutrient channel encoding gene in Toxoplasma.

Tatiana C Paredes-Santos, Mebratu A Bitew, Christopher Swale, Felipe Rodriguez, Shruthi Krishnamurthy, Yifan Wang, Parag Maru, Lamba Omar Sangaré, Jeroen P J Saeij.

Toxoplasma gondii is a parasite that replicates within a specialized compartment called the parasitophorous vacuole (PV), which is surrounded by the PV membrane (PVM). To obtain essential nutrients, Toxoplasma must transport molecules across the PVM, a process mediated by the secreted parasite proteins GRA17 and GRA23. These proteins form pores in the PVM through which small molecules can diffuse in and out of the PV. GRA17 and GRA23 are synthetically lethal, suggesting that at least one pore type is essential for parasite survival. In the 'nutrient sensitized' Δgra17 strain it is likely that other Toxoplasma genes become essential, because they mediate nutrient acquisition from the host or are involved in the trafficking of GRA23 to the PVM. To identify these genes, a genome-wide loss-of-function screen was performed in wild-type and Δgra17 parasites, which identified multiple genes that were synthetically sick/lethal with GRA17. Several of these genes were involved in the correct localization of GRAs, including GRA17/GRA23, to the PVM. One of the top hits, GRA72, was predicted to form a pore on the PVM, and its deletion led to the formation of enlarged "bubble vacuoles" with reduced PVM small molecule permeability, similar to what was previously observed for Δgra17 parasites. Furthermore, Δgra72 parasites had reduced in vitro growth and virulence in mice. These findings suggest that in the absence of GRA17, other genes become essential, likely because they play a role in the proper localization of GRA23 (and other GRAs) or because they determine host-derived nutrient acquisition at the PVM.

DOI: https://doi.org/10.1371/journal.ppat.1011543
Infect Dis Poverty. 2023 Jul 25. 12(1): 68

Dynamic RNA profiles in the small intestinal epithelia of cats after Toxoplasma gondii infection.

Bintao Zhai, Shi-Chen Xie, Jiyu Zhang, Jun-Jun He, Xing-Quan Zhu.

  BACKGROUND: Felids are the only definitive hosts of Toxoplasma gondii. However, the biological features of the feline small intestine following T. gondii infection are poorly understood. We investigated the changes in the expression of RNAs (including mRNAs, long non-coding RNAs and circular RNAs) in the small intestinal epithelia of cats following T. gondii infection to improve our understanding of the life cycle of T. gondii and cat responses to T. gondii infection.METHODS: Fifteen cats were randomly assigned to five groups, and the infection groups were inoculated with 600 tissue cysts of the T. gondii Pru strain by gavage. The small intestinal epithelia of cats were collected at 6, 10, 14, and 30 days post infection (DPI). Using high-throughput RNA sequencing (RNA-seq), we investigated the changes in RNA expression. The expression levels of differentially expressed (DE) genes and non-coding RNAs (ncRNAs) identified by RNA-seq were validated by quantitative reverse transcription PCR (qRT-PCR). Differential expression was determined using the DESeq R package.
RESULTS: In total, 207 annotated lncRNAs, 20,552 novel lncRNAs, 3342 novel circRNAs and 19,409 mRNAs were identified. Among these, 70 to 344 DE mRNAs, lncRNAs and circRNAs were detected, and the post-cleavage binding sites between 725 ncRNAs and 2082 miRNAs were predicted. Using the co-location method, we predicted that a total of 235 lncRNAs target 1044 protein-coding genes, while the results of co-expression analysis revealed that 174 lncRNAs target 2097 mRNAs. Pathway enrichment analyses of the genes targeted by ncRNAs suggested that most ncRNAs were significantly enriched in immune or diseases-related pathways. NcRNA regulatory networks revealed that a single ncRNA could be directly or indirectly regulated by multiple genes or ncRNAs that could influence the immune response of cats. Co-expression analysis showed that 242 circRNAs, mainly involved in immune responses, were significantly associated with T. gondii infection. In contrast, 1352 protein coding RNAs, mainly involved in nucleic acid process/repair pathways or oocyte development pathways, were negatively associated with T. gondii infection.
CONCLUSIONS: This study is the first to reveal the expression profiles of circRNAs, lncRNAs and mRNAs in the cat small intestine following T. gondii infection and will facilitate the elucidation of the role of ncRNAs in the pathogenesis of T. gondii infection in its definitive host, thereby facilitating the development of novel intervention strategies against T. gondii infection in humans and animals.

Keywords:  Cat; Circular RNA; Definitive host; Long non-coding RNA; Small intestinal epithelia; Toxoplasma gondii; mRNA

DOI:  https://doi.org/10.1186/s40249-023-01121-z
Front Cell Infect Microbiol. 2023 ;13 1209755

Protective efficacy of Toxoplasma gondii GRA12 or GRA7 recombinant proteins encapsulated in PLGA nanoparticles against acute Toxoplasma gondii infection in mice.

Hong-Chao Sun, Pu-Ming Deng, Yuan Fu, Jin-Hua Deng, Rong-Hui Xie, Jing Huang, Meng Qi, Tuan-Yuan Shi.

  Background: Toxoplasma gondii is an apicomplexan parasite that affects the health of humans and livestock, and an effective vaccine is urgently required. Nanoparticles can modulate and improve cellular and humoral immune responses.Methods: In the current study, poly (D, L-lactic-co-glycolic acid) (PLGA) nanoparticles were used as a delivery system for the T. gondii dense granule antigens GRA12 and GRA7. BALB/c mice were injected with the vaccines and protective efficacy was evaluated.
Results: Mice immunized with PLGA+GRA12 exhibited significantly higher IgG, and a noticeable predominance of IgG2a over IgG1 was also observed. There was a 1.5-fold higher level of lymphocyte proliferation in PLGA+GRA12-injected mice compared to Alum+GRA12-immunized mice. Higher levels of IFN-g and IL-10 and a lower level of IL-4 were detected, indicating that Th1 and Th2 immune responses were induced but the predominant response was Th1. There were no significant differences between Alum+GRA7-immunized and PLGA+GRA7-immunized groups. Immunization with these four vaccines resulted in significantly reduced parasite loads, but they were lowest in PLGA+GRA12-immunized mice. The survival times of mice immunized with PLGA+GRA12 were also significantly longer than those of mice in the other vaccinated groups.
Conclusion: The current study indicated that T. gondii GRA12 recombinant protein encapsulated in PLGA nanoparticles is a promising vaccine against acute toxoplasmosis, but PLGA is almost useless for enhancing the immune response induced by T. gondii GRA7 recombinant protein.

Keywords:  GRA12; GRA7; PLGA; Toxoplasma gondii; nanoparticles; vaccine

DOI:  https://doi.org/10.3389/fcimb.2023.1209755
Pathogens. 2023 Jun 25. pii: 870. [Epub ahead of print]12(7):

Quantitative Risk Assessment of Oocyst Versus Bradyzoite Foodborne Transmission of Toxoplasma gondii in Brazil.

Sophie Zhu, Elizabeth VanWormer, Beatriz Martínez-López, Lílian Maria Garcia Bahia-Oliveira, Renato Augusto DaMatta, Pedro Souto Rodrigues, Karen Shapiro.

  Toxoplasma gondii is a globally distributed zoonotic protozoan parasite. Infection with T. gondii can cause congenital toxoplasmosis in developing fetuses and acute outbreaks in the general population, and the disease burden is especially high in South America. Prior studies found that the environmental stage of T. gondii, oocysts, is an important source of infection in Brazil; however, no studies have quantified this risk relative to other parasite stages. We developed a Bayesian quantitative risk assessment (QRA) to estimate the relative attribution of the two primary parasite stages (bradyzoite and oocyst) that can be transmitted in foods to people in Brazil. Oocyst contamination in fruits and greens contributed significantly more to overall estimated T. gondii infections than bradyzoite-contaminated foods (beef, pork, poultry). In sensitivity analysis, treatment, i.e., cooking temperature for meat and washing efficiency for produce, most strongly affected the estimated toxoplasmosis incidence rate. Due to the lack of regional food contamination prevalence data and the high level of uncertainty in many model parameters, this analysis provides an initial estimate of the relative importance of food products. Important knowledge gaps for oocyst-borne infections were identified and can drive future studies to improve risk assessments and effective policy actions to reduce human toxoplasmosis in Brazil.

Keywords:  Toxoplasma gondii; bradyzoite; foodborne pathogen; oocyst; quantitative risk assessment

DOI:  https://doi.org/10.3390/pathogens12070870
mBio. 2023 Jul 25. e0141323

Global analysis of putative phospholipases in Plasmodium falciparum reveals an essential role of the phosphoinositide-specific phospholipase C in parasite maturation.

Paul-Christian Burda, Abhinay Ramaprasad, Sabrina Bielfeld, Emma Pietsch, Anna Woitalla, Christoph Söhnchen, Mehar Nihal Singh, Jan Strauss, Aaron Sait, Lucy M Collinson, Dominik Schwudke, Michael J Blackman, Tim-Wolf Gilberger.

  For its replication within red blood cells, the malaria parasite depends on a highly active and regulated lipid metabolism. Enzymes involved in lipid metabolic processes such as phospholipases are, therefore, potential drug targets. Here, using reverse genetics approaches, we show that only 1 out of the 19 putative phospholipases expressed in asexual blood stages of Plasmodium falciparum is essential for proliferation in vitro, pointing toward a high level of redundancy among members of this enzyme family. Using conditional mislocalization and gene disruption techniques, we show that this essential phosphoinositide-specific phospholipase C (PI-PLC, PF3D7_1013500) has a previously unrecognized essential role during intracellular parasite maturation, long before its previously perceived role in parasite egress and invasion. Subsequent lipidomic analysis suggests that PI-PLC mediates cleavage of phosphatidylinositol bisphosphate (PIP2) in schizont-stage parasites, underlining its critical role in regulating phosphoinositide levels in the parasite. IMPORTANCE The clinical symptoms of malaria arise due to repeated rounds of replication of Plasmodium parasites within red blood cells (RBCs). Central to this is an intense period of membrane biogenesis. Generation of membranes not only requires de novo synthesis and acquisition but also the degradation of phospholipids, a function that is performed by phospholipases. In this study, we investigate the essentiality of the 19 putative phospholipase enzymes that the human malaria parasite Plasmodium falciparum expresses during its replication within RBCs. We not only show that a high level of functional redundancy exists among these enzymes but, at the same time, also identify an essential role for the phosphoinositide-specific phospholipase C in parasite development and cleavage of the phospholipid phosphatidylinositol bisphosphate.

Keywords:  blood stage; malaria; phosphoinositides; phospholipase

DOI:  https://doi.org/10.1128/mbio.01413-23
bioRxiv. 2023 Jul 10. pii: 2023.07.09.548290. [Epub ahead of print]

Gene editing of putative cAMP and Ca 2+ -regulated proteins using an efficient cloning-free CRISPR/Cas9 system in Trypanosoma cruzi.

Miguel A Chiurillo, Milad Ahmed, César González, Aqsa Raja, Noelia Lander.

Trypanosoma cruzi is the causative agent of Chagas disease, a prominent cause of heart disease in the Americas, for which there is no vaccine or satisfactory treatment available. The life cycle of this protozoan parasite alternates between mammalian and insect hosts, during which, in order to survive, it must adapt to a diversity of environmental conditions it faces. The adaptation to these changes is mediated by signaling pathways that coordinate the cellular responses to the new environmental settings. Cyclic AMP (cAMP) and Calcium (Ca +2 ) signaling pathways regulate critical cellular processes in this parasite, such as differentiation, osmoregulation, flagellar function, host cell invasion and cell bioenergetics. From the adaptation of CRISPR/Cas9 technology in T. cruzi the reverse genetic approaches for functional analysis of genes have experienced a significant impulse However, the toolbox for genome editing in this parasite still needs to be expanded, for example, to perform multiple gene deletion analyses. Here we used a T7RNAP/Cas9-mediated strategy to tag and delete three genes putatively involved in cAMP and Ca 2+ signaling pathways: a putative Ca 2+ /calmodulin-dependent protein kinase ( CAMK ), FLAgellar Member 6 ( FLAM6 ) and Cyclic nucleotide-binding domain/C2 domain-containing protein ( CC2CP ). We were able to endogenously tag these three genes and determine the subcellular localization of the tagged proteins. Furthermore, the strategy used for gene knockout experiments allows us to suggest that TcCC2CP is an essential gene in T. cruzi epimastigotes. Our results obtained in T. cruzi epimastigote forms on these proteins will open new venues for future research.

DOI: https://doi.org/10.1101/2023.07.09.548290
J Am Chem Soc. 2023 Jul 24.

Chemoproteomics Yields a Selective Molecular Host for Acetyl-CoA.

Whitney K Lieberman, Zachary A Brown, Daniel S Kantner, Yihang Jing, Emily Megill, Nya D Evans, McKenna C Crawford, Isita Jhulki, Carissa Grose, Jane E Jones, Nathaniel W Snyder, Jordan L Meier.

Chemoproteomic profiling is a powerful approach to define the selectivity of small molecules and endogenous metabolites with the human proteome. In addition to mechanistic studies, proteome specificity profiling also has the potential to identify new scaffolds for biomolecular sensing. Here, we report a chemoproteomics-inspired strategy for selective sensing of acetyl-CoA. First, we use chemoproteomic capture experiments to validate the N-terminal acetyltransferase NAA50 as a protein capable of differentiating acetyl-CoA and CoA. A Nanoluc-NAA50 fusion protein retains this specificity and can be used to generate a bioluminescence resonance energy transfer (BRET) signal in the presence of a CoA-linked fluorophore. This enables the development of a ligand displacement assay in which CoA metabolites are detected via their ability to bind the Nanoluc-NAA50 protein "host" and compete binding of the CoA-linked fluorophore "guest". We demonstrate that the specificity of ligand displacement reflects the molecular recognition of the NAA50 host, while the window of dynamic sensing can be controlled by tuning the binding affinity of the CoA-linked fluorophore guest. Finally, we show that the method's specificity for acetyl-CoA can be harnessed for gain-of-signal optical detection of enzyme activity and quantification of acetyl-CoA from cellular samples. Overall, our studies demonstrate the potential of harnessing insights from chemoproteomics for molecular sensing and provide a foundation for future applications in target engagement and selective metabolite detection.

DOI: https://doi.org/10.1021/jacs.3c05489
Biology (Basel). 2023 Jul 14. pii: 1007. [Epub ahead of print]12(7):

Glucose Inhibits Yeast AMPK (Snf1) by Three Independent Mechanisms.

Kobi Simpson-Lavy, Martin Kupiec.

  Snf1, the fungal homologue of mammalian AMP-dependent kinase (AMPK), is a key protein kinase coordinating the response of cells to a shortage of glucose. In fungi, the response is to activate respiratory gene expression and metabolism. The major regulation of Snf1 activity has been extensively investigated: In the absence of glucose, it becomes activated by phosphorylation of its threonine at position 210. This modification can be erased by phosphatases when glucose is restored. In the past decade, two additional independent mechanisms of Snf1 regulation have been elucidated. In response to glucose (or, surprisingly, also to DNA damage), Snf1 is SUMOylated by Mms21 at lysine 549. This inactivates Snf1 and leads to Snf1 degradation. More recently, glucose-induced proton export has been found to result in Snf1 inhibition via a polyhistidine tract (13 consecutive histidine residues) at the N-terminus of the Snf1 protein. Interestingly, the polyhistidine tract plays also a central role in the response to iron scarcity. This review will present some of the glucose-sensing mechanisms of S. cerevisiae, how they interact, and how their interplay results in Snf1 inhibition by three different, and independent, mechanisms.

Keywords:  AMPK; Saccharomyces cerevisiae; Snf1; fermentation; glucose metabolism; hexose; respiration; yeast

DOI:  https://doi.org/10.3390/biology12071007
Pathogens. 2023 Jun 27. pii: 882. [Epub ahead of print]12(7):

Toxoplasma gondii Investigation of Home-Reared Pigs through Real-Time PCR and Digital Droplet PCR: A Very Low Prevalence.

Claudio de Martinis, Alessia Pucciarelli, Maria Ottaiano, Roberta Pellicanò, Loredana Baldi, Vincenzo Veneziano, Giovanni Sgroi, Federica Boccia, Carmine Carbone, Lorena Cardillo, Giovanna Fusco.

  Toxoplasma gondii is a widespread protozoon that can infect both animals and humans. The main route of human infection is the consumption of the raw or undercooked meat of several animal species, including pigs. Although T. gondii represents a public health concern, control during slaughter is not mandatory, leading to a lack of information on the impact on human contagion as well as poor data availability in domestic animals intended for human consumption. We studied the presence of T. gondii in home-reared pigs, an unconventional type of farming subjected to stringent breeding conditions dictated by Italian regulation. Thus, the diaphragms, livers and masseter muscles from 480 pigs in Napoli Province (Italy) were analyzed using real-time PCR and digital droplet PCR. The results showed four matrices that tested positive for T. gondii with very low protozoan loads (0.62%), belonging to three different animals. The low density of the animals (the maximum was four animals per farm) and the biosafety farming features decisively contributed to the bioexclusion of this pathogen. Comparing these results to intensive and extensive farm data, lower exposure to the parasite was revealed, suggesting that this farming method might mitigate the risk of human exposure through meat consumption.

Keywords:  Toxoplasma gondii; biosecurity; molecular biology; pig

DOI:  https://doi.org/10.3390/pathogens12070882
Epidemiol Infect. 2023 Jul 28. 1-22

Seroprevalence of Toxoplasma gondii and associated risk factors for infection in the Netherlands: third cross-sectional national study.

Oda E van den Berg, Kamelia R Stanoeva, Rens Zonneveld, Denise Hoek-van Deursen, Fiona van der Klis, Jan van de Kassteele, Eelco Franz, Marieke Opsteegh, Ingrid H M Friesema, Laetitia M Kortbeek.

DOI: https://doi.org/10.1017/S095026882300122X
Front Immunol. 2023 ;14 1186231

Sirtuin family in autoimmune diseases.

Zhengjie Tao, Zihan Jin, Jiabiao Wu, Gaojun Cai, Xiaolong Yu.

  In recent years, epigenetic modifications have been widely researched. As humans age, environmental and genetic factors may drive inflammation and immune responses by influencing the epigenome, which can lead to abnormal autoimmune responses in the body. Currently, an increasing number of studies have emphasized the important role of epigenetic modification in the progression of autoimmune diseases. Sirtuins (SIRTs) are class III nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases and SIRT-mediated deacetylation is an important epigenetic alteration. The SIRT family comprises seven protein members (namely, SIRT1-7). While the catalytic core domain contains amino acid residues that have remained stable throughout the entire evolutionary process, the N- and C-terminal regions are structurally divergent and contribute to differences in subcellular localization, enzymatic activity and substrate specificity. SIRT1 and SIRT2 are localized in the nucleus and cytoplasm. SIRT3, SIRT4, and SIRT5 are mitochondrial, and SIRT6 and SIRT7 are predominantly found in the nucleus. SIRTs are key regulators of various physiological processes such as cellular differentiation, apoptosis, metabolism, ageing, immune response, oxidative stress, and mitochondrial function. We discuss the association between SIRTs and common autoimmune diseases to facilitate the development of more effective therapeutic strategies.

Keywords:  autoimmune diseases; immune inflammation; oxidative stress; review; sirtuins; treatment

DOI:  https://doi.org/10.3389/fimmu.2023.1186231
J Chem Inf Model. 2023 Jul 24.

Discovery of Novel SIRT1/2 Inhibitors with Effective Cytotoxicity against Human Leukemia Cells.

Haiyan Cai, Yingying Wang, Jing Zhang, Zhenquan Wei, Teng Yan, Chenxi Feng, Zhijian Xu, Aiwu Zhou, Yingli Wu.

The sirtuin enzyme family members, SIRT1 and SIRT2, play both tumor-promoting and tumor-suppressing roles, depending on the context and experimental conditions. Compounds that inhibit either SIRT1 or SIRT2 show promising antitumor effects in several types of cancer models, both in vitro and in vivo. The simultaneous inhibition of SIRT1 and SIRT2 is helpful in treating cancer by completely blocking p53 deacetylation, leading to cell death. However, only a few SIRT1/2 dual inhibitors have been developed. Here, we report the discovery of a novel series of SIRT1/2 dual inhibitors via a rational drug design that involved virtual screening and a substructure search. Eleven of the derived compounds exhibited high inhibitory activities, with IC50 < 5 μM and high specificity for both SIRT1 and SIRT2. Compounds hsa55 and PS9 strongly induced apoptosis and showed antiproliferative effects against human leukemia cell lines, which could be due to their ability to increase of p53 and α-tubulin acetylation, as we observed in MOLM-13 cells. Therefore, the new scaffolds of these compounds and their efficacy in leukemia cell lines provide important clues for the further development of novel anti-leukemia drugs.

DOI: https://doi.org/10.1021/acs.jcim.3c00556
Pharmaceuticals (Basel). 2023 Jul 06. pii: 968. [Epub ahead of print]16(7):

Application of Ligand- and Structure-Based Prediction Models for the Design of Alkylhydrazide-Based HDAC3 Inhibitors as Novel Anti-Cancer Compounds.

Emre F Bülbül, Dina Robaa, Ping Sun, Fereshteh Mahmoudi, Jelena Melesina, Matthes Zessin, Mike Schutkowski, Wolfgang Sippl.

  Histone deacetylases (HDAC) represent promising epigenetic targets for several diseases including different cancer types. The HDAC inhibitors approved to date are pan-HDAC inhibitors and most show a poor selectivity profile, side effects, and in particular hydroxamic-acid-based inhibitors lack good pharmacokinetic profiles. Therefore, the development of isoform-selective non-hydroxamic acid HDAC inhibitors is a highly regarded field in medicinal chemistry. In this study, we analyzed different ligand-based and structure-based drug design techniques to predict the binding mode and inhibitory activity of recently developed alkylhydrazide HDAC inhibitors. Alkylhydrazides have recently attracted more attention as they have shown promising effects in various cancer cell lines. In this work, pharmacophore models and atom-based quantitative structure-activity relationship (QSAR) models were generated and evaluated. The binding mode of the studied compounds was determined using molecular docking as well as molecular dynamics simulations and compared with known crystal structures. Calculated free energies of binding were also considered to generate QSAR models. The created models show a good explanation of in vitro data and were used to develop novel HDAC3 inhibitors.

Keywords:  alkylhydrazide; atom-based QSAR; binding free energy; docking; histone deacetylases (HDAC); pharmacophore

DOI:  https://doi.org/10.3390/ph16070968
Life Sci. 2023 Jul 24. pii: S0024-3205(23)00584-2. [Epub ahead of print] 121949

Role of SIRT2 in intestinal barrier under cold exposure.

Guo Jingru, Xu Jing, Chen Leichong, Chen Zhuo, Hu Huijie, Nie Junshu, Yuan Jianbin, Ma Li, Lu Jingjing, Ji Hong, Xu Bin.

  Prolonged cold exposure causes body stress and damages health. The intestinal environment is complex and variable, and direct contact with the external environment can easily cause stress, damage and even lead to diseases such as diarrhea.AIMS: This study aimed to reveal the role of cold exposure on ileum damage and the role of SIRT2 in this process.
MAIN METHODS: C57BL6 mice and SIRT2 knockout mice were used to construct a chronic cold exposure model (21 days, random 4 °C exposure for 3 h per day), which was tested by various methods, including intestinal permeability assays, morphological assays, ultrastructural assays, western blotting, and fluorescence staining. In vitro assays were performed on the mouse small intestinal epithelial cell line MODE-K to investigate the role of endoplasmic reticulum stress, SIRT2 knockout, and autophagy on tight junctions.
KEY FINDINGS: The results showed that chronic cold exposure damaged the ileal epithelial barrier, with endoplasmic reticulum stress. Knockout of SIRT2 alleviates ileal injury via enhanced autophagy under cold exposure. And autophagy can restore the expression of ZO-1 under stress.
SIGNIFICANCE: This study can provide potential target and basic data for the treatment of IBD and other disorders of the intestinal barrier. Autophagy may be an important means of restoring damage to the intestinal barrier.

Keywords:  Autophagy; ER stress; FoxO1; Intestinal barrier; SIRT2; Tight junction

DOI:  https://doi.org/10.1016/j.lfs.2023.121949
Biochim Biophys Acta Mol Basis Dis. 2023 Jul 25. pii: S0925-4439(23)00181-3. [Epub ahead of print] 166815

SIRT1 and SIRT6: The role in aging-related diseases.

Yuzi You, Wei Liang.

  Aging is characterized by progressive functional deterioration with increased risk of mortality. It is a complex biological process driven by a multitude of intertwined mechanisms such as increased DNA damage, chronic inflammation, and metabolic dysfunction. Sirtuins (SIRTs) are a family of NAD+-dependent enzymes that regulate fundamental biological functions from genomic stability and lifespan to energy metabolism and tumorigenesis. Of the seven mammalian SIRT isotypes (SIRT1-7), SIRT1 and SIRT6 are well-recognized for regulating signaling pathways related to aging. Herein, we review the protective role of SIRT1 and SIRT6 in aging-related diseases at molecular, cellular, tissue, and whole-organism levels. We also discuss the therapeutic potential of SIRT1 and SIRT6 modulators in the treatment of these diseases and challenges thereof.

Keywords:  Aging; Aging-related diseases; SIRT1; SIRT6; Sirtuins

DOI:  https://doi.org/10.1016/j.bbadis.2023.166815