bims-polyam 2021-02-07 papers

bims-polyam

Biomed News

on Polyamines

Issue of 2021–02–07
fiveteen papers selected by
Sebastian J. Hofer, University of Graz

Preventive and Therapeutic Spermidine Treatment Attenuates Acute Colitis in Mice.
Translational Regulation of Clock Genes BMAL1 and REV-ERBα by Polyamines.
Exogenous spermine attenuates diabetic kidney injury in rats by inhibiting AMPK/mTOR signaling pathway.
Autophagy induction by exogenous polyamines is an artifact of bovine serum amine oxidase activity in culture serum.
Role of Antizyme Inhibitor Proteins in Cancers and Beyond.
Hydrogen sulfide in longevity and pathologies: inconsistency is malodorous.
Molecular Mechanisms of the 1-Aminocyclopropane-1-Carboxylic Acid (ACC) Deaminase Producing Trichoderma asperellum MAP1 in Enhancing Wheat Tolerance to Waterlogging Stress.
Spermine: Its Emerging Role in Regulating Drought Stress Responses in Plants.
Deletion of Polyamine Transport Protein PotD Exacerbates Virulence in Glaesserella (Haemophilus) parasuis in the Form of Non-biofilm-generated Bacteria in a Murine Acute Infection Model.
Natural Products That Target the Arginase in Leishmania Parasites Hold Therapeutic Promise.
Novel aspects of age-protection by spermidine supplementation are associated with preserved telomere length.
Geroprotective potential of genetic and pharmacological interventions to endogenous hydrogen sulfide synthesis in Drosophila melanogaster.
Inhibition of the mTORC1/NF-κB Axis Alters Amino Acid Metabolism in Human Hepatocytes.
The importance of genetic research on the dominant species of human intestinal indigenous microbiota.
Identification of Chalcone Derivatives as Inhibitors of Leishmania infantum Arginase and Promising Antileishmanial Agents.

J Agric Food Chem. 2021 Feb 04.

Preventive and Therapeutic Spermidine Treatment Attenuates Acute Colitis in Mice.

Lingyan Ma, Liyang Ni, Tianqi Yang, Pei Mao, Xin Huang, Yeqin Luo, Zhiyuan Jiang, Luting Hu, Yufeng Zhao, Zhengwei Fu, Yinhua Ni.

  Inflammatory bowel disease (IBD) is associated with acute and chronic inflammation of the gastrointestinal tract and has emerged to be a global disease. Spermidine, a natural polyamine, plays a critical role in maintaining cellular homeostasis. Herein, we investigated the impact and mechanism of spermidine on both dextran sulfate sodium (DSS)- and 2,4,6-trinitrobenzenesulfonic acid solution (TNBS)-induced colitis in mice. We found that spermidine exerted protective effects against acute colitis, evidenced by reduced disease activity index (DAI) and colonic inflammation, increased colonic length, and upregulated tight junction proteins in these two colitis models. Importantly, spermidine exerted significant therapeutic and preventive effects against DSS-induced colitis. Pre- and post-treatment with spermidine reduced the expression of proinflammatory cytokines, phosphorylation of (nuclear factor-κB) NF-κB and (mitogen-activated protein kinase) MAPK, and the activation of F4/80 macrophages and T cells in the colon. Furthermore, spermidine upregulated M2 macrophage markers, whereas it downregulated M1 markers in the inflamed colons. In parallel, spermidine reduced M1 pro-inflammatory markers and enhanced M2 anti-inflammatory genes in RAW264.7 cells. These results revealed that spermidine-ameliorated colitis might be through the regulation of M1/M2 macrophage polarization. In addition, spermidine treatment also alleviated LPS/TNF-α-induced inflammation in Caco-2 cells. Taken together, spermidine prevented and reversed colonic inflammation in colitis mice and might be a promising candidate for IBD intervention.

Keywords:  colonic inflammation; inflammatory bowel disease; intestinal barrier; macrophage; spermidine

DOI:  https://doi.org/10.1021/acs.jafc.0c07095
Int J Mol Sci. 2021 Jan 28. pii: 1307. [Epub ahead of print]22(3):

Translational Regulation of Clock Genes BMAL1 and REV-ERBα by Polyamines.

Akihiko Sakamoto, Yusuke Terui, Takeshi Uemura, Kazuei Igarashi, Keiko Kashiwagi.

  Polyamines stimulate the synthesis of specific proteins at the level of translation, and the genes encoding these proteins are termed as the "polyamine modulon". The circadian clock generates daily rhythms in mammalian physiology and behavior. We investigated the role of polyamines in the circadian rhythm using control and polyamine-reduced NIH3T3 cells. The intracellular polyamines exhibited a rhythm with a period of about 24 h. In the polyamine-reduced NIH3T3 cells, the circadian period of circadian clock genes was lengthened and the synthesis of BMAL1 and REV-ERBα was significantly reduced at the translation level. Thus, the mechanism of polyamine stimulation of these protein syntheses was analyzed using NIH3T3 cells transiently transfected with genes encoding enhanced green fluorescent protein (EGFP) fusion mRNA with normal or mutated 5'-untranslated region (5'-UTR) of Bmal1 or Rev-erbα mRNA. It was found that polyamines stimulated BMAL1 and REV-ERBα synthesis through the enhancement of ribosomal shunting during the ribosome shunting within the 5'-UTR of mRNAs. Accordingly, the genes encoding Bmal1 and Rev-erbα were identified as the members of "polyamine modulon", and these two proteins are significantly involved in the circadian rhythm control.

Keywords:  BMAL1; REV-ERBα; circadian clock; polyamine modulon; translation

DOI:  https://doi.org/10.3390/ijms22031307
Int J Mol Med. 2021 Mar;pii: 27. [Epub ahead of print]47(3):

Exogenous spermine attenuates diabetic kidney injury in rats by inhibiting AMPK/mTOR signaling pathway.

Xinying Zhang, Li Zhang, Zhe Chen, Siwei Li, Bingbing Che, Ningning Wang, Junting Chen, Changqing Xu, Can Wei.

Diabetic nephropathy (DN) is the primary cause of end‑stage renal disease, which is closely associated with dysfunction of the podocytes, the main component of the glomerular filtration membrane; however, the exact underlying mechanism is unknown. Polyamines, including spermine, spermidine and putrescine, have antioxidant and anti‑aging properties that are involved in the progression of numerous diseases, but their role in DN has not yet been reported. The present study aimed to explore the role of polyamines in DN, particularly in podocyte injury, and to reveal the molecular mechanism underlying the protective effect of exogenous spermine. Streptozotocin intraperitoneal injection‑induced type 1 diabetic (T1D) rat models and high glucose (HG)‑stimulated podocyte injury models were established. It was found that in T1D rat kidneys and HG‑induced podocytes, ornithine decarboxylase (a key enzyme for polyamine synthesis) was downregulated, while spermidine/spermine N1‑acetyltransferase (a key enzyme for polyamines degradation) was upregulated, which suggested that reduction of the polyamine metabolic pool particularly decreased spermine content, is a major factor in DN progression. In addition, hyperglycemia can induce an increased rat kidney weight ratio, serum creatinine, urea, urinary albumin excretion and glomerular cell matrix levels, and promote mesangial thickening and loss or fusion of podocytes. The expression levels of podocyte marker proteins (nephrin, CD2‑associated protein and podocin) and autophagy‑related proteins [autophagy protein 5, microtube‑associated proteins 1A/1B light chain 3 (LC3)II/LC3I, Beclin 1 and phosphorylated (p)‑AMPK] were downregulated, while cleaved caspase‑3, P62 and p‑mTOR were increased. These changes could be improved by pretreatment with exogenous spermine or rapamycin (autophagic agonist). In conclusion, spermine may have the potential to prevent diabetic kidney injury in rats by promoting autophagy via regulating the AMPK/mTOR signaling pathway.

DOI: https://doi.org/10.3892/ijmm.2021.4860
J Biol Chem. 2020 Jul 03. pii: S0021-9258(17)50328-2. [Epub ahead of print]295(27): 9061-9068

Autophagy induction by exogenous polyamines is an artifact of bovine serum amine oxidase activity in culture serum.

Cassandra E Holbert, Matthew Dunworth, Jackson R Foley, Tiffany T Dunston, Tracy Murray Stewart, Robert A Casero.

  Polyamines are small polycationic alkylamines involved in many fundamental cellular processes, including proliferation, nucleic acid synthesis, apoptosis, and protection from oxidative damage. It has been proposed that in addition to these functions, elevated levels of polyamines promote longevity in various biological systems, including yeast, Drosophila, and murine models. A series of in vitro mechanistic studies by multiple investigators has led to the conclusion that addition of exogenous spermidine promotes longevity through autophagy induction; however, these experiments were confounded by the use of mammalian cell culture systems supplemented with fetal bovine serum. Using cell viability assays, LC3B immunoblots, and live-cell fluorescence microscopy, we report here that in the presence of ruminant serum, exogenously added polyamines are quickly oxidized by the copper-containing bovine serum amine oxidase. This polyamine oxidation resulted in the production of harmful byproducts including hydrogen peroxide, ammonia, and reactive aldehydes. Our data demonstrate that it is critically important to prevent confounding bovine serum amine oxidase-induced cytotoxicity in mechanistic studies of the roles of polyamines in autophagy.

Keywords:  amine oxidase; autophagy; beta-oxidation; bovine serum amine oxidase (BSAO); cytotoxicity; hydrogen peroxide; oxidative stress; polyamine; spermidine; spermine

DOI:  https://doi.org/10.1074/jbc.RA120.013867
Onco Targets Ther. 2021 ;14 667-682

Role of Antizyme Inhibitor Proteins in Cancers and Beyond.

Vennela Tulluri, Venkatesh V Nemmara.

  Polyamines are multivalent organic cations essential for many cellular functions, including cell growth, differentiation, and proliferation. However, elevated polyamine levels are associated with a slew of pathological conditions, including multiple cancers. Intracellular polyamine levels are primarily controlled by the autoregulatory circuit comprising two different protein types, Antizymes (OAZ) and Antizyme Inhibitors (AZIN), which regulate the activity of the polyamine biosynthetic enzyme ornithine decarboxylase (ODC). While OAZ functions to decrease the intracellular polyamine levels by inhibiting ODC activity and exerting a negative control of polyamine uptake, AZIN operates to increase intracellular polyamine levels by binding and sequestering OAZ to relieve ODC inhibition and to increase polyamine uptake. Interestingly, OAZ and AZIN exhibit autoregulatory functions on polyamine independent pathways as well. A growing body of evidence demonstrates the dysregulation of AZIN expression in multiple cancers. Additionally, RNA editing of the Azin1 transcript results in a "gain-of-function" phenotype, which is shown to drive aggressive tumor types. This review will discuss the recent advances in AZIN's role in cancers via aberrant polyamine upregulation and its polyamine-independent protein regulation. This report will also highlight AZIN interaction with proteins outside the polyamine biosynthetic pathway and its potential implication to cancer pathogenesis. Finally, this review will reveal the protein interaction network of AZIN isoforms by analyzing three different interactome databases.

Keywords:  26S proteasome; antizyme; antizyme inhibitor; degradation; mRNA editing; ornithine decarboxylase; polyamine; protein interactome; putrescine; spermidine; spermine; ubiquitin-independent

DOI:  https://doi.org/10.2147/OTT.S281157
Ageing Res Rev. 2021 Jan 28. pii: S1568-1637(21)00009-X. [Epub ahead of print] 101262

Hydrogen sulfide in longevity and pathologies: inconsistency is malodorous.

Alexander S Sokolov, Pavel V Nekrasov, Mikhail V Shaposhnikov, Alexey A Moskalev.

  Hydrogen sulfide (H2S) is one of the biologically active gases (gasotransmitters), which plays an important role in various physiological processes and aging. Its production in the course of methionine and cysteine catabolism and its degradation are finely balanced, and impairment of H2S homeostasis is associated with various pathologies. Despite the strong geroprotective action of exogenous H2S in C. elegans, there are controversial effects of hydrogen sulfide and its donors on longevity in other models, as well as on stress resistance, age-related pathologies and aging processes, including regulation of senescence-associated secretory phenotype (SASP) and senescent cell anti-apoptotic pathways (SCAPs). Here we discuss that the translation potential of H2S as a geroprotective compound is influenced by a multiplicity of its molecular targets, pleiotropic biological effects, and the overlapping ranges of toxic and beneficial doses. We also consider the challenges of the targeted delivery of H2S at the required dose. Along with this, the complexity of determining the natural levels of H2S in animal and human organs and their ambiguous correlations with longevity are reviewed.

Keywords:  aging; dietary restriction; diseases; hydrogen sulfide; hypoxia; longevity

DOI:  https://doi.org/10.1016/j.arr.2021.101262
Front Plant Sci. 2020 ;11 614971

Molecular Mechanisms of the 1-Aminocyclopropane-1-Carboxylic Acid (ACC) Deaminase Producing Trichoderma asperellum MAP1 in Enhancing Wheat Tolerance to Waterlogging Stress.

Mamoona Rauf, Muhammad Awais, Aziz Ud-Din, Kazim Ali, Humaira Gul, Muhammad Mizanur Rahman, Muhammad Hamayun, Muhammad Arif.

  Waterlogging stress (WS) induces ethylene (ET) and polyamine (spermine, putrescine, and spermidine) production in plants, but their reprogramming is a decisive element for determining the fate of the plant upon waterlogging-induced stress. WS can be challenged by exploring symbiotic microbes that improve the plant's ability to grow better and resist WS. The present study deals with identification and application of 1-aminocyclopropane-1-carboxylic acid (ACC) deaminase-producing fungal endophyte Trichoderma asperellum (strain MAP1), isolated from the roots of Canna indica L., on wheat growth under WS. MAP1 positively affected wheat growth by secreting phytohormones/secondary metabolites, strengthening the plant's antioxidant system and influencing the physiology through polyamine production and modulating gene expression. MAP1 inoculation promoted yield in comparison to non-endophyte inoculated waterlogged seedlings. Exogenously applied ethephon (ET synthesis inducer) and 1-aminocyclopropane carboxylic acid (ACC; ET precursor) showed a reduction in growth, compared to MAP1-inoculated waterlogged seedlings, while amino-oxyacetic acid (AOA; ET inhibitor) application reversed the negative effect imposed by ET and ACC, upon waterlogging treatment. A significant reduction in plant growth rate, chlorophyll content, and stomatal conductance was noticed, while H2O2, MDA production, and electrolyte leakage were increased in non-inoculated waterlogged seedlings. Moreover, in comparison to non-inoculated waterlogged wheat seedlings, MAP1-inoculated waterlogged wheat exhibited antioxidant-enzyme activities. In agreement with the physiological results, genes associated with the free polyamine (PA) biosynthesis were highly induced and PA content was abundant in MAP1-inoculated seedlings. Furthermore, ET biosynthesis/signaling gene expression was reduced upon MAP1 inoculation under WS. Briefly, MAP1 mitigated the adverse effect of WS in wheat, by reprogramming the PAs and ET biosynthesis, which leads to optimal stomatal conductance, increased photosynthesis, and membrane stability as well as reduced ET-induced leaf senescence.

Keywords:  ACC deaminase enzyme; Trichoderma asperellum; biofertilizer; endophytic fungus; ethylene; polyamines; waterlogging stress; wheat

DOI:  https://doi.org/10.3389/fpls.2020.614971
Cells. 2021 Jan 28. pii: 261. [Epub ahead of print]10(2):

Spermine: Its Emerging Role in Regulating Drought Stress Responses in Plants.

Md Mahadi Hasan, Milan Skalicky, Mohammad Shah Jahan, Md Nazmul Hossain, Zunaira Anwar, Zheng-Fei Nie, Nadiyah M Alabdallah, Marian Brestic, Vaclav Hejnak, Xiang-Wen Fang.

  In recent years, research on spermine (Spm) has turned up a lot of new information about this essential polyamine, especially as it is able to counteract damage from abiotic stresses. Spm has been shown to protect plants from a variety of environmental insults, but whether it can prevent the adverse effects of drought has not yet been reported. Drought stress increases endogenous Spm in plants and exogenous application of Spm improves the plants' ability to tolerate drought stress. Spm's role in enhancing antioxidant defense mechanisms, glyoxalase systems, methylglyoxal (MG) detoxification, and creating tolerance for drought-induced oxidative stress is well documented in plants. However, the influences of enzyme activity and osmoregulation on Spm biosynthesis and metabolism are variable. Spm interacts with other molecules like nitric oxide (NO) and phytohormones such as abscisic acid, salicylic acid, brassinosteroids, and ethylene, to coordinate the reactions necessary for developing drought tolerance. This review focuses on the role of Spm in plants under severe drought stress. We have proposed models to explain how Spm interacts with existing defense mechanisms in plants to improve drought tolerance.

Keywords:  abscisic acid; antioxidant enzymes; drought; polyamines; stomata

DOI:  https://doi.org/10.3390/cells10020261
Virulence. 2021 Dec;12(1): 520-546

Deletion of Polyamine Transport Protein PotD Exacerbates Virulence in Glaesserella (Haemophilus) parasuis in the Form of Non-biofilm-generated Bacteria in a Murine Acute Infection Model.

Ke Dai, Zhen Yang, Xiaoyu Ma, Yung-Fu Chang, Sanjie Cao, Qin Zhao, Xiaobo Huang, Rui Wu, Yong Huang, Jing Xia, Qigui Yan, Xinfeng Han, Xiaoping Ma, Xintian Wen, Yiping Wen.

  Polyamines are small, polycationic molecules with a hydrocarbon backbone and multiple amino groups required for optimal cell growth. The potD gene, belonging to the ABC (ATP-binding cassette) transport system potABCD, encodes the bacterial substrate-binding subunit of the polyamine transport system, playing a pivotal role in bacterial metabolism and growth. The swine pathogen Glaesserella parasuis possesses an intact pot operon, and the studies presented here mainly examined the involvement of PotD in Glaesserella pathogenesis. A potD-deficient mutant was constructed using a virulent G. parasuis strain SC1401 by natural transformation; immuno-electron microscopy was used to identify the subcellular location of native PotD protein; an electron microscope was adopted to inspect biofilm and bacterial morphology; immunofluorescence technique was employed to study cellular adhesion, the levels of inflammation and apoptosis. The TSA++-pre-cultured mutant strain showed a significantly reduced adhesion capacity to PK-15 and MLE-12 cells. Likewise, we also found attenuation in virulence using murine models focusing on the clinical sign, H&E, and IFA for inflammation and apoptosis. However, when the mutant was grown in TSB++, virulence recovered to normal levels, along with a high level of radical oxygen species formation in the host. The expression of PotD could actively stimulate the production of ROS in Raw 264.7. Our data suggested that PotD from G. parasuis has a high binding potential to polyamine, and is essential for the full bacterial virulence within mouse models. However, the virulence of the potD mutant is highly dependent on its TSA++ culture conditions rather than on biofilm-formation.

Keywords:   Haemophilus parasuis ; glaesserella parasuis ; apoptosis; pathogenesis; polyamine; potD

DOI:  https://doi.org/10.1080/21505594.2021.1878673
Microorganisms. 2021 Jan 28. pii: 267. [Epub ahead of print]9(2):

Natural Products That Target the Arginase in Leishmania Parasites Hold Therapeutic Promise.

Nicola S Carter, Brendan D Stamper, Fawzy Elbarbry, Vince Nguyen, Samuel Lopez, Yumena Kawasaki, Reyhaneh Poormohamadian, Sigrid C Roberts.

  Parasites of the genus Leishmania cause a variety of devastating and often fatal diseases in humans worldwide. Because a vaccine is not available and the currently small number of existing drugs are less than ideal due to lack of specificity and emerging drug resistance, the need for new therapeutic strategies is urgent. Natural products and their derivatives are being used and explored as therapeutics and interest in developing such products as antileishmanials is high. The enzyme arginase, the first enzyme of the polyamine biosynthetic pathway in Leishmania, has emerged as a potential therapeutic target. The flavonols quercetin and fisetin, green tea flavanols such as catechin (C), epicatechin (EC), epicatechin gallate (ECG), and epigallocatechin-3-gallate (EGCG), and cinnamic acid derivates such as caffeic acid inhibit the leishmanial enzyme and modulate the host's immune response toward parasite defense while showing little toxicity to the host. Quercetin, EGCG, gallic acid, caffeic acid, and rosmarinic acid have proven to be effective against Leishmania in rodent infectivity studies. Here, we review research on these natural products with a focus on their promise for the development of treatment strategies as well as unique structural and pharmacokinetic/pharmacodynamic features of the most promising agents.

Keywords:  Leishmania; arginase; cinnamic acid; green tea polyphenols; natural products; polyamines; putrescine; quercetin; spermidine

DOI:  https://doi.org/10.3390/microorganisms9020267
Geroscience. 2021 Jan 31.

Novel aspects of age-protection by spermidine supplementation are associated with preserved telomere length.

Alexander Wirth, Bettina Wolf, Cheng-Kai Huang, Silke Glage, Sebastian J Hofer, Marion Bankstahl, Christian Bär, Thomas Thum, Kai G Kahl, Stephan J Sigrist, Frank Madeo, Jens P Bankstahl, Evgeni Ponimaskin.

  Ageing provokes a plethora of molecular, cellular and physiological deteriorations, including heart failure, neurodegeneration, metabolic maladaptation, telomere attrition and hair loss. Interestingly, on the molecular level, the capacity to induce autophagy, a cellular recycling and cleaning process, declines with age across a large spectrum of model organisms and is thought to be responsible for a subset of age-induced changes. Here, we show that a 6-month administration of the natural autophagy inducer spermidine in the drinking water to aged mice is sufficient to significantly attenuate distinct age-associated phenotypes. These include modulation of brain glucose metabolism, suppression of distinct cardiac inflammation parameters, decreased number of pathological sights in kidney and liver and decrease of age-induced hair loss. Interestingly, spermidine-mediated age protection was associated with decreased telomere attrition, arguing in favour of a novel cellular mechanism behind the anti-ageing effects of spermidine administration.

Keywords:  Ageing; Cardiac telomeres; Glucose metabolism; Hair growth; PET; Spermidine

DOI:  https://doi.org/10.1007/s11357-020-00310-0
Biogerontology. 2021 Feb 05.

Geroprotective potential of genetic and pharmacological interventions to endogenous hydrogen sulfide synthesis in Drosophila melanogaster.

Mikhail V Shaposhnikov, Nadezhda V Zemskaya, Liubov A Koval, Eugenia V Schegoleva, Daria V Yakovleva, Natalia S Ulyasheva, Anastasia A Gorbunova, Natalya R Minnikhanova, Alexey A Moskalev.

  Endogenous hydrogen sulfide (H2S) is a gasotransmitter with a wide range of physiological functions. Aging is accompanied by disruption of H2S homeostasis, therefore, interventions to the processes of H2S metabolism to maintain its balance may have geroprotective potential. Here we demonstrated the additive geroprotective effect of combined genetic and pharmacological interventions to the hydrogen sulfide biosynthesis system by overexpression of cystathionine-β-synthase and cystathionine-γ-lyase genes and treatment with precursors of H2S synthesis cysteine (Cys) and N-acetyl-L-cysteine (NAC). The obtained results suggest that additive effects of genetic and pharmacological interventions to H2S metabolism may be associated with the complex interaction between beneficial action of H2S production and prevention of adverse effects of excess H2S production by Cys and NAC treatment.

Keywords:  Anti-aging intervention; Drosophila melanogaster; Hydrogen sulfide; Lifespan extension

DOI:  https://doi.org/10.1007/s10522-021-09911-4
Biomed Res Int. 2021 ;2021 8621464

Inhibition of the mTORC1/NF-κB Axis Alters Amino Acid Metabolism in Human Hepatocytes.

Meng Zhang, Yuting Fu, Yuhao Chen, Yuze Ma, Zhixin Guo, Yanfeng Wang, Huifang Hao, Quan Fu, Zhigang Wang.

In addition to serving as the building blocks for protein synthesis, amino acids can be used as an energy source, through catabolism. The transamination, oxidative deamination, and decarboxylation processes that occur during amino acid catabolism are catalyzed by specific enzymes, including aspartate aminotransferase (AST), glutamate dehydrogenase (GDH), glutamic acid decarboxylase (GAD), and ornithine decarboxylase (ODC); however, the overall molecular mechanisms through which amino acid catabolism occurs remain largely unknown. To examine the role of mechanistic target of rapamycin complex 1 (mTORC1) on amino acid catabolism, mTORC1 was inactivated by rapamycin or shRNA targeting Raptor, versus activated by overexpressing Rheb or amino acids in human hepatocytes. The expression of amino acid catabolic genes and related transcription factor was investigated by RT/real-time PCR and western blot analysis. A few types of amino acid metabolite were examined by ELISA and HPLC analysis. The data showed that inactivated mTORC1 resulted in inhibition of NF-κB and the expression of AST, GDH, GAD, and ODC, whereas activated mTORC1 enhanced NF-κB activation and the expression levels of the catabolism-associated genes. Further, inhibition of NF-κB reduced the expression levels of AST, GDH, GAD, and ODC. mTORC1 upregulated NF-κB activation and the expression of AST and ODC in response to glutamate and ornithine treatments, whereas rapamycin inhibited the utilization of glutamate and ornithine in hepatocytes. Taken together, these results indicated that the mTORC1/NF-κB axis modulates the rate of amino acid catabolism by regulating the expression of key catabolic enzymes in hepatocytes.

DOI: https://doi.org/10.1155/2021/8621464
Biosci Microbiota Food Health. 2021 ;40(1): 19-26

The importance of genetic research on the dominant species of human intestinal indigenous microbiota.

Shin Kurihara.

  Comparisons of the changes in the gut microbiota and transcriptomes as a result of changes in diet have demonstrated that the regulation of the gene functions of intestinal bacteria is fundamental for the regulation of the intestinal environment. However, the functions of only about half of the genes can be predicted using nucleotide sequences obtained from the metagenomic data of the human gut microbiota. Therefore, the regulation of gut bacterial gene functions is hindered. To resolve this issue, the functions of the genes of intestinal bacteria must be identified. In our previous study, a high-throughput cultivation system was established for the dominant species of indigenous human intestinal microbiota. Using this system, we analyzed the synthesis and transport of polyamines by intestinal bacteria. Comparison of the results with those obtained by in silico analysis indicated the existence of novel polyamine synthetic enzymes and transport proteins. Next, strains with gene deletions and complementation for the polyamine synthetic system of the genus Bacteroides were analyzed. Furthermore, we co-cultured genetically engineered Escherichia coli and Enterococcus faecalis strains to demonstrate the presence of a polyamine synthetic pathway spanning multiple bacterial species. Here, we outline the trends of research using genetically engineered intestinal bacteria and the ripple effects of studies in which intestinal bacteria have been analyzed genetically. Moreover, because studies on intestinal bacteria at the gene level are indispensable for improving our understanding of their regulation, the importance of this research will continue to increase in the future.

Keywords:  co-culture; cultivation; genetic engineering; metabolites of intestinal bacteria

DOI:  https://doi.org/10.12938/bmfh.2020-011
Front Chem. 2020 ;8 624678

Identification of Chalcone Derivatives as Inhibitors of Leishmania infantum Arginase and Promising Antileishmanial Agents.

Andreza R Garcia, Danielle M P Oliveira, Jessica B Jesus, Alessandra M T Souza, Ana Carolina R Sodero, Alane B Vermelho, Ivana C R Leal, Rodrigo Octavio M A Souza, Leandro S M Miranda, Anderson S Pinheiro, Igor A Rodrigues.

  Arginase catalyzes the hydrolysis of l-arginine into l-ornithine and urea, acting as a key enzyme in the biosynthesis of polyamines. Leishmania growth and survival is dependent on polyamine biosynthesis; therefore, inhibition of Leishmania arginase may be a promising therapeutic strategy. Here, we evaluated a series of thirty-six chalcone derivatives as potential inhibitors of Leishmania infantum arginase (LiARG). In addition, the activity of selected inhibitors against L. infantum parasites was assessed in vitro. Seven compounds exhibited LiARG inhibition above 50% at 100 μM. Among them, compounds LC41, LC39, and LC32 displayed the greatest inhibition values (72.3 ± 0.3%, 71.9 ± 11.6%, and 69.5 ± 7.9%, respectively). Molecular docking studies predicted hydrogen bonds and hydrophobic interactions between the most active chalcones (LC32, LC39, and LC41) and specific residues from LiARG's active site, such as His140, Asn153, His155, and Ala193. Compound LC32 showed the highest activity against L. infantum promastigotes (IC50 of 74.1 ± 10.0 μM), whereas compounds LC39 and LC41 displayed the best results against intracellular amastigotes (IC50 of 55.2 ± 3.8 and 70.4 ± 9.6 μM, respectively). Moreover, compound LC39 showed more selectivity against parasites than host cells (macrophages), with a selectivity index (SI) of 107.1, even greater than that of the reference drug Fungizone®. Computational pharmacokinetic and toxicological evaluations showed high oral bioavailability and low toxicity for the most active compounds. The results presented here support the use of substituted chalcone skeletons as promising LiARG inhibitors and antileishmanial drug candidates.

Keywords:  Leishmania infantum; antileishmanial activity; arginase; chalcone; inhibition

DOI:  https://doi.org/10.3389/fchem.2020.624678