Naphthyridine Derivatives Induce Programmed Cell Death in Naegleria fowleri

Primary amoebic encephalitis (PAM) caused by the opportunistic pathogen Naegleria fowleri is characterized as a rapid and lethal infection of the brain which ends in the death of the patient in more than 90% of the reported cases. This amoeba thrives in warm water bodies and causes infection after individuals perform risky activities such as splashing or diving, mostly in non-treated water bodies such as lakes and ponds. Moreover, the infection progresses very fast and no fully effective molecules have currently been found to treat PAM. In this study, naphthyridines fused with chromenes or chromenones previously synthetized by the group were tested in vitro against the trophozoite stage of two strains of N. fowleri. In addition, the most active molecule was evaluated in order to check the induction of programmed cell death (PCD) in the treated amoebae. Compound 3 showed good anti-Naegleria activity (61.45 ± 5.27 and 76.61 ± 10.84 µM, respectively) against the two different strains (ATCC® 30808 and ATCC® 30215) and a good selectivity compared to the cytotoxicity values (>300 µM). In addition, it was able to induce PCD, causing DNA condensation, damage at the cellular membrane, reduction in mitochondrial membrane potential and ATP levels, and ROS generation. Hence, naphthyridines fused with chromenes or chromenones could be potential therapeutic agents against PAM in the near future.

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Laurinterol from Laurencia johnstonii eliminates Naegleria fowleri triggering PCD by inhibition of ATPases

Scientific Reports ◽

10.1038/s41598-020-74729-y ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Iñigo Arberas-Jiménez ◽

Sara García-Davis ◽

Aitor Rizo-Liendo ◽

Ines Sifaoui ◽

María Reyes-Batlle ◽

...

Keyword(s):

Cell Death ◽

Apoptotic Cell ◽

Treatment Options ◽

Opportunistic Pathogen ◽

Current Treatment ◽

Ion Pump ◽

Naegleria Fowleri ◽

Trophozoite Stage ◽

Nægleria Fowleri

Abstract Primary amoebic encephalitis (PAM) is a lethal disease caused by the opportunistic pathogen, Naegleria fowleri. This amoebic species is able to live freely in warm aquatic habitats and to infect children and young adults when they perform risk activities in these water bodies such as swimming or splashing. Besides the need to increase awareness of PAM which will allow an early diagnosis, the development of fully effective therapeutic agents is needed. Current treatment options are amphotericin B and miltefosine which are not fully effective and also present toxicity issues. In this study, the in vitro activity of various sesquiterpenes isolated from the red alga Laurencia johnstonii were tested against the trophozoite stage of a strain of Naegleria fowleri. Moreover, the induced effects (apoptotic cell death) of the most active compound, laurinterol (1), was evaluated by measuring DNA condensation, damages at the mitochondrial level, cell membrane disruption and production of reactive oxygen species (ROS). The obtained results demonstrated that laurinterol was able to eliminate the amoebae at concentrations of 13.42 ± 2.57 µM and also to induced programmed cell death (PCD) in the treated amoebae. Moreover, since ATP levels were highly affected and laurinterol has been previously reported as an inhibitor of the Na+/K+-ATPase sodium–potassium ion pump, comparison with known inhibitors of ATPases were carried out. Our results points out that laurinterol was able to inhibit ENA ATPase pump at concentrations 100 times lower than furosemide.

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Exploring the Anti-Infective Value of Inuloxin A Isolated from Inula viscosa against the Brain-Eating Amoeba (Naegleria fowleri) by Activation of Programmed Cell Death

ACS Chemical Neuroscience ◽

10.1021/acschemneuro.0c00685 ◽

2020 ◽

Vol 12 (1) ◽

pp. 195-202

Author(s):

Ikrame Zeouk ◽

Ines Sifaoui ◽

Aitor Rizo-Liendo ◽

Iñigo Arberas-Jiménez ◽

María Reyes-Batlle ◽

...

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Naegleria Fowleri ◽

Nægleria Fowleri ◽

The Brain

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The type 2 statins, cerivastatin, rosuvastatin and pitavastatin eliminate Naegleria fowleri at low concentrations and by induction of programmed cell death (PCD)

Bioorganic Chemistry ◽

10.1016/j.bioorg.2021.104784 ◽

2021 ◽

pp. 104784

Author(s):

Aitor Rizo-Liendo ◽

Iñigo Arberas-Jiménez ◽

Inés Sifaoui ◽

María Reyes-Batlle ◽

José E. Piñero ◽

...

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Naegleria Fowleri ◽

Low Concentrations ◽

Nægleria Fowleri

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Amphotericin B induces apoptosis-like programmed cell death in Naegleria fowleri and Naegleria gruberi

Microbiology ◽

10.1099/mic.0.000500 ◽

2017 ◽

Vol 163 (7) ◽

pp. 940-949 ◽

Cited By ~ 3

Author(s):

Roberto Cárdenas-Zúñiga ◽

Angélica Silva-Olivares ◽

José D' Artagnan Villalba-Magdaleno ◽

Virginia Sánchez-Monroy ◽

Jesús Serrano-Luna ◽

...

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Amphotericin B ◽

Naegleria Fowleri ◽

Nægleria Fowleri ◽

Naegleria Gruberi

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DHEA protects mitochondria against dual modes of apoptosis and necroptosis in human granulosa HO23 cells

Reproduction ◽

10.1530/rep-17-0016 ◽

2017 ◽

Vol 154 (2) ◽

pp. 101-110 ◽

Cited By ~ 11

Author(s):

Kuan-Hao Tsui ◽

Peng-Hui Wang ◽

Li-Te Lin ◽

Chia-Jung Li

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Culture Conditions ◽

Human Oocyte ◽

Ros Generation ◽

Mitochondrial Morphology ◽

Ros Scavenging ◽

Chinese Translation ◽

Cell Death Pathway

Because ovarian granulosa cells are essential for oocyte maturation and development, we validated human granulosa HO23 cells to evaluate the ability of the DHEA to prevent cell death after starvation. The present study was aimed to investigate whether DHEA could protect against starvation-induced apoptosis and necroptosis in human oocyte granulosa HO23 cells. The starvation was induced by treatment of serum-free (SF) medium for 4 h in vitro. Starvation-induced mitochondrial depolarization, cytochrome c release and caspase-3 activation were largely prevented by DHEA in HO23 cells. We found that treatment with DHEA can restore starvation-induced reactive oxygen species (ROS) generation and mitochondrial membrane potential imbalance. In addition, treatment of DHEA prevents cell death via upregulation of cytochrome c and downregulation of BAX in mitochondria. Most importantly, DHEA is ameliorated to mitochondrial function mediated through the decrease in mitochondrial ROS, maintained mitochondrial morphology, and enhancing the ability of cell proliferation and ROS scavenging. Our present data strongly indicate that DHEA reduces programmed cell death (apoptosis and necroptosis) in granulosa HO23 cells through multiple interactions with the mitochondrion-dependent programmed cell death pathway. Taken together, our data suggest that the presence of DHEA could be beneficial to protect human oocyte granulosa HO23 cells under in vitro culture conditions during various assisted reproductive technology (ART) programs. Free Chinese abstract: A Chinese translation of this abstract is freely available at http://www.reproduction-online.org/content/154/2/101/suppl/DC1

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Fluvastatin and atorvastatin induce programmed cell death in the brain eating amoeba Naegleria fowleri

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2020.110583 ◽

2020 ◽

Vol 130 ◽

pp. 110583

Author(s):

Aitor Rizo-Liendo ◽

Ines Sifaoui ◽

Iñigo Arberas-Jiménez ◽

María Reyes-Batlle ◽

José E. Piñero ◽

...

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Naegleria Fowleri ◽

Nægleria Fowleri ◽

The Brain

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Control of a programmed cell death pathway in Pseudomonas aeruginosa by an antiterminator

Nature Communications ◽

10.1038/s41467-021-21941-7 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jennifer M. Peña ◽

Samantha M. Prezioso ◽

Kirsty A. McFarland ◽

Tracy K. Kambara ◽

Kathryn M. Ramsey ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Dna Damage ◽

Cell Death ◽

Programmed Cell Death ◽

Rna Polymerase ◽

Virulence Genes ◽

Opportunistic Pathogen ◽

Transcription Activator ◽

Present Evidence ◽

Cell Death Pathway

AbstractIn Pseudomonas aeruginosa the alp system encodes a programmed cell death pathway that is switched on in a subset of cells in response to DNA damage and is linked to the virulence of the organism. Here we show that the central regulator of this pathway, AlpA, exerts its effects by acting as an antiterminator rather than a transcription activator. In particular, we present evidence that AlpA positively regulates the alpBCDE cell lysis genes, as well as genes in a second newly identified target locus, by recognizing specific DNA sites within the promoter, then binding RNA polymerase directly and allowing it to bypass intrinsic terminators positioned downstream. AlpA thus functions in a mechanistically unusual manner to control the expression of virulence genes in this opportunistic pathogen.

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In vitro antioxidant treatment recovers proliferative responses of anergic CD4+ lymphocytes from human immunodeficiency virus-infected individuals

Blood ◽

10.1182/blood.v87.11.4746.bloodjournal87114746 ◽

1996 ◽

Vol 87 (11) ◽

pp. 4746-4753 ◽

Cited By ~ 30

Author(s):

A Cayota ◽

F Vuillier ◽

G Gonzalez ◽

G Dighiero

Keyword(s):

Human Immunodeficiency Virus ◽

Cell Death ◽

Programmed Cell Death ◽

Redox Status ◽

Therapeutic Strategies ◽

Antioxidant Treatment ◽

Immunodeficiency Virus ◽

Cd4 Lymphocytes ◽

Cellular Thiol

Oxidative stress has been proposed to be involved in the immunologic defeat observed in effector calls of the immune system as well as in lymphocyte cell death and viral replication in human immunodeficiency virus (HIV)-infected patients. Because thiol-containing antioxidants such as N-acetyl-L-cysteine have been shown to have beneficial effects on CD4+ lymphocyte survival and to inhibit programmed cell death and HIV-1 replication, they may play a role in therapeutic strategies of this disease. In this work we have studied the cellular thiol levels and the affect of in vitro antioxidant treatment of purified CD4+ lymphocytes from HIV-infected patients, and correlated these parameters to proliferative responses and programmed cell death. We show that CD4+ lymphocytes from HIV-infected patients display impaired proliferative responses and a significant decrease in cellular thiol levels, indicating a disturbed redox status. Interestingly, antioxidant treatment succeeded to restore defective proliferative responses to CD3- mediated activation in 8 of 11 patients (high antioxidant responders). In contrast to high responders, patients failing to respond to antioxidant treatment (low antioxidant responders), were characterized by an abnormal ratio of apoptotic cells, which was not affected by N- acetyl-L-cysteine and/or 2-beta-mercaptoethanol preincubation. These results demonstrate for the first time that antioxidant treatment is able to revert the impaired proliferative activity of CD4 cells from HIV-infected patients and could help designing therapeutic strategies with antioxidant drugs. However, this action is not observed in cells undergoing programmed cell death.

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Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2

Journal of Experimental Medicine ◽

10.1084/jem.20112741 ◽

2012 ◽

Vol 209 (6) ◽

pp. 1201-1217 ◽

Cited By ~ 442

Author(s):

Tadashi Yokosuka ◽

Masako Takamatsu ◽

Wakana Kobayashi-Imanishi ◽

Akiko Hashimoto-Tane ◽

Miyuki Azuma ◽

...

Keyword(s):

Cell Death ◽

T Cell ◽

Programmed Cell Death ◽

T Cell Activation ◽

Cell Activation ◽

Tyrosine Phosphatase ◽

Cell Receptor ◽

Programmed Cell Death 1

Programmed cell death 1 (PD-1) is a negative costimulatory receptor critical for the suppression of T cell activation in vitro and in vivo. Single cell imaging elucidated a molecular mechanism of PD-1–mediated suppression. PD-1 becomes clustered with T cell receptors (TCRs) upon binding to its ligand PD-L1 and is transiently associated with the phosphatase SHP2 (Src homology 2 domain–containing tyrosine phosphatase 2). These negative costimulatory microclusters induce the dephosphorylation of the proximal TCR signaling molecules. This results in the suppression of T cell activation and blockade of the TCR-induced stop signal. In addition to PD-1 clustering, PD-1–TCR colocalization within microclusters is required for efficient PD-1–mediated suppression. This inhibitory mechanism also functions in PD-1hi T cells generated in vivo and can be overridden by a neutralizing anti–PD-L1 antibody. Therefore, PD-1 microcluster formation is important for regulation of T cell activation.

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