bims-polyam 2020-09-13 papers

on Polyamines

Issue of 2020–09–13
eight papers selected by
Sebastian J. Hofer, University of Graz and Alexander Ivanov, Engelhardt Institute of Molecular Biology

Targeting polyamine as a novel therapy in xenograft models of malignant pleural mesothelioma.
Thymoquinone and Difluoromethylornithine (DFMO) Synergistically Induce Apoptosis of Human Acute T Lymphoblastic Leukemia Jurkat Cells Through the Modulation of Epigenetic Pathways.
An Evaluation of Norspermidine on Anti-fungal Effect on Mature Candida albicans Biofilms and Angiogenesis Potential of Dental Pulp Stem Cells.
Warmth Prevents Bone Loss Through the Gut Microbiota.
Spermine Protects Cardiomyocytes from High Glucose-Induced Energy Disturbance by Targeting the CaSR-gp78-Ubiquitin Proteasome System.
Protective Effects of Spermidine Against Cirrhotic Cardiomyopathy in Bile Duct-Ligated Rats.
Metabolic Characterization and Consequences of Mitochondrial Pyruvate Carrier Deficiency in Drosophila melanogaster.
Spermidine inhibits neurodegeneration and delays aging via the PINK1-PDR1-dependent mitophagy pathway in C. elegans.

Lung Cancer. 2020 Sep 01. pii: S0169-5002(20)30590-0. [Epub ahead of print]148 138-148

Targeting polyamine as a novel therapy in xenograft models of malignant pleural mesothelioma.

Sze-Kwan Lam, Sheng Yan, Shi Xu, James Chung-Man Ho.

   INTRODUCTION: Inhalation of asbestos fibers is the key culprit in malignant pleural mesothelioma (MPM). Although the import and use of asbestos have been restricted, the incidence of MPM continues to increase globally due to the prolonged lag time in malignant transformation. The development of a novel adjuvant therapy for the minority of individuals with resectable early-stage disease and effective treatment for those with unresectable MPM are urgently needed. Our preliminary data revealed that ornithine decarboxylase (ODC) is highly expressed in MPM xenografts. This study aimed to determine the treatment effects of α-difluoromethylornithine (DFMO), a specific ODC inhibitor, in MPM xenografts.
RESULTS: In an "extended adjuvant DFMO treatment" setting, nude mice were fed with DFMO for 7 days prior to inoculation of 200,000 cells. DFMO suppressed tumor growth and increased median survival in both xenografts. In H226 xenograft, 43 % of treated mice had not reached the humane endpoint by day 132, mimicking long-term survival. DFMO decreased spermidine, increased nitrotyrosine and activated apoptosis in both xenografts. Furthermore, increase in nitrosocysteine, intratumoral IL-6, keratinocyte chemoattractant and TNFα, DNA lesion and inhibition of the Akt/mTOR pathway were induced by DFMO in H226 xenograft. In "DFMO treatment" setting, 107 cells were inoculated into nude mice and DFMO treatment commenced when tumor size reached ∼50-100 mm3. DFMO also suppressed tumor growth by similar mechanisms. Supplementation with spermidine reversed the therapeutic effect of DFMO. DFMO increased actin nitration at tyrosine 53 and inhibited actin polymerization.
CONCLUSION: DFMO is preclinically effective in treating MPM.

Keywords:  Apoptosis; Malignant pleural mesothelioma; Ornithine decarboxylase; Spermidine; Xenografts; α-difluoromethylornithine (DFMO)

DOI:  https://doi.org/10.1016/j.lungcan.2020.08.016
Technol Cancer Res Treat. 2020 Jan-Dec;19:19 1533033820947489

Thymoquinone and Difluoromethylornithine (DFMO) Synergistically Induce Apoptosis of Human Acute T Lymphoblastic Leukemia Jurkat Cells Through the Modulation of Epigenetic Pathways.

Mahmoud Alhosin, Syed Shoeb I Razvi, Ryan A Sheikh, Jalaluddin A Khan, Mazin A Zamzami, Hani Choudhry.

  Thymoquinone (TQ), a natural anticancer agent exerts cytotoxic effects on several tumors by targeting multiple pathways, including apoptosis. Difluoromethylornithine (DFMO), an irreversible inhibitor of the ornithine decarboxylase (ODC) enzyme, has shown promising inhibitory activities in many cancers including leukemia by decreasing the biosynthesis of the intracellular polyamines. The present study aimed to investigate the combinatorial cytotoxic effects of TQ and DFMO on human acute T lymphoblastic leukemia Jurkat cells and to determine the underlying mechanisms. Here, we show that the combination of DFMO and TQ significantly reduced cell viability and resulted in significant synergistic effects on apoptosis when compared to either DFMO or TQ alone. RNA-sequencing showed that many key epigenetic players including Ubiquitin-like containing PHD and Ring finger 1 (UHRF1) and its 2 partners DNA methyltransferase 1 (DNMT1) and histone deacetylase 1 (HDAC1) were down-regulated in DFMO-treated Jurkat cells. The combination of DFMO and TQ dramatically decreased the expression of UHRF1, DNMT1 and HDAC1 genes compared to either DFMO or TQ alone. UHRF1 knockdown led to a decrease in Jurkat cell viability. In conclusion, these results suggest that the combination of DFMO and TQ could be a promising new strategy for the treatment of human acute T lymphoblastic leukemia by targeting the epigenetic code.

Keywords:  DFMO; apoptosis; epigenetics; gene expression; thymoquinone

DOI:  https://doi.org/10.1177/1533033820947489
Front Bioeng Biotechnol. 2020 ;8 948

An Evaluation of Norspermidine on Anti-fungal Effect on Mature Candida albicans Biofilms and Angiogenesis Potential of Dental Pulp Stem Cells.

Yan He, Yanfan Cao, Yangfan Xiang, Fengting Hu, Fengyu Tang, Yanni Zhang, Abdullkhaleg Ali Albashari, Zhenjie Xing, Lihua Luo, Yan Sun, Qiang Huang, Qingsong Ye, Keke Zhang.

  Norspermidine (Nspd) is a kind of polyamine molecule, which is common in eukaryotes and prokaryotes. It has been reported as a potential anti-biofilms agent of bacteria, but its anti-fungal effect remains unclear. Candida albicans (C. albicans) is a common opportunistic pathogen in oral cavity of human beings. C. albicans biofilm is often seen in dental caries. In this work, we aimed to study the effect of Nspd on mature Candida albicans biofilms and to investigate how Nspd would influence human dental pulp stem cells (DPSCs). Our biofilm assays indicated that 111.7 and 55.9 mM Nspd dispersed 48 h mature fungal biofilms and showed significant fungicidal effect. 27.9 and 14.0 mM Nspd showed moderate fungicidal effect. Live/dead staining echoed the fungicidal effect. 111.7-14.0 mM Nspd showed a dose- inhibitory effect on mature fungal biofilm, where 14.0 mM Nspd reduced the metabolic activity by half compared with blank control. Moreover, we demonstrated that 111.7-27.9 mM Nspd restrained the production of hyphae form of C. albicans via SEM. Low dose Nspd (27.9 and 14.0 mM) could significantly reduce virulence related gene expression in C. albicans biofilms. MTT assay displayed a dose effect relation between 2.5-0.08 mM Nspd and DPSCs viability, where 0.63 mM Nspd reduced the viable level of DPSCs to 75% compared with blank control. Live/dead staining of DPSCs did not show distinctive difference between 0.63 mM Nspd and blank control. Vascular differentiation assay showed capillary-like structure of inducted DPSCs culture with and without 0.63 mM Nspd suggesting that it did not significantly affect angiogenic differentiation of DPSCs. Nspd can penetrate remaining dentin at low level, which is confirmed by an in vitro caries model. In conclusion, our study indicated high dosage Nspd (111.7 and 55.9 mM) could effectively disrupt and kill mature fungal biofilms. Low dosage (27.9 and 14.0 mM) showed mild anti-fungal effect on mature C. albicans biofilms. Human DPSCs were tolerate to 0.08-0.63 mM Nspd, where viability was over 75%. 0.63 mM Nspd did not affect the proliferation and angiogenetic differentiation of DPSCs.

Keywords:  Candida albicans; anti-fungal effect; dental pulp stem cells; differentiation; norspermidine; regenerative dentistry

DOI:  https://doi.org/10.3389/fbioe.2020.00948
Cell Metab. 2020 Sep 03. pii: S1550-4131(20)30425-3. [Epub ahead of print]

Warmth Prevents Bone Loss Through the Gut Microbiota.

Claire Chevalier, Silas Kieser, Melis Çolakoğlu, Noushin Hadadi, Julia Brun, Dorothée Rigo, Nicolas Suárez-Zamorano, Martina Spiljar, Salvatore Fabbiano, Björn Busse, Julijana Ivanišević, Andrew Macpherson, Nicolas Bonnet, Mirko Trajkovski.

  Osteoporosis is the most prevalent metabolic bone disease, characterized by low bone mass and microarchitectural deterioration. Here, we show that warmth exposure (34°C) protects against ovariectomy-induced bone loss by increasing trabecular bone volume, connectivity density, and thickness, leading to improved biomechanical bone strength in adult female, as well as in young male mice. Transplantation of the warm-adapted microbiota phenocopies the warmth-induced bone effects. Both warmth and warm microbiota transplantation revert the ovariectomy-induced transcriptomics changes of the tibia and increase periosteal bone formation. Combinatorial metagenomics/metabolomics analysis shows that warmth enhances bacterial polyamine biosynthesis, resulting in higher total polyamine levels in vivo. Spermine and spermidine supplementation increases bone strength, while inhibiting polyamine biosynthesis in vivo limits the beneficial warmth effects on the bone. Our data suggest warmth exposure as a potential treatment option for osteoporosis while providing a mechanistic framework for its benefits in bone disease.

Keywords:  bone; metabolomics; metadata; metagenomics; microbiota; osteoporosis; ovariectomy; polyamines; post-menopause; warm

DOI:  https://doi.org/10.1016/j.cmet.2020.08.012
Cardiovasc Drugs Ther. 2020 Sep 12.

Spermine Protects Cardiomyocytes from High Glucose-Induced Energy Disturbance by Targeting the CaSR-gp78-Ubiquitin Proteasome System.

Yuehong Wang, Yuwen Wang, Fadong Li, Xinying Zhang, Hongzhu Li, Guangdong Yang, Changqing Xu, Can Wei.

   PURPOSE: To determine the mediation of spermine on energy metabolism disorder and diabetic cardiomyopathy (DCM) development as well as the underlying mechanisms.
METHODS: An in vitro model of DCM was established by incubating primary cultured neonatal rat cardiomyocytes with high glucose (HG). Spermine content was assessed by RP-HPLC. The protein levels were detected by western blot. Mitochondrial functions were analyzed using the respiratory chain complex assay kit and immunofluorescence staining.
RESULTS: The endogenous content of spermine was decreased in the HG group, and the protein levels of ornithine decarboxylase, respiratory chain complex (I-V), mitochondrial fusion-related protein (Mfn1, Mfn2), Cx43, N-cadherin, CaSR, and β-catenin (in cytomembrane) were also down-regulated by HG. In contrast, the protein levels of spermine-N1-acetyltransferase, gp78, Fis1, Drp1, and β-catenin were up-regulated by HG. Meanwhile, we observed that HG increased ubiquitination levels of Mfn1, Mfn2, and Cx43, decreased membrane potential (ΔΨm), and the opening of mitochondrial permeability transport pore (mPTP) followed by intracellular ATP leakage. The supplement of spermine or siRNA-mediated knockdown of gp78 significantly alleviated the detrimental effects of HG, while downregulation of CaSR aggravated the development of DCM. We further confirmed that the lower level of spermine by HG activates the gp78-ubiquitin-proteasome pathway via downregulation of CaSR protein level, which in turn damages mitochondrial gap junction intercellular communication and leads to reduced ATP level.
CONCLUSION: The protective role of spermine on energy metabolism disorder is based on higher CaSR protein level and lower gp78 activation, pointing to the possibility that spermine can be a target for the prevention and treatment of DCM.

Keywords:  ATP; Connexin43; Diabetic cardiomyopathy; Gp78; Spermine

DOI:  https://doi.org/10.1007/s10557-020-07064-z
J Cardiovasc Pharmacol. 2020 Sep;76(3): 286-295

Protective Effects of Spermidine Against Cirrhotic Cardiomyopathy in Bile Duct-Ligated Rats.

Mohammad Sheibani, Sadaf Nezamoleslami, Seyyedeh E Mousavi, Hedyeh Faghir-Ghanesefat, Hasan Yousefi-Manesh, Seyed M Rezayat, Ahmadreza Dehpour.

Cirrhotic cardiomyopathy is a critical factor that causes morbidity and mortality in crucial conditions such as liver transplantation. In animal model, the common pathophysiologic mechanisms of cirrhotic cardiomyopathy are similar to those associated with bile duct ligation (BDL). Overproduction of inflammatory and oxidant markers plays a crucial role in cirrhotic cardiomyopathy. Spermidine, a multifunctional polyamine, is known for its antioxidant and anti-inflammatory effects. In this study, we investigated the effects of spermidine on development of cirrhotic cardiomyopathy in BDL rats. Rats were randomly housed in 6 groups. Except the normal and sham groups, BDL was performed for all the control and spermidine groups. Seven days after operation, 3 different doses of spermidine (5, 10 and 50 mg/kg) were administrated until day 28, in spermidine groups. At the end of the fourth week, the electrocardiography (ECG) and papillary muscle isolation were performed. The serum level of tumor necrosis factor-a (TNF-α), interleukin-1β (IL-1β), and IL-10 and cardiac level of superoxide dismutase, glutathione (GSH). and malondialdehyde (MDA) were assessed. Furthermore, the nuclear factor-κB (NF-κB) expression was assessed by western blot. Cardiac histopathological changes were monitored. The serum levels of magnesium (Mg) and potassium (K) were investigated. Control group, exhibited exaggerated signs of cirrhotic cardiomyopathy in comparison with the sham group. Co-administration of spermidine at the dose of 10 mg/kg in BDL rats significantly improved the cardiac condition, reduced the inflammatory mediators, and increased antioxidant enzymes. In addition, the histopathologic findings were in accordance with the other results of the study. Besides, there was no significant alteration in serum levels of Mg and K. This study demonstrates that spermidine at the dose of 10 mg/kg significantly improved the cirrhotic cardiomyopathy in BDL model in rats.

DOI: https://doi.org/10.1097/FJC.0000000000000872
Metabolites. 2020 Sep 06. pii: E363. [Epub ahead of print]10(9):

Metabolic Characterization and Consequences of Mitochondrial Pyruvate Carrier Deficiency in Drosophila melanogaster.

Chloé Simard, Andréa Lebel, Eric Pierre Allain, Mohamed Touaibia, Etienne Hebert-Chatelain, Nicolas Pichaud.

  In insect, pyruvate is generally the predominant oxidative substrate for mitochondria. This metabolite is transported inside mitochondria via the mitochondrial pyruvate carrier (MPC), but whether and how this transporter controls mitochondrial oxidative capacities in insects is still relatively unknown. Here, we characterize the importance of pyruvate transport as a metabolic control point for mitochondrial substrate oxidation in two genotypes of an insect model, Drosophila melanogaster, differently expressing MPC1, an essential protein for the MPC function. We evaluated the kinetics of pyruvate oxidation, mitochondrial oxygen consumption, metabolic profile, activities of metabolic enzymes, and climbing abilities of wild-type (WT) flies and flies harboring a deficiency in MPC1 (MPC1def). We hypothesized that MPC1 deficiency would cause a metabolic reprogramming that would favor the oxidation of alternative substrates. Our results show that the MPC1def flies display significantly reduced climbing capacity, pyruvate-induced oxygen consumption, and enzymatic activities of pyruvate kinase, alanine aminotransferase, and citrate synthase. Moreover, increased proline oxidation capacity was detected in MPC1def flies, which was associated with generally lower levels of several metabolites, and particularly those involved in amino acid catabolism such as ornithine, citrulline, and arginosuccinate. This study therefore reveals the flexibility of mitochondrial substrate oxidation allowing Drosophila to maintain cellular homeostasis.

Keywords:  drosophila; kinetics; metabolomics; mitochondrial pyruvate carrier; mitochondrial respiration

DOI:  https://doi.org/10.3390/metabo10090363
Aging (Albany NY). 2020 Sep 09. 12

Spermidine inhibits neurodegeneration and delays aging via the PINK1-PDR1-dependent mitophagy pathway in C. elegans.

Xin Yang, Mohan Zhang, Yuhua Dai, Yuchao Sun, Yahyah Aman, Yuying Xu, Peilin Yu, Yifan Zheng, Jun Yang, Xinqiang Zhu.

  Aging is the primary driver of various diseases, including common neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Currently there is no cure for AD and PD, and the development of novel drug candidates is demanding. Spermidine is a small anti-aging molecule with elimination of damaged mitochondria via the process of mitophagy identified as a molecular mechanism of action. Here, we show that spermidine inhibits memory loss in AD worms and improves behavioral performance, e.g., locomotor capacity, in a PD worm model, both via the PINK1-PDR1-dependent mitophagy pathway. Additionally, spermidine delays accelerated aging and improves healthspan in the DNA repair-deficient premature aging Werner syndrome (WS) worm model. While possible intertwined interactions between mitophagy/autophagy induction and DNA repair by spermidine are to be determined, our data support further translation of spermidine as a possible therapeutic intervention for such diseases.

Keywords:  aging; caenorhabditis elegans; mitophagy; neurodegenerative diseases; spermidine

DOI:  https://doi.org/10.18632/aging.103578