bims-polyam Biomed News
on Polyamines
Issue of 2022–02–27
seventeen papers selected by
Sebastian J. Hofer, University of Graz
  1. Inhibitory Effect of Ursolic Acid on the Migration and Invasion of Doxorubicin-Resistant Breast Cancer.
  2. Exogenous application of spermidine mitigates the adverse effects of drought stress in faba bean (Vicia faba L.).
  3. Transgenic Mouse Overexpressing Spermine Oxidase in Cerebrocortical Neurons: Astrocyte Dysfunction and Susceptibility to Epileptic Seizures.
  4. Dysregulation of S-adenosylmethionine Metabolism in Nonalcoholic Steatohepatitis Leads to Polyamine Flux and Oxidative Stress.
  5. Can polyamine metabolism in T helper cell lineage commitment be a new target in allergy research?
  6. The role of Astragalus polysaccharides in promoting IEC-6 cell migration from polyamine-mediated Ca2+ regulation.
  7. Pharmacological Inhibition of Spermine Oxidase Suppresses Excitotoxicity Induced Neuroinflammation in Mouse Retina.
  8. PAs Regulate Early Somatic Embryo Development by Changing the Gene Expression Level and the Hormonal Balance in Dimocarpus longan Lour.
  9. Insights into polyamine metabolism: homospermidine is double-oxidized in two discrete steps by a single copper-containing amine oxidase in pyrrolizidine alkaloid biosynthesis.
  10. Metabolic Impact of Anticancer Drugs Pd2Spermine and Cisplatin on the Brain of Healthy Mice.
  11. Determination of spermine and spermidine in meat with a ratiometric fluorescence nanoprobe and a combinational logic gate.
  12. Nutraceutical and Dietary Strategies for Up-Regulating Macroautophagy.
  13. Pd2Spermine Complex Shows Cancer Selectivity and Efficacy to Inhibit Growth of Triple-Negative Breast Tumors in Mice.
  14. Hyperammonaemic Encephalopathy Caused by Adult-Onset Ornithine Transcarbamylase Deficiency.
  15. Effect of Ornithine Transcarbamylase (OTC) Deficiency on Pregnancy and Puerperium.
  16. Prednisolone reduces the interferon response to AAV in cynomolgus macaques and may increase liver gene expression.
  17. Hemizygous deletion in the OTC gene results in ornithine transcarbamylase deficiency: A case report.
  1. Molecules. 2022 Feb 14. pii: 1282. [Epub ahead of print]27(4):
    Inhibitory Effect of Ursolic Acid on the Migration and Invasion of Doxorubicin-Resistant Breast Cancer.
    Li Zong, Guorong Cheng, Jingwu Zhao, Xiaoyu Zhuang, Zhong Zheng, Zhiqiang Liu, Fengrui Song.
      The cause of death in most breast cancer patients is disease metastasis and the occurrence of multidrug resistance (MDR). Ornithine decarboxylase (ODC), which is involved into multiple pathways, is closely related to carcinogenesis and development. Ursolic acid (UA), a natural triterpenoid compound, has been shown to reverse the MDR characteristics of tumor cells. However, the effect of UA on the invasion and metastasis of tumor cells with MDR is not known. Therefore, we investigated the effects of UA on invasion and metastasis, ODC-related polyamine metabolism, and MAPK-Erk-VEGF/MMP-9 signaling pathways in a doxorubicin-resistant breast cancer cell (MCF-7/ADR) model. The obtained results showed that UA significantly inhibited the adhesion and migration of MCF-7/ADR cells, and had higher affinities with key active cavity residues of ODC compared to the known inhibitor di-fluoro-methyl-ornithine (DFMO). UA could downregulate ODC, phosphorylated Erk (P-Erk), VEGF, and matrix metalloproteinase-9 (MMP-9) activity. Meanwhile, UA significantly reduced the content of metabolites of the polyamine metabolism. Furthermore, UA increased the intracellular accumulation of Dox in MCF-7/ADR cells. Taken together, UA can inhibit against tumor progression during the treatment of breast cancer with Dox, and possibly modulate the Erk-VEGF/MMP-9 signaling pathways and polyamine metabolism by targeting ODC to exert these effects.
    Keywords:  metastasis; multidrug resistance; ornithine decarboxylase; polyamine metabolism; ursolic acid
    DOI:  https://doi.org/10.3390/molecules27041282
  2. Funct Plant Biol. 2022 Feb 25.
    Exogenous application of spermidine mitigates the adverse effects of drought stress in faba bean (Vicia faba L.).
    Ghassen Abid, Rim Nefissi Ouertani, Emna Ghouili, Yordan Muhovski, Salwa Harzalli Jebara, Souhir Abdelkarim, Oumaima Chaieb, Yosr Ben Redjem, Mohamed El Ayed, Fathi Barhoumi, Fatma Souissi, Moez Jebara.
      In Tunisia, drought stress is a major environmental factor limiting crop production and causing relatively low and unstable faba bean yields. In the present study, we explored the putative role of spermidine (0.5, 1, 1.5 and 2mM) in ameliorating the effects of drought stress induced by polyethylene glycol (PEG-6000, -0.58MPa) in faba bean seedlings. Drought stress reduced photosynthetic performance, chlorophyll and relative water content in leaves of faba bean variety Badii. Moreover, drought increased proline, electrolyte leakage and malondialdehyde content by inducing reactive oxygen species (hydrogen peroxide) generation in leaves. However, applying spermidine increased the activities of catalase, superoxide dismutase, ascorbate peroxidase and guaiacol peroxidase. The results show that the application of spermidine especially at a rate of 1.5mM effectively reduces oxidative damage and alleviates negative effects caused by drought stress. In addition, exogenous spermidine increased the expression of polyamine biosynthetic enzymes' genes (VfADC, VfSAMDC and VfSPDS), and reduced the expression of VfSPMS suggesting that exogenous spermidine can regulate polyamines' metabolic status under drought challenge, and consequently may enhance drought stress tolerance in faba bean. Real-time quantitative polymerase chain reaction analysis revealed that some drought responsive genes (VfNAC, VfHSP, VfNCED, VfLEA, VfCAT, VfAPX, VfRD22, VfMYB, VfDHN, VfERF, VfSOD and VfWRKY) from various metabolic pathways were differentially expressed under drought stress. Overall, these genes were more abundantly transcribed in the spermidine-treated plants compared to untreated suggesting an important role of spermidine in modulating faba bean drought stress response and tolerance.
    DOI:  https://doi.org/10.1071/FP21125
  3. Biomolecules. 2022 Jan 25. pii: 204. [Epub ahead of print]12(2):
    Transgenic Mouse Overexpressing Spermine Oxidase in Cerebrocortical Neurons: Astrocyte Dysfunction and Susceptibility to Epileptic Seizures.
    Manuela Marcoli, Chiara Cervetto, Sarah Amato, Cristian Fiorucci, Guido Maura, Paolo Mariottini, Manuela Cervelli.
      Polyamines are organic polycations ubiquitously present in living cells. Polyamines are involved in many cellular processes, and their content in mammalian cells is tightly controlled. Among their function, these molecules modulate the activity of several ion channels. Spermine oxidase, specifically oxidized spermine, is a neuromodulator of several types of ion channel and ionotropic glutamate receptors, and its deregulated activity has been linked to several brain pathologies, including epilepsy. The Dach-SMOX mouse line was generated using a Cre/loxP-based recombination approach to study the complex and critical functions carried out by spermine oxidase and spermine in the mammalian brain. This mouse genetic model overexpresses spermine oxidase in the neocortex and is a chronic model of excitotoxic/oxidative injury and neuron vulnerability to oxidative stress and excitotoxic, since its phenotype revealed to be more susceptible to different acute oxidative insults. In this review, the molecular mechanisms underlined the Dach-SMOX phenotype, linked to reactive astrocytosis, neuron loss, chronic oxidative and excitotoxic stress, and susceptibility to seizures have been discussed in detail. The Dach-SMOX mouse model overexpressing SMOX may help in shedding lights on the susceptibility to epileptic seizures, possibly helping to understand the mechanisms underlying epileptogenesis in vulnerable individuals and contributing to provide new molecular mechanism targets to search for novel antiepileptic drugs.
    Keywords:  Polyamines; SMOX; epilepsy; glutamate excitotoxicity; reactive astrocytosis; transgenic mouse model
    DOI:  https://doi.org/10.3390/biom12020204
  4. Int J Mol Sci. 2022 Feb 11. pii: 1986. [Epub ahead of print]23(4):
    Dysregulation of S-adenosylmethionine Metabolism in Nonalcoholic Steatohepatitis Leads to Polyamine Flux and Oxidative Stress.
    Connor Quinn, Mario C Rico, Carmen Merali, Salim Merali.
      Nonalcoholic fatty liver disease (NAFLD) is the number one cause of chronic liver disease worldwide, with 25% of these patients developing nonalcoholic steatohepatitis (NASH). NASH significantly increases the risk of cirrhosis and decompensated liver failure. Past studies in rodent models have shown that glycine-N-methyltransferase (GNMT) knockout results in rapid steatosis, fibrosis, and hepatocellular carcinoma progression. However, the attenuation of GNMT in subjects with NASH and the molecular basis for its impact on the disease process is still unclear. To address this knowledge gap, we show the reduction of GNMT protein levels in the liver of NASH subjects compared to healthy controls. To gain insight into the impact of decreased GNMT in the disease process, we performed global label-free proteome studies on the livers from a murine modified amylin diet-based model of NASH. Histological and molecular characterization of the animal model demonstrate a high resemblance to human disease. We found that a reduction of GNMT leads to a significant increase in S-adenosylmethionine (AdoMet), an essential metabolite for transmethylation reactions and a substrate for polyamine synthesis. Further targeted proteomic and metabolomic studies demonstrated a decrease in GNMT transmethylation, increased flux through the polyamine pathway, and increased oxidative stress production contributing to NASH pathogenesis.
    Keywords:  S-adenosylmethionine; glycine-N-methyl transferase; nonalcoholic steatohepatitis; polyamines
    DOI:  https://doi.org/10.3390/ijms23041986
  5. Allergy. 2022 Feb 21.
    Can polyamine metabolism in T helper cell lineage commitment be a new target in allergy research?
    Mengting Huang, Juan Rodriguez-Coira.
      
    DOI:  https://doi.org/10.1111/all.15265
  6. Int J Biol Macromol. 2022 Feb 22. pii: S0141-8130(22)00355-5. [Epub ahead of print]
    The role of Astragalus polysaccharides in promoting IEC-6 cell migration from polyamine-mediated Ca2+ regulation.
    Dong Zhang, Yiping Zhu, Zhijin Li, Meng Luo, Xinyi Liang, Anrong Wang, Huibin Zhu, Ling Hu, Ruliu Li.
      Astragalus polysaccharide (APS) has a protective effect on injured intestinal mucosa by promoting intestinal cell migration, but the specific mechanism is unclear. The polyamine-mediated calcium signaling pathway is an important mechanism of cell migration, generally, and we tested the hypothesis that APS can protect damaged intestinal mucosa through the polyamine-mediated calcium signaling pathway. High-performance liquid chromatography (HPLC), infrared chromatography, cell scratch test, Western blot, co-immunoprecipitation, polyamine inhibitor (DFMO), si-Cav1, RhoA inhibitor (Rhosin) and Rac1 inhibitor (NSC23766) were used to detect the pharmacodynamic of APS. The results show that APS can promote cell migration. In addition, APS increased the formations of RhoA/TRPC1, Cav1/TRPC1, and Rac1/PLCγ-1 complexes as well as the expressions of TRPC1, PLCγ-1, RhoA, Cav1, and Rac1, and it reversed the inhibitory effect of DFMO on the above factors. APS also reversed the inhibitory effect of si-Cav1 on Cav1 expression, cytoplasmic Ca2+ concentrations ([Ca2+]cyt), and cell migration. Moreover, APS removed the inhibition of NSC23766 and Rhosin on [Ca2+]cyt and cell migration. In vivo study, the water extract of Astragalus membranaceus (WEA) (15 g/kg) reduced the indomethacin-induced injury of intestinal mucosa as well. These observations suggest that APS can treat gastrointestinal mucosal injury through the polyamine calcium signaling pathway.
    Keywords:  Astragalus polysaccharides; Ca(2+) regulatory protein; IEC-6 cells; Intestinal mucosal injury; Polyamines
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.02.109
  7. Int J Mol Sci. 2022 Feb 15. pii: 2133. [Epub ahead of print]23(4):
    Pharmacological Inhibition of Spermine Oxidase Suppresses Excitotoxicity Induced Neuroinflammation in Mouse Retina.
    Moaddey Alfarhan, Fang Liu, Shengshuai Shan, Prahalathan Pichavaram, Payaningal R Somanath, S Priya Narayanan.
      Polyamine oxidation plays a major role in neurodegenerative diseases. Previous studies from our laboratory demonstrated that spermine oxidase (SMOX, a member of the polyamine oxidase family) inhibition using MDL 72527 reduced neurodegeneration in models of retinal excitotoxicity and diabetic retinopathy. However, the mechanisms behind the neuroprotection offered by SMOX inhibition are not completely studied. Utilizing the experimental model of retinal excitotoxicity, the present study determined the impact of SMOX blockade in retinal neuroinflammation. Our results demonstrated upregulation in the number of cells positive for Iba-1 (ionized calcium-binding adaptor molecule 1), CD (Cluster Differentiation) 68, and CD16/32 in excitotoxicity-induced retinas, while MDL 72527 treatment reduced these changes, along with increases in the number of cells positive for Arginase1 and CD206. When retinal excitotoxicity upregulated several pro-inflammatory genes, MDL 72527 treatment reduced many of them and increased anti-inflammatory genes. Furthermore, SMOX inhibition upregulated antioxidant signaling (indicated by elevated Nrf2 and HO-1 levels) and reduced protein-conjugated acrolein in excitotoxic retinas. In vitro studies using C8-B4 cells showed changes in cellular morphology and increased reactive oxygen species formation in response to acrolein (a product of SMOX activity) treatment. Overall, our findings indicate that the inhibition SMOX pathway reduced neuroinflammation and upregulated antioxidant signaling in the retina.
    Keywords:  acrolein; antioxidant signaling; microglia; neuroinflammation; oxidative damage; polyamine oxidation; spermine oxidase
    DOI:  https://doi.org/10.3390/ijms23042133
  8. Genes (Basel). 2022 Feb 08. pii: 317. [Epub ahead of print]13(2):
    PAs Regulate Early Somatic Embryo Development by Changing the Gene Expression Level and the Hormonal Balance in Dimocarpus longan Lour.
    Chunwang Lai, Xiaojuan Zhou, Shuting Zhang, Xueying Zhang, Mengyu Liu, Chunyu Zhang, Xiaoqiong Xu, Xiaoping Xu, Xiaohui Chen, Yan Chen, Wenzhong Lin, Zhongxiong Lai, Yuling Lin.
      Polyamines (PAs) play an important regulatory role in many basic cellular processes and physiological and biochemical processes. However, there are few studies on the identification of PA biosynthesis and metabolism family members and the role of PAs in the transition of plant embryogenic calli (EC) into globular embryos (GE), especially in perennial woody plants. We identified 20 genes involved in PA biosynthesis and metabolism from the third-generation genome of longan (Dimocarpus longan Lour.). There were no significant differences between longan and other species regarding the number of members, and they had high similarity with Citrus sinensis. Light, plant hormones and a variety of stress cis-acting elements were found in these family members. The biosynthesis and metabolism of PAs in longan were mainly completed by DlADC2, DlSAMDC2, DlSAMDC3, DlSPDS1A, DlSPMS, DlCuAOB, DlCuAO3A, DlPAO2 and DlPAO4B. In addition, 0.01 mmol∙L-1 1-aminocyclopropane-1-carboxylic acid (ACC), putrescine (Put) and spermine (Spm), could promote the transformation of EC into GE, and Spm treatment had the best effect, while 0.01 mmol∙L-1 D-arginine (D-arg) treatment inhibited the process. The period between the 9th and 11th days was key for the transformation of EC into GE in longan. There were higher levels of gibberellin (GA), salicylic acid (SA) and abscisic acid (ABA) and lower levels of indole-3-acetic acid (IAA), ethylene and hydrogen peroxide (H2O2) in this key period. The expression levels in this period of DlADC2, DlODC, DlSPDS1A, DlCuAOB and DlPAO4B were upregulated, while those of DlSAMDC2 and DlSPMS were downregulated. These results showed that the exogenous ACC, D-arg and PAs could regulate the transformation of EC into GE in longan by changing the content of endogenous hormones and the expression levels of PA biosynthesis and metabolism genes. This study provided a foundation for further determining the physicochemical properties and molecular evolution characteristics of the PA biosynthesis and metabolism gene families, and explored the mechanism of PAs and ethylene for regulating the transformation of plant EC into GE.
    Keywords:  embryogenic callus; ethylene; genome-wide identification; globular embryo; longan; plant endogenous hormones; polyamines
    DOI:  https://doi.org/10.3390/genes13020317
  9. Plant Cell. 2022 Feb 25. pii: koac068. [Epub ahead of print]
    Insights into polyamine metabolism: homospermidine is double-oxidized in two discrete steps by a single copper-containing amine oxidase in pyrrolizidine alkaloid biosynthesis.
    Mahmoud M Zakaria, Thomas Stegemann, Christian Sievert, Lars H Kruse, Elisabeth Kaltenegger, Ulrich Girreser, Serhat S Çiçek, Manfred Nimtz, Dietrich Ober.
      Polyamines are important metabolites in plant development and abiotic and biotic stress responses. Copper-containing amine oxidases (CuAOs) are involved in the regulation of polyamine levels in the cell. CuAOs oxidize primary amines to their respective aldehydes and hydrogen peroxide. In plants, aldehydes are intermediates in various biosynthetic pathways of alkaloids. CuAOs are thought to oxidize polyamines at only one of the primary amino groups, a process frequently resulting in monocyclic structures. These oxidases have been postulated to be involved in pyrrolizidine alkaloid (PA) biosynthesis. Here, we describe the identification and characterization of homospermidine oxidase (HSO), a CuAO of Heliotropium indicum (Indian heliotrope), involved in PA biosynthesis. Virus-induced gene silencing of HSO in H. indicum leads to significantly reduced PA levels. By in vitro enzyme assays after transient in planta expression, we show that this enzyme prefers homospermidine over other amines. NMR and MS analyses of the reaction products demonstrate that HSO oxidizes both primary amino groups of homospermidine to form a bicyclic structure, 1-formylpyrrolizidine. Using tracer feeding, we have further revealed that 1-formylpyrrolizidine is an intermediate in the biosynthesis of PAs. Our study therefore establishes that HSO, a canonical CuAO, catalyzes the second step of PA biosynthesis and provides evidence for an undescribed and unusual mechanism involving two discrete steps of oxidation that might also be involved in the biosynthesis of complex structures in other alkaloidal pathways.
    DOI:  https://doi.org/10.1093/plcell/koac068
  10. Pharmaceutics. 2022 Jan 22. pii: 259. [Epub ahead of print]14(2):
    Metabolic Impact of Anticancer Drugs Pd2Spermine and Cisplatin on the Brain of Healthy Mice.
    Tatiana J Carneiro, Martin Vojtek, Salomé Gonçalves-Monteiro, João R Neves, Ana L M Batista de Carvalho, Maria Paula M Marques, Carmen Diniz, Ana M Gil.
      The new palladium agent Pd2Spermine (Spm) has been reported to exhibit promising cytotoxic properties, while potentially circumventing the known disadvantages associated to cisplatin therapeutics, namely acquired resistance and high toxicity. This work presents a nuclear magnetic resonance (NMR) metabolomics study of brain extracts obtained from healthy mice, to assess the metabolic impacts of the new Pd2Spm complex in comparison to that of cisplatin. The proton NMR spectra of both polar and nonpolar brain extracts were analyzed by multivariate and univariate statistics, unveiling several metabolite variations during the time course of exposition to each drug (1-48 h). The distinct time-course dependence of such changes revealed useful information on the drug-induced dynamics of metabolic disturbances and recovery periods, namely regarding amino acids, nucleotides, fatty acids, and membrane precursors and phospholipids. Putative biochemical explanations were proposed, based on existing pharmacokinetics data and previously reported metabolic responses elicited by the same metal complexes in the liver of the same animals. Generally, results suggest a more effective response of brain metabolism towards the possible detrimental effects of Pd2Spm, with more rapid recovery back to metabolites' control levels and, thus, indicating that the palladium drug may exert a more beneficial role than cDDP in relation to brain toxicity.
    Keywords:  NMR; Pd2Spm; brain extracts; cisplatin; metabolomics; mice; palladium(II); platinum(II); spermine; toxicity
    DOI:  https://doi.org/10.3390/pharmaceutics14020259
  11. Food Chem. 2022 Feb 16. pii: S0308-8146(22)00421-6. [Epub ahead of print]384 132459
    Determination of spermine and spermidine in meat with a ratiometric fluorescence nanoprobe and a combinational logic gate.
    Samira Abbasi-Moayed, Arafeh Bigdeli, Mohammad Reza Hormozi-Nezhad.
      A ratiometric fluorescent nanoprobe is developed with a wide color variation for visual determination of spermine (SP) and spermidine (SD) in meat samples. The green emission provided from the combination of yellow emissive quantum dots and blue emissive carbon dots turns into pink when SP or SD are present. The results show that the developed sensor has good linearity in the range of 0.5-10 and 0.5-80 µM for SP and SD and suitable detection limits were achieved including 0.2 and 2.1 µM for SP and SD. The probe was highly selective in the presence of amino acids and other biogenic amines. RGB indices were extracted to build a combinational logic gate for visual and simultaneous detection of SP and SD. The dual functional logic gate was easy to design and convenient to operate. Finally, a portable sensor was fabricated for visual, rapid and on-site assessment of meat freshness.
    Keywords:  Biogenic amine; Logic gate system; Meat freshness; Ratiometric nanoprobe; Spermidine; Spermine; Visual detection
    DOI:  https://doi.org/10.1016/j.foodchem.2022.132459
  12. Int J Mol Sci. 2022 Feb 12. pii: 2054. [Epub ahead of print]23(4):
    Nutraceutical and Dietary Strategies for Up-Regulating Macroautophagy.
    Mark F McCarty.
      Macroautophagy is a "cell cleansing" process that rids cells of protein aggregates and damaged organelles that may contribute to disease pathogenesis and the dysfunctions associated with aging. Measures which boost longevity and health span in rodents typically up-regulate macroautophagy, and it has often been suggested that safe strategies which can promote this process in humans may contribute to healthful aging. The kinase ULK1 serves as a trigger for autophagy initiation, and the transcription factors TFEB, FOXO1, ATF4 and CHOP promote expression of a number of proteins which mediate macroautophagy. Nutraceutical or dietary measures which stimulate AMPK, SIRT1, eIF5A, and that diminish the activities of AKT and mTORC1, can be expected to boost the activities of these pro-autophagic factors. The activity of AMPK can be stimulated with the phytochemical berberine. SIRT1 activation may be achieved with a range of agents, including ferulic acid, melatonin, urolithin A, N1-methylnicotinamide, nicotinamide riboside, and glucosamine; correction of ubiquinone deficiency may also be useful in this regard, as may dietary strategies such as time-restricted feeding or intermittent fasting. In the context of an age-related decrease in cellular polyamine levels, provision of exogenous spermidine can boost the hypusination reaction required for the appropriate post-translational modification of eIF5A. Low-protein plant-based diets could be expected to increase ATF4 and CHOP expression, while diminishing IGF-I-mediated activation of AKT and mTORC1. Hence, practical strategies for protecting health by up-regulating macroautophagy may be feasible.
    Keywords:  AMPK; N1-methylnicotinamide; SIRT1; autophagy; berberine; ferulic acid; glucosamine; macroautophagy; melatonin; nicotinamide riboside; plant-based diets; ubiquinone; urolithin A
    DOI:  https://doi.org/10.3390/ijms23042054
  13. Biomedicines. 2022 Jan 19. pii: 210. [Epub ahead of print]10(2):
    Pd2Spermine Complex Shows Cancer Selectivity and Efficacy to Inhibit Growth of Triple-Negative Breast Tumors in Mice.
    Martin Vojtek, Salomé Gonçalves-Monteiro, Patrícia Šeminská, Katarína Valová, Loreto Bellón, Patrícia Dias-Pereira, Franklim Marques, Maria P M Marques, Ana L M Batista de Carvalho, Helder Mota-Filipe, Isabel M P L V O Ferreira, Carmen Diniz.
      Pd2Spm is a dinuclear palladium(II)-spermine chelate with promising anticancer properties against triple-negative breast cancer (TNBC), a breast carcinoma subset with poor prognosis and limited treatment options. The present study evaluated the in vitro and in vivo anticancer effects of Pd2Spm compared to the reference metal-based drug cisplatin. Triple-negative breast cancer MDA-MB-231 cells, non-cancerous MCF-12A breast cells and chorioallantoic membrane (CAM) assay were used for antiproliferative, antimigratory and antiangiogenic studies. For an in vivo efficacy study, female CBA nude mice with subcutaneously implanted MDA-MB-231 breast tumors were treated with Pd2Spm (5 mg/kg/day) or cisplatin (2 mg/kg/day) administered intraperitoneally during 5 consecutive days. Promising selective antiproliferative activity of Pd2Spm was observed in MDA-MB-231 cells (IC50 values of 7.3-8.3 µM), with at least 10-fold lower activity in MCF-12A cells (IC50 values of 89.5-228.9 µM). Pd2Spm inhibited the migration of MDA-MB-231 cells, suppressed angiogenesis in CAM and decreased VEGF secretion from MDA-MB-231 cells with similar potency as cisplatin. Pd2Spm-treated mice showed a significant reduction in tumor growth progression, and tumors evidenced a reduction in the Ki-67 proliferation index and number of mitotic figures, as well as increased DNA damage, similar to cisplatin-treated animals. Encouragingly, systemic toxicity (hematotoxicity and weight loss) observed in cisplatin-treated animals was not observed in Pd2Spm-treated mice. The present study reports, for the first time, promising cancer selectivity, in vivo antitumor activity towards TNBC and a low systemic toxicity of Pd2Spm. Thus, this agent may be viewed as a promising Pd(II) drug candidate for the treatment of this type of low-prognosis neoplasia.
    Keywords:  Pd(II)-based drugs; cisplatin; in vivo; metal complexes; triple-negative breast cancer; xenografts
    DOI:  https://doi.org/10.3390/biomedicines10020210
  14. Brain Sci. 2022 Feb 08. pii: 231. [Epub ahead of print]12(2):
    Hyperammonaemic Encephalopathy Caused by Adult-Onset Ornithine Transcarbamylase Deficiency.
    Bjarke Hammer Niclasen, Maria Therese Schelde-Olesen, Mads Astvad, Anders Løkke, Thomas Krøigård, Helle H Nielsen.
      Hyperammonaemic encephalopathy in adults is a rare condition in the absence of liver disease and is associated with a high mortality and risk of permanent neurological deficits. Seldomly, the condition is caused by an inborn error of metabolism in the urea cycle, triggered by an exogenic factor such as gastrointestinal haemorrhage, gastric bypass surgery, starvation, seizures, vigorous exercise, burn injuries, or drugs hampering the elimination of ammonia. Here, we present a fatal case of an unrecognized genetic ornithine transcarbamylase deficiency (OTCD) presenting with a subacute progressive encephalopathy. We review the current literature and discuss the differential diagnosis and treatment options. As swift diagnosis and initiation of treatment is vital, awareness of hyperammonaemic encephalopathy and its possible causes can help improve the prognosis of this condition.
    Keywords:  adult onset; brain oedema; hyperammonaemia; ornithine transcarbamylase deficiency; subacute encephalopathy
    DOI:  https://doi.org/10.3390/brainsci12020231
  15. Diagnostics (Basel). 2022 Feb 05. pii: 415. [Epub ahead of print]12(2):
    Effect of Ornithine Transcarbamylase (OTC) Deficiency on Pregnancy and Puerperium.
    Rastislav Sysák, Katarína Brennerová, Romana Krlín, Peter Štencl, Igor Rusňák, Mária Vargová.
      Ornithine transcarbamylase (OTC) deficiency is the most common inherited metabolic disorder in urea cycles with an incidence of 1:14,000 live births. Pregnancy, childbirth and the postpartum period are considered challenging for women with this hereditary metabolic disorder, with a risk of hyperammonemia, especially in the first week after delivery. In our article, we discuss severe hepatic failure, a pregnancy complication in an OTC deficient patient that has not previously been published. Firstly, our aim is to highlight the need for a strict adherence to the recommendation of the gradual increase of protein intake during pregnancy and the importance of multidisciplinary monitoring of pregnant patients with OTC deficiency. Secondly, we refer to critical postpartum hyperammonemia in patients with this hereditary metabolic disorder.
    Keywords:  hepatic failure; hyperammonemia; ornithine transcarbamylase deficiency in pregnancy; puerperium
    DOI:  https://doi.org/10.3390/diagnostics12020415
  16. Mol Ther Methods Clin Dev. 2022 Mar 10. 24 292-305
    Prednisolone reduces the interferon response to AAV in cynomolgus macaques and may increase liver gene expression.
    Lili Wang, Claude C Warzecha, Alexander Kistner, Jessica A Chichester, Peter Bell, Elizabeth L Buza, Zhenning He, M Betina Pampena, Julien Couthouis, Sunjay Sethi, Kathleen McKeever, Michael R Betts, Emil Kakkis, James M Wilson, Samuel Wadsworth, Barbara A Sullivan.
      Ornithine transcarbamylase deficiency is a rare X-linked genetic urea cycle disorder leading to episodes of acute hyperammonemia, adverse cognitive and neurological effects, hospitalizations, and in some cases death. DTX301, a non-replicating, recombinant self-complimentary adeno-associated virus vector serotype 8 (scAAV8)-encoding human ornithine transcarbamylase, is a promising gene therapy for ornithine transcarbamylase deficiency; however, the impact of sex and prophylactic immunosuppression on ornithine transcarbamylase gene therapy outcomes is not well characterized. This study sought to describe the impact of sex and immunosuppression in adult, sexually mature female and male cynomolgus macaques through day 140 after DTX301 administration. Four study groups (n = 3/group) were included: male non-immunosuppressed; male immunosuppressed; female non-immunosuppressed; and female immunosuppressed. DTX301 was well tolerated with and without immunosuppression; no notable differences were observed between female and male groups across outcome measures. Prednisolone-treated animals exhibited a trend toward greater vector genome and transgene expression, although the differences were not statistically significant. The hepatic interferon gene signature was significantly decreased in prednisolone-treated animals, and a significant inverse relationship was observed between interferon gene signature levels and hepatic vector DNA and transgene RNA. These observations were not sustained upon immunosuppression withdrawal. Further studies may determine whether the observed effect can be prolonged.
    Keywords:  AAV8; IFN gene signature; adeno-associated virus; immunosuppression; liver; non-human primates; ornithine transcarbamylase deficiency; sex
    DOI:  https://doi.org/10.1016/j.omtm.2022.01.007
  17. World J Clin Cases. 2022 Feb 06. 10(4): 1417-1422
    Hemizygous deletion in the OTC gene results in ornithine transcarbamylase deficiency: A case report.
    Li-Ping Wang, Hou-Zhong Luo, Mao Song, Zuo-Zhen Yang, Fan Yang, Yun-Tao Cao, Juan Chen.
       BACKGROUND: Ornithine transcarbamylase deficiency (OTCD) is a common ornithine cycle disorder, and OTC gene variation is the main pathogenic factor of this disease. This study explored and validated a variant in the OTC gene.
    CASE SUMMARY: The neonate exhibited high blood ammonia, lactic acid, and homocysteine levels on the fifth day after birth. A novel deletion variant in the OTC gene [NM_000531.5, c.970_979delTTCCCAGAGG, p.Phe324GlnfsTer16] was uncovered by exome sequencing. The variant caused a protein-coding frameshift and resulted in early translation termination at the 16th amino acid after the variant site.
    CONCLUSION: Our results provide a novel pathogenic variant in OTC and related clinical features for further OTCD screening and clinical consultation.
    Keywords:  Case report; Deletion variant; Early translation termination; Exome sequencing; OTC; Ornithine transcarbamylase deficiency
    DOI:  https://doi.org/10.12998/wjcc.v10.i4.1417
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