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Indika NLR, Senarathne UD, Malvaso A, Darshana D, Owens SC, Mansouri B, Semenova Y, Bjørklund G. Abnormal Porphyrin Metabolism in Autism Spectrum Disorder and Therapeutic Implications. Mol Neurobiol 2024; 61:3851-3866. [PMID: 38032468 DOI: 10.1007/s12035-023-03722-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 10/17/2023] [Indexed: 12/01/2023]
Abstract
Autism spectrum disorder (ASD) is a mosaic of neurodevelopmental conditions composed of early-onset social interaction and communication deficits, along with repetitive and/or restricted patterns of activities, behavior, and interests. ASD affects around 1% of children worldwide, with a male predominance. Energy, porphyrin, and neurotransmitter homeostasis are the key metabolic pathways affected by heavy metal exposure, potentially implicated in the pathogenesis of ASD. Exposure to heavy metals can lead to an altered porphyrin metabolism due to enzyme inhibition by heavy metals. Heavy metal exposure, inborn genetic susceptibility, and abnormal thiol and selenol metabolism may play a significant role in the urinary porphyrin profile anomalies observed in ASD. Altered porphyrin metabolism in ASD may also be associated with, vitamin B6 deficiency, hyperoxalemia, hyperhomocysteinemia, and hypomagnesemia. The present review considers the abnormal porphyrin metabolism in ASD in relation to the potential pathogenic mechanism and discusses the possible metabolic therapies such as vitamins, minerals, cofactors, and antioxidants that need to be explored in future research. Such targeted therapeutic therapies would bring about favorable outcomes such as improvements in core and co-occurring symptoms.
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Affiliation(s)
- Neluwa-Liyanage R Indika
- Department of Biochemistry, Faculty of Medical Sciences, University of Sri Jayewardenepura, Nugegoda, 10250, Sri Lanka.
| | - Udara D Senarathne
- Department of Biochemistry, Faculty of Medical Sciences, University of Sri Jayewardenepura, Nugegoda, 10250, Sri Lanka
- Department of Chemical Pathology, Monash Health Pathology, Monash Health, Clayton, Victoria, Australia
| | - Antonio Malvaso
- IRCCS "C. Mondino" Foundation, National Neurological Institute, Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy
| | - Dhanushka Darshana
- Department of Pharmacy, Faculty of Allied Health Sciences, University of Ruhuna, Galle, Sri Lanka
| | - Susan C Owens
- Autism Oxalate Project, Autism Research Institute, San Diego, CA, USA
| | - Borhan Mansouri
- Substance Abuse Prevention Research Center, Research Institute for Health, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Yuliya Semenova
- Nazarbayev University School of Medicine, Astana, Kazakhstan
| | - Geir Bjørklund
- Council for Nutritional and Environmental Medicine, Toften 24, 8610, Mo i Rana, Norway.
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Menezes PR, Trufen CEM, Lichtenstein F, Pellegrina DVDS, Reis EM, Onuki J. Transcriptome profile analysis reveals putative molecular mechanisms of 5-aminolevulinic acid toxicity. Arch Biochem Biophys 2023; 738:109540. [PMID: 36746260 DOI: 10.1016/j.abb.2023.109540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 12/23/2022] [Accepted: 02/03/2023] [Indexed: 02/05/2023]
Abstract
5-aminolevulinic acid (5-ALA) is the first precursor of the heme biosynthesis pathway, accumulated in acute intermittent porphyria (AIP), an inherited metabolic disease characterized by porphobilinogen deaminase deficiency. An increased incidence of hepatocellular carcinoma (HCC) has been reported as a long-term manifestation in symptomatic AIP patients. 5-ALA is an α-aminoketone prone to oxidation, yielding reactive oxygen species and 4,5-dioxovaleric acid. A high concentration of 5-ALA presents deleterious pro-oxidant potential. It can induce apoptosis, DNA damage, mitochondrial dysfunction, and altered expression of carcinogenesis-related proteins. Several hypotheses of the increased risk of HCC rely on the harmful effect of elevated 5-ALA in the liver of AIP patients, which could promote a pro-carcinogenic environment. We investigated the global transcriptional changes and perturbed molecular pathways in HepG2 cells following exposure to 5-ALA 25 mM for 2 h and 24 h using DNA microarray. Distinct transcriptome profiles were observed. 5-ALA '25 mM-2h' upregulated 10 genes associated with oxidative stress response and carcinogenesis. Enrichment analysis of differentially expressed genes by KEGG, Reactome, MetaCore™, and Gene Ontology, showed that 5-ALA '25 mM-24h' enriched pathways involved in drug detoxification, oxidative stress, DNA damage, cell death/survival, cell cycle, and mitochondria dysfunction corroborating the pro-oxidant properties of 5-ALA. Furthermore, our results disclosed other possible processes such as senescence, immune responses, endoplasmic reticulum stress, and also some putative effectors, such as sequestosome, osteopontin, and lon peptidase 1. This study provided additional knowledge about molecular mechanisms of 5-ALA toxicity which is essential to a deeper understanding of AIP and HCC pathophysiology. Furthermore, our findings can contribute to improving the efficacy of current therapies and the development of novel biomarkers and targets for diagnosis, prognosis, and therapeutic strategies for AHP/AIP and associated HCC.
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Affiliation(s)
- Patricia Regina Menezes
- Laboratório de Desenvolvimento e Inovação, Instituto Butantan, Av. Vital Brazil, 1500, 05503-900, São Paulo, SP, Brazil
| | - Carlos Eduardo Madureira Trufen
- Laboratório de Desenvolvimento e Inovação, Instituto Butantan, Av. Vital Brazil, 1500, 05503-900, São Paulo, SP, Brazil; Centro de Excelência para Descoberta de Novos Alvos Moleculares, Instituto Butantan, Av. Vital Brazil, 1500, 05503-900, São Paulo, SP, Brazil; Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, Průmyslová 595, 252 50, Vestec, Czech Republic
| | - Flavio Lichtenstein
- Laboratório de Desenvolvimento e Inovação, Instituto Butantan, Av. Vital Brazil, 1500, 05503-900, São Paulo, SP, Brazil; Centro de Excelência para Descoberta de Novos Alvos Moleculares, Instituto Butantan, Av. Vital Brazil, 1500, 05503-900, São Paulo, SP, Brazil
| | | | - Eduardo Moraes Reis
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, 05508-900, São Paulo, SP, Brazil
| | - Janice Onuki
- Laboratório de Desenvolvimento e Inovação, Instituto Butantan, Av. Vital Brazil, 1500, 05503-900, São Paulo, SP, Brazil; Centro de Excelência para Descoberta de Novos Alvos Moleculares, Instituto Butantan, Av. Vital Brazil, 1500, 05503-900, São Paulo, SP, Brazil; Laboratório de Herpetologia, Instituto Butantan, Av. Vital Brazil, 1500, 05503-900, São Paulo, SP, Brazil.
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Ricci A, Di Pierro E, Marcacci M, Ventura P. Mechanisms of Neuronal Damage in Acute Hepatic Porphyrias. Diagnostics (Basel) 2021; 11:diagnostics11122205. [PMID: 34943446 PMCID: PMC8700611 DOI: 10.3390/diagnostics11122205] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 11/22/2021] [Accepted: 11/24/2021] [Indexed: 01/12/2023] Open
Abstract
Porphyrias are a group of congenital and acquired diseases caused by an enzymatic impairment in the biosynthesis of heme. Depending on the specific enzyme involved, different types of porphyrias (i.e., chronic vs. acute, cutaneous vs. neurovisceral, hepatic vs. erythropoietic) are described, with different clinical presentations. Acute hepatic porphyrias (AHPs) are characterized by life-threatening acute neuro-visceral crises (acute porphyric attacks, APAs), featuring a wide range of neuropathic (central, peripheral, autonomic) manifestations. APAs are usually unleashed by external "porphyrinogenic" triggers, which are thought to cause an increased metabolic demand for heme. During APAs, the heme precursors δ-aminolevulinic acid (ALA) and porphobilinogen (PBG) accumulate in the bloodstream and urine. Even though several hypotheses have been developed to explain the protean clinical picture of APAs, the exact mechanism of neuronal damage in AHPs is still a matter of debate. In recent decades, a role has been proposed for oxidative damage caused by ALA, mitochondrial and synaptic ALA toxicity, dysfunction induced by relative heme deficiency on cytochromes and other hemeproteins (i.e., nitric oxide synthases), pyridoxal phosphate functional deficiency, derangements in the metabolic pathways of tryptophan, and other factors. Since the pathway leading to the biosynthesis of heme is inscribed into a complex network of interactions, which also includes some fundamental processes of basal metabolism, a disruption in any of the steps of this pathway is likely to have multiple pathogenic effects. Here, we aim to provide a comprehensive review of the current evidence regarding the mechanisms of neuronal damage in AHPs.
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Affiliation(s)
- Andrea Ricci
- Internal Medicine Unit, Department of Medical and Surgical Science for Children and Adults, University of Modena e Reggio Emilia, 41124 Modena, Italy; (A.R.); (M.M.)
| | - Elena Di Pierro
- Dipartimento di Medicina Interna, Fondazione IRCSS Cà Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy;
| | - Matteo Marcacci
- Internal Medicine Unit, Department of Medical and Surgical Science for Children and Adults, University of Modena e Reggio Emilia, 41124 Modena, Italy; (A.R.); (M.M.)
| | - Paolo Ventura
- Internal Medicine Unit, Department of Medical and Surgical Science for Children and Adults, University of Modena e Reggio Emilia, 41124 Modena, Italy; (A.R.); (M.M.)
- Correspondence: ; Tel.: +39-059-4225-542
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Asano K, Tsukada A, Yanagisawa Y, Higuchi M, Takagi K, Ono M, Tanaka T, Tomita K, Yamada K. Melatonin stimulates transcription of the rat phosphoenolpyruvate carboxykinase gene in hepatic cells. FEBS Open Bio 2020; 10:2712-2721. [PMID: 33070478 PMCID: PMC7714082 DOI: 10.1002/2211-5463.13007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 09/24/2020] [Accepted: 10/16/2020] [Indexed: 12/22/2022] Open
Abstract
Melatonin plays physiological roles in various critical processes, including circadian rhythms, oxidative stress defenses, anti-inflammation responses, and immunity; however, the current understanding of the role of melatonin in hepatic glucose metabolism is limited. In this study, we examined whether melatonin affects gene expression of the key gluconeogenic enzyme, phosphoenolpyruvate carboxykinase (PEPCK). We found that melatonin treatment increased PEPCK mRNA levels in rat highly differentiated hepatoma (H4IIE) cells and primary cultured hepatocytes. In addition, we found that melatonin induction was synergistically enhanced by dexamethasone, whereas it was dominantly inhibited by insulin. We also report that the effect of melatonin was blocked by inhibitors of mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK), RNA polymerase II, and protein synthesis. Furthermore, the phosphorylated (active) forms of ERK1 and ERK2 (ERK1/2) increased 15 min after melatonin treatment. We performed luciferase reporter assays to show that melatonin specifically stimulated promoter activity of the PEPCK gene. Additional reporter analysis using 5'-deleted constructs revealed that the regulatory regions responsive to melatonin mapped to two nucleotide regions, one between -467 and -398 nucleotides and the other between -128 and +69 nucleotides, of the rat PEPCK gene. Thus, we conclude that melatonin induces PEPCK gene expression via the ERK1/2 pathway at the transcriptional level, and that induction requires de novo protein synthesis.
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Affiliation(s)
- Kosuke Asano
- Department of Health and Nutritional Science, Faculty of Human Health Science, Matsumoto University, Matsumoto, Japan
| | - Akiko Tsukada
- Department of Health and Nutritional Science, Faculty of Human Health Science, Matsumoto University, Matsumoto, Japan
| | - Yuki Yanagisawa
- Matsumoto University Graduate School of Health Science, Matsumoto, Japan
| | - Mariko Higuchi
- Matsumoto University Graduate School of Health Science, Matsumoto, Japan
| | - Katsuhiro Takagi
- Department of Health and Nutritional Science, Faculty of Human Health Science, Matsumoto University, Matsumoto, Japan.,Matsumoto University Graduate School of Health Science, Matsumoto, Japan
| | - Moe Ono
- Laboratory of Molecular Biology, Faculty of Pharmacy, Osaka Ohtani University, Tondabayashi, Japan
| | - Takashi Tanaka
- Laboratory of Molecular Biology, Faculty of Pharmacy, Osaka Ohtani University, Tondabayashi, Japan
| | - Koji Tomita
- Laboratory of Molecular Biology, Faculty of Pharmacy, Osaka Ohtani University, Tondabayashi, Japan
| | - Kazuya Yamada
- Department of Health and Nutritional Science, Faculty of Human Health Science, Matsumoto University, Matsumoto, Japan.,Matsumoto University Graduate School of Health Science, Matsumoto, Japan
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Fatima SA, Jurair H, Abbas Q, Rehman AJ. Paediatric porphyria and human hemin: a treatment challenge in a lower middle income country. BMJ Case Rep 2020; 13:e232236. [PMID: 31919062 PMCID: PMC6954746 DOI: 10.1136/bcr-2019-232236] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/26/2019] [Indexed: 11/04/2022] Open
Abstract
Here, we report a case of a 15-year-old girl who presented to the emergency department with symptoms of abdominal pain, nausea, vomiting and seizures. She was diagnosed with acute intermittent porphyria. Treatment was started by removing all porphogenic drugs, providing high glucose intake (oral and intravenous), which initially resulted in good clinical outcomes. However, she deteriorated again and also developed neurological manifestation (paraplegia) for which she required mechanical ventilation because of acute respiratory failure. This time she was initiated on human hemin for four consecutive days. After 2 days of therapy, her porphobilinogen levels decreased to 50% of the initial raised value. Increased lactic acid and blood urea nitrogen were the two side effects observed after the treatment, with no apparent signs of acute kidney injury. To the best of our knowledge, in paediatric population, this is the first reported case of treatment of acute intermittent porphyria with human hemin in Pakistan.
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Affiliation(s)
- Syeda Anum Fatima
- Department of Pharmacy Services, Aga Khan University Hospital, Karachi, Pakistan
| | - Humaira Jurair
- Pediatrics and Child Health, Aga Khan University Hospital, Karachi, Pakistan
| | - Qalab Abbas
- Pediatrics and Child Health, Aga Khan University Hospital, Karachi, Pakistan
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