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Cell Death & Disease Jun 2017Cytoprotective gene heme oxygenase 1 (HO-1) could be induced by nuclear factor E2-related factor 2 (Nrf2) nuclear translocation. The purpose of this study was to...
Cytoprotective gene heme oxygenase 1 (HO-1) could be induced by nuclear factor E2-related factor 2 (Nrf2) nuclear translocation. The purpose of this study was to determine the role of Brahma-related gene 1 (Brg1), a catalytic subunit of SWI2/SNF2-like chromatin remodeling complexes, in Nrf2/HO-1 pathway activation during hepatic ischemia-reperfusion (HIR). Our results showed that hepatic Brg1 was inhibited during early HIR while Brg1 overexpression reduced oxidative injury in CMV-Brg1 mice subjected to HIR. Moreover, promoter-driven luciferase assay showed that overexpression of Brg1 by adenovirus transfection in AML12 cells selectively enhanced HO-1 gene expression after hypoxia/reoxygenation (H/R) treatment but did not affect the other Nrf2 target gene NQO1. Furthermore, inhibition of HO-1 by the selective HO-1 inhibitor zinc protoporphyria could partly reverse the hepatic protective effects of Brg1 overexpression while HO-1-Adv attenuated AML12 cells H/R damage. Further, chromatin immunoprecipitation analysis revealed that Brg1 overexpression, which could significantly increase the recruitment of Brg1 protein to HO-1 but not NQO1 promoter, was recruited by Nrf2 to the HO-1 regulatory regions in AML12 hepatocytes subjected to H/R. In conclusion, our results demonstrated that restoration of Brg1 during reperfusion could enhance Nrf2-mediated inducible expression of HO-1 during HIR to effectively increase antioxidant ability to combat against hepatocytes damage.
Topics: Active Transport, Cell Nucleus; Adenoviridae; Animals; Cell Line; Chromatin; DNA Helicases; Gene Expression Regulation; Genes, Reporter; Genetic Vectors; Heme Oxygenase-1; Hepatocytes; Liver; Luciferases; Membrane Proteins; Mice; Mice, Transgenic; NAD(P)H Dehydrogenase (Quinone); NF-E2-Related Factor 2; Nuclear Proteins; Promoter Regions, Genetic; Protein Transport; Protoporphyrins; Reperfusion Injury; Signal Transduction; Transcription Factors
PubMed: 28569786
DOI: 10.1038/cddis.2017.236 -
Nature Reviews. Endocrinology Sep 2023A large body of preclinical and clinical data shows that the central melanocortin system is a promising therapeutic target for treating various metabolic disorders such... (Review)
Review
A large body of preclinical and clinical data shows that the central melanocortin system is a promising therapeutic target for treating various metabolic disorders such as obesity and cachexia, as well as anorexia nervosa. Setmelanotide, which functions by engaging the central melanocortin circuitry, was approved by the FDA in 2020 for use in certain forms of syndromic obesity. Furthermore, the FDA approvals in 2019 of two peptide drugs targeting melanocortin receptors for the treatment of generalized hypoactive sexual desire disorder (bremelanotide) and erythropoietic protoporphyria-associated phototoxicity (afamelanotide) demonstrate the safety of this class of peptides. These approvals have also renewed excitement in the development of therapeutics targeting the melanocortin system. Here, we review the anatomy and function of the melanocortin system, discuss progress and challenges in developing melanocortin receptor-based therapeutics, and outline potential metabolic and behavioural disorders that could be addressed using pharmacological agents targeting these receptors.
Topics: Humans; Melanocortins; Sexual Dysfunctions, Psychological; Obesity; Cachexia; Metabolic Diseases
PubMed: 37365323
DOI: 10.1038/s41574-023-00855-y -
The Netherlands Journal of Medicine Jul 2020Porphyrias are rare metabolic disorders. Lack of awareness and knowledge about the clinical features of porphyrias results in diagnostic and therapeutic delays for many... (Review)
Review
Porphyrias are rare metabolic disorders. Lack of awareness and knowledge about the clinical features of porphyrias results in diagnostic and therapeutic delays for many patients. Delays in diagnosing and treating porphyrias can result in severe, progressive morbidity (and mortality) and psychological distress for patients. This review discusses the pathophysiology, diagnosis, treatment, and follow-up of the most prevalent porphyrias: acute intermittent porphyria, porphyria cutanea tarda, and erythropoietic protoporphyria.
Topics: Delayed Diagnosis; Humans; Porphyria Cutanea Tarda; Porphyria, Acute Intermittent; Porphyrias; Practice Guidelines as Topic; Time-to-Treatment
PubMed: 32641543
DOI: No ID Found -
Acta Dermato-venereologica Jun 2019Erythropoietic protoporphyria is caused by a partial deficiency of ferrochelatase, which is the last enzyme in the heme biosynthesis pathway. In a typical erythropoietic... (Review)
Review
Erythropoietic protoporphyria is caused by a partial deficiency of ferrochelatase, which is the last enzyme in the heme biosynthesis pathway. In a typical erythropoietic protoporphyria, photosensitivity initially appears, following the first exposure to the sun in early infancy or childhood. Erythropoietic protoporphyria has been reported worldwide, but there is a regional variation in its epidemiology. Approximately 20% of the Japanese patients were recognized to have symptoms of erythropoietic protoporphyria after 10 years of age. Physicians occasionally encounter Japanese patients with erythropoietic protoporphyria, mild symptoms and no FECH gene mutations. The homozygous IVS3-48C polymorphism may cause a mild phenotype of the erythropoietic protoporphyria via a slight increase in protoporphyrin. The frequency of the homozygous IVS3-48C polymorphism in the Japanese population is higher than that observed in European countries. Japanese type of erythropoietic protopor-phyria shows a characteristic phenotype of the late onset and mild symptoms compared to the Caucasian erythropoietic protoporphyria. This review describes the characteristics of erythropoietic protoporphyria in Japanese patients.
Topics: Age of Onset; Anemia; Cholelithiasis; Europe; Ferrochelatase; Homozygote; Humans; Japan; Liver Diseases; Mutation; North America; Phenotype; Polymorphism, Genetic; Prevalence; Protoporphyria, Erythropoietic
PubMed: 30938825
DOI: 10.2340/00015555-3184 -
Molecular Genetics and Metabolism Nov 2019Erythropoietic Protoporphyria (EPP) and X-linked Protoporphyria (XLP) are rare, genetic photodermatoses resulting from defects in enzymes of the heme-biosynthetic... (Review)
Review
Erythropoietic Protoporphyria (EPP) and X-linked Protoporphyria (XLP) are rare, genetic photodermatoses resulting from defects in enzymes of the heme-biosynthetic pathway. EPP results from the partial deficiency of ferrochelatase, and XLP results from gain-of-function mutations in erythroid specific ALAS2. Both disorders result in the accumulation of erythrocyte protoporphyrin, which is released in the plasma and taken up by the liver and vascular endothelium. The accumulated protoporphyrin is activated by sunlight exposure, generating singlet oxygen radical reactions leading to tissue damage and excruciating pain. About 2-5% of patients develop clinically significant liver dysfunction due to protoporphyrin deposition in bile and/or hepatocytes which can advance to cholestatic liver failure requiring transplantation. Clinically these patients present with acute, severe, non-blistering phototoxicity within minutes of sun-exposure. Anemia is seen in about 47% of patients and about 27% of patients will develop abnormal serum aminotransferases. The diagnosis of EPP and XLP is made by detection of markedly increased erythrocyte protoporphyrin levels with a predominance of metal-free protoporphyrin. Genetic testing by sequencing the FECH or ALAS2 gene confirms the diagnosis. Treatment is limited to sun-protection and there are no currently available FDA-approved therapies for these disorders. Afamelanotide, a synthetic analogue of α-melanocyte stimulating hormone was found to increase pain-free sun exposure and improve quality of life in adults with EPP. It has been approved for use in the European Union since 2014 and is not available in the U.S. In addition to the development of effective therapeutics, future studies are needed to establish the role of iron and the risks related to the development of hepatopathy in these patients.
Topics: 5-Aminolevulinate Synthetase; Anemia; Clinical Trials as Topic; Dermatitis, Phototoxic; Disease Management; Genes, X-Linked; Heme; Humans; Liver Diseases; Porphyrias, Hepatic; Protoporphyria, Erythropoietic
PubMed: 30704898
DOI: 10.1016/j.ymgme.2019.01.020 -
Clinics and Research in Hepatology and... Sep 2015The hereditary porphyrias comprise a group of eight metabolic disorders of the heme biosynthesis pathway. Each porphyria is caused by abnormal function at a separate... (Review)
Review
The hereditary porphyrias comprise a group of eight metabolic disorders of the heme biosynthesis pathway. Each porphyria is caused by abnormal function at a separate enzymatic step resulting in a specific accumulation of heme precursors. Porphyrias are classified as hepatic or erythropoietic, based on the organ system in which heme precursors (δ-aminolevulinic acid [ALA], porphobilinogen and porphyrins) are overproduced. Clinically, porphyrias are characterized by acute neurovisceral symptoms, skin lesions or both. However, most if not all the porphyrias impair hepatic or gastrointestinal function. Acute hepatic porphyrias present with severe abdominal pain, nausea, constipation, confusion and seizure, which may be life threatening, and patients are at risk of hepatocellular carcinoma without cirrhosis. Porphyria Cutanea presents with skin fragility and blisters, and patients are at risk of hepatocellular carcinoma with liver iron overload. Erythropoietic protoporphyria and X-linked protoporphyria present with acute painful photosensitivity, and patients are at risk of acute liver failure. Altogether, porphyrias are still underdiagnosed, but once they are suspected, early diagnosis based on measurement of biochemical metabolites that accumulate in the blood, urine, or feces is essential so specific treatment can be started as soon as possible and long-term liver complications are prevented. Screening families to identify presymptomatic carriers is also crucial to prevent overt disease and chronic hepatic complications.
Topics: Humans; Porphyrias; Risk Factors
PubMed: 26142871
DOI: 10.1016/j.clinre.2015.05.009 -
F1000Research 2017This is an overview of the cutaneous porphyrias. It is a narrative review based on the published literature and my personal experience; it is not based on a formal... (Review)
Review
This is an overview of the cutaneous porphyrias. It is a narrative review based on the published literature and my personal experience; it is not based on a formal systematic search of the literature. The cutaneous porphyrias are a diverse group of conditions due to inherited or acquired enzyme defects in the porphyrin-haem biosynthetic pathway. All the cutaneous porphyrias can have (either as a consequence of the porphyria or as part of the cause of the porphyria) involvement of other organs as well as the skin. The single commonest cutaneous porphyria in most parts of the world is acquired porphyria cutanea tarda, which is usually due to chronic liver disease and liver iron overload. The next most common cutaneous porphyria, erythropoietic protoporphyria, is an inherited disorder in which the accumulation of bile-excreted protoporphyrin can cause gallstones and, rarely, liver disease. Some of the porphyrias that cause blistering (usually bullae) and fragility (clinically and histologically identical to porphyria cutanea tarda) can also be associated with acute neurovisceral porphyria attacks, particularly variegate porphyria and hereditary coproporphyria. Management of porphyria cutanea tarda mainly consists of visible-light photoprotection measures while awaiting the effects of treating the underlying liver disease (if possible) and treatments to reduce serum iron and porphyrin levels. In erythropoietic protoporphyria, the underlying cause can be resolved only with a bone marrow transplant (which is rarely justifiable in this condition), so management consists particularly of visible-light photoprotection and, in some countries, narrowband ultraviolet B phototherapy. Afamelanotide is a promising and newly available treatment for erythropoietic protoporphyria and has been approved in Europe since 2014.
PubMed: 29152226
DOI: 10.12688/f1000research.10101.1 -
Diagnostics (Basel, Switzerland) Jan 2022Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are inherited disorders resulting from defects in two different enzymes of the heme biosynthetic... (Review)
Review
Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are inherited disorders resulting from defects in two different enzymes of the heme biosynthetic pathway, i.e., ferrochelatase (FECH) and delta-aminolevulinic acid synthase-2 (ALAS2), respectively. The ubiquitous FECH catalyzes the insertion of iron into the protoporphyrin ring to generate the final product, heme. After hemoglobinization, FECH can utilize other metals like zinc to bind the remainder of the protoporphyrin molecules, leading to the formation of zinc protoporphyrin. Therefore, FECH deficiency in EPP limits the formation of both heme and zinc protoporphyrin molecules. The erythroid-specific ALAS2 catalyses the synthesis of delta-aminolevulinic acid (ALA), from the union of glycine and succinyl-coenzyme A, in the first step of the pathway in the erythron. In XLP, ALAS2 activity increases, resulting in the amplified formation of ALA, and iron becomes the rate-limiting factor for heme synthesis in the erythroid tissue. Both EPP and XLP lead to the systemic accumulation of protoporphyrin IX (PPIX) in blood, erythrocytes, and tissues causing the major symptom of cutaneous photosensitivity and several other less recognized signs that need to be considered. Although significant advances have been made in our understanding of EPP and XLP in recent years, a complete understanding of the factors governing the variability in clinical expression and the severity (progression) of the disease remains elusive. The present review provides an overview of both well-established facts and the latest findings regarding these rare diseases.
PubMed: 35054318
DOI: 10.3390/diagnostics12010151 -
Journal Der Deutschen Dermatologischen... Dec 2015Solar urticaria is a rare IgE-mediated and chromophore-dependent photodermatosis. In some cases, these chromophores, designated as "serum factor", may be detected in... (Review)
Review
Solar urticaria is a rare IgE-mediated and chromophore-dependent photodermatosis. In some cases, these chromophores, designated as "serum factor", may be detected in serum or plasma. To date, the exact pathogenesis of solar urticaria has, however, not been elucidated. Typical clinical features include the onset of urticarial lesions within a few minutes after light exposure, which already raises diagnostic suspicion. The most common triggers are UVA and visible light. Determination of the action spectrum as well as the minimal urticarial dose (MDU) is diagnostically crucial. Other photodermatoses such as polymorphic light eruption or porphyrias (especially erythropoietic protoporphyria) have to be ruled out. Apart from sunlight avoidance, which is always required, further therapeutic options used include nonsedating antihistamines as well as light hardening. Newer treatment modalities such as plasmapheresis or the anti-IgE antibody omalizumab are reserved for severe, recalcitrant forms of solar urticaria.
Topics: Anti-Allergic Agents; Diagnosis, Differential; Histamine Antagonists; Humans; Omalizumab; Plasmapheresis; Sunlight; Urticaria
PubMed: 26612794
DOI: 10.1111/ddg.12809 -
Journal of the American Academy of... Dec 2023Erythropoietic protoporphyria and X-linked protoporphyria are rare genetic photodermatoses. Limited expertise with these disorders among physicians leads to diagnostic...
Erythropoietic protoporphyria and X-linked protoporphyria are rare genetic photodermatoses. Limited expertise with these disorders among physicians leads to diagnostic delays. Here, we present evidence-based consensus guidelines for the diagnosis, monitoring, and management of erythropoietic protoporphyria and X-linked protoporphyria. A systematic literature review was conducted, and reviewed among subcommittees of experts, divided by topic. Consensus on guidelines was reached within each subcommittee and then among all members of the committee. The appropriate biochemical and genetic testing to establish the diagnosis is reviewed in addition to the interpretation of results. Prevention of symptoms, management of acute phototoxicity, and pharmacologic and nonpharmacologic treatment options are discussed. The importance of ongoing monitoring for liver disease, iron deficiency, and vitamin D deficiency is discussed with management guidance. Finally, management of pregnancy and surgery and the safety of other therapies are summarized. We emphasize that these are multisystemic disorders that require longitudinal monitoring. These guidelines provide a structure for evidence-based diagnosis and management for practicing physicians. Early diagnosis and management of these disorders are essential, particularly given the availability of new and emerging therapies.
Topics: Humans; Dermatitis, Phototoxic; Genetic Diseases, X-Linked; Liver Diseases; Protoporphyria, Erythropoietic; Practice Guidelines as Topic
PubMed: 36041558
DOI: 10.1016/j.jaad.2022.08.036