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Cutis Aug 2020
Topics: Biopsy; Child; Cicatrix; Female; Humans; Protoporphyria, Erythropoietic
PubMed: 32941557
DOI: 10.12788/cutis.0027 -
Actas Dermo-sifiliograficas Feb 2021
Topics: Colombia; Ferrochelatase; Humans; Incidence; Prevalence; Protoporphyria, Erythropoietic
PubMed: 32991848
DOI: 10.1016/j.ad.2019.04.019 -
Allergologia Et Immunopathologia 2023Acute lung injury (ALI) is a common complication of critical diseases with high morbidity and mortality. This study explored the regulatory role and mechanism of high...
OBJECTIVE
Acute lung injury (ALI) is a common complication of critical diseases with high morbidity and mortality. This study explored the regulatory role and mechanism of high mobility histone box 1 protein (HMGB1) on pulmonary fibrosis (PF) after ALI in rats through nucleotide oligomerization domain-like receptor protein-3 (NLRP3) inflammasome.
METHODS
PF rat models after ALI were established by induction of bleomycin. Degree of fibrosis was assessed by Masson staining and Ashcroft scoring. Hydroxyproline (Hyp) contents in lung tissues and rat lung tissue morphology were detected by enzyme-linked-immunosorbent serologic assay (ELISA) and hematoxylin and eosin staining. The levels of NLRP3, major proteins of NLRP3 inflammasome (NLRP3/ASC/caspase-1), and downstream inflammatory cytokines interleukin (IL)-1 and IL-18 were determined using immunohistochemistry, Western blotting analysis, and ELISA. The nuclear/cytoplasmic nuclear factor erythroid 2-related factor 2 (Nrf2) levels and HO-1 levels were measured by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blotting analysis. Rats was injected with lentivirus carrying short hairpin (sh)-HMGB1 and zinc protoporphyria (ZNPP) (HO-1 inhibitor) to assess the effects of HMGB1 and HO-1 on PF and NLRP3 inflammasome activation.
RESULTS
Bleomycin induced PF after ALI in rats, manifested as patchy fibrosis, atelectasis, and excessive expansion, and increased Aschcroft score and Hyp content. Bleomycin treatment enhanced levels of NLRP3, ASC, caspase-1, IL-1, and IL-18 in rat lung tissues, which promoted activation of NLRP3 inflammasome. HMGB1 was up-regulated in bleomycin-induced rats. HMGB1 knockdown partially reversed NLRP3 inflammasome activation and PF progression. HMGB1 knockdown promoted Nrf2 nuclear translocation and up-regulated HO-1. Suppression of HO-1 partially reversed inhibition of HMGB1 knockdown on NLRP3 inflammasome activation and PF.
CONCLUSION
HMGB1 can activate NLRP3 inflammasomes and promote PF by inhibiting the Nrf2/HO-1 pathway.
Topics: Animals; Rats; Acute Lung Injury; Bleomycin; Caspases; HMGB1 Protein; Inflammasomes; Interleukin-18; NF-E2-Related Factor 2; NLR Family, Pyrin Domain-Containing 3 Protein; Pulmonary Fibrosis
PubMed: 37169561
DOI: 10.15586/aei.v51i3.668 -
Frontiers in Immunology 2021The homeostasis of tissues in a chronic disease is an essential function of the alternative pathway (AP) of the complement system (CS). However, if not controlled, it...
The homeostasis of tissues in a chronic disease is an essential function of the alternative pathway (AP) of the complement system (CS). However, if not controlled, it may also be detrimental to healthy cells with a consequent aggravation of symptoms. The protoporphyria (PP) is a rare chronic disease that causes phototoxicity in visible light with local skin pain and general malaise. In order to establish if there is a systemic involvement of the CS during sun exposure, we designed a non-invasive method with a serum collection in winter and summer from 19 PP and 13 controls to detect the levels of CS protein: Properdin, Factor H (FH), and C5. Moreover, the global radiation data were collected from the regional agency of environmental protection (ARPA). The results show growing values for every protein in patients with PP, compared to control, in both seasons, in particular in summer compared to winter. To reinforce the evidence, we have estimated the personal exposure of patients based on the global radiation data. The main factors of the AP increased over the season, confirming the involvement of the AP in relation to light exposure. The systemic response could justify the general malaise of patients after long light exposure and can be exploited to elucidate new therapeutic approaches.
Topics: Adult; Biomarkers; Complement C5; Complement Factor H; Complement Pathway, Alternative; Complement System Proteins; Disease Susceptibility; Female; Humans; Male; Middle Aged; Properdin; Protoporphyria, Erythropoietic; Seasons; Sunlight
PubMed: 33664746
DOI: 10.3389/fimmu.2021.615620 -
Der Hautarzt; Zeitschrift Fur... Oct 2020Melanocortins are peptides that share a common central pharmacophor. Melanin pigmentation of interfollicular epidermis and hair via MC1R remains the key physiologic... (Review)
Review
Melanocortins are peptides that share a common central pharmacophor. Melanin pigmentation of interfollicular epidermis and hair via MC1R remains the key physiologic function of the naturally occurring melanocortin peptides in skin. Moreover, the melanocortins are crucially involved in the ultraviolet light-induced tanning response. Under pathophysiologic conditions, melanocortin peptides induce cutaneous hyperpigmentation, likewise via the MC1R axis, e.g. in patients with Addison's disease, ectopic precursor pro-opiomelanocortin (POMC) syndrome and in those with abnormally elevated melanocortin blood levels. Translational research on α‑MSH (melanocyte-stimulating hormones) and their antagonists has further revealed a variety of other biological activities beyond pigmentation. They include cytoprotection, antioxidative effects, regulation of collagen metabolism and fibrosis, sebum production, and cutaneous wound healing. These findings have also promoted the development of novel therapies in clinical dermatology including the exploitation of afamelanotide. In 2015, this agent became the first in-class synthetic α‑MSH analogue to be approved in dermatology for the treatment of erythropoetic protoporphyria. In addition to afamelanotide, setmelanotide has recently emerged as a highly selective MC4R agonist useful for the treatment of distinct forms of genetically determined obesity, e.g., POMC deficiency. Future perspectives in dermatology reside in treatment of other difficult-to-treat skin diseases with α‑MSH analogues, either with topical or systemic formulations. Moreover, synthetic melanocortin peptide derivatives lacking the central pharmacophor but with maintained anti-inflammatory effects could become a promising strategy for the design of new therapies in dermatology.
Topics: Dermatology; Humans; Inflammation; Melanocortins; Peptides; Pro-Opiomelanocortin; Skin; Translational Research, Biomedical; alpha-MSH
PubMed: 32880662
DOI: 10.1007/s00105-020-04680-6 -
JIMD Reports Nov 2019Erythropoietic protoporphyria (EPP) and X-linked Protoporphyria (XLP) are rare photodermatoses presenting with severe phototoxicity. Although anecdotally, providers who...
BACKGROUND
Erythropoietic protoporphyria (EPP) and X-linked Protoporphyria (XLP) are rare photodermatoses presenting with severe phototoxicity. Although anecdotally, providers who treat EPP patients acknowledge their life-altering effects, tools that fully capture their impact on quality of life (QoL) are lacking.
METHODS
Adult patients with EPP/XLP were given four validated QoL tools: the Patient Reported Outcomes Measurement Information System 57 (PROMIS-57), the Hospital Anxiety and Depression Scale (HADS), the Illness Perception Questionnaire Revised (IPQR), and an EPP-Specific tool. All patients received the PROMIS-57 while the HADS, IPQR, and EPP-Specific tools were introduced at a later date. Associations between responses and clinical phenotypes were explored.
RESULTS
Two hundred and two patients were included; 193 completed PROMIS-57, 104 completed IPQR, 103 completed HADS, and 107 completed the EPP-Specific tool. The IPQR showed that patients strongly believed EPP/XLP had a negative impact on their lives. Mean scores in anxiety and depression domains of both HADS and PROMIS-57 were normal; however, anxiety scores from HADS were borderline/abnormal in 20% of patients. The EPP-Specific tool revealed a decreased QoL in most patients. The PROMIS-57 showed that 21.8% of patients have clinically significant pain interference. Several tool domains correlated with measures of disease severity, most being from the PROMIS-57.
CONCLUSIONS
Impaired QoL is an important consequence of EPP/XLP. PROMIS-57 was most sensitive in evaluating impaired QoL in EPP/XLP. Further research is needed to compare the effectiveness of it for assessing response to treatment.
PubMed: 31741822
DOI: 10.1002/jmd2.12052 -
Bioorganic & Medicinal Chemistry Letters Dec 2022Melanocortin-1 receptor (MC1R) is primarily activated by α-melanocyte-stimulating hormone (α-MSH) and plays a crucial role, such as keeping homeostasis in the skin...
Melanocortin-1 receptor (MC1R) is primarily activated by α-melanocyte-stimulating hormone (α-MSH) and plays a crucial role, such as keeping homeostasis in the skin against melanogenesis and external stimuli, anti-inflammatory effects, and tissue fibrosis suppression. Afamelanotide, an α-MSH analog MC1R agonist, is clinically used for treating erythroblastic protoporphyria (EPP) by subcutaneous implantation administration. Therefore, we initiated an investigation aimed at orally available small molecule nonpeptide MC1R agonists. Optimization from the internal hit compound 6a finally resulted in the discovery of N-(1-benzyl-1H-imidazol-2-yl)amide derivative 9g bearing isonipecotinic acid moiety, which demonstrated good MC1R agonistic activity and metabolic stability.
Topics: Receptor, Melanocortin, Type 1; Amides; alpha-MSH; Erythroblasts; Homeostasis
PubMed: 36367494
DOI: 10.1016/j.bmcl.2022.129040 -
European Journal of Dermatology : EJD Oct 2020Erythropoietic protoporphyria (EPP) is a rare inherited disease associated with heme metabolism, characterized by severe life-long photosensitivity and liver involvement.
BACKGROUND
Erythropoietic protoporphyria (EPP) is a rare inherited disease associated with heme metabolism, characterized by severe life-long photosensitivity and liver involvement.
OBJECTIVE
To provide epidemiological data of EPP in Italy.
MATERIALS & METHODS
Prospective/retrospective data of EPP patients were collected by an Italian network of porphyria specialist centres (Gruppo Italiano Porfiria, GrIP) over a 20-year period (1996-2017).
RESULTS
In total, 179 patients (79 females) with a clinical and biochemical diagnosis of EPP were assessed, revealing a prevalence of 3.15 cases per million persons and an incidence of 0.13 cases per million persons/year. Incidence significantly increased after 2009 (due to the availability of alfa-melanotide, which effectively limits skin photosensitivity). Mean age at diagnosis was 28 years, with only 22 patients (12.2%) diagnosed ≤10 years old. Gene mutations were assessed in 173 (96.6%) patients; most (164; 91.3%) were FECH mutations on one allele in association with the hypomorphic variant, c.315-48C, on the other (classic EPP), and nine (5.2%) were ALAS2 mutations (X-linked EPP). Only one case of autosomal recessive EPP was observed. Of the 42 different FECH mutations, 15 are novel, three mutations collectively accounted for 45.9% (75/164) of the mutations (c.215dupT [27.2%], c.901_902delTG [11.5%] and c.67 + 5G > A [7.2%]), and frameshift mutations were prevalent (33.3%). A form of light protection was used by 109/179 (60.8%) patients, and 100 (56%) had at least one α-melanotide implant. Three cases of severe acute liver involvement, requiring OLT, were observed.
CONCLUSION
These data define, for the first time, the clinical and molecular epidemiology of EPP in Italy.
Topics: 5-Aminolevulinate Synthetase; Adult; Cross-Sectional Studies; Female; Ferrochelatase; Genes, Recessive; Genes, X-Linked; Humans; Incidence; Italy; Male; Molecular Epidemiology; Mutation; Prevalence; Prospective Studies; Protoporphyria, Erythropoietic; Retrospective Studies
PubMed: 33021473
DOI: 10.1684/ejd.2020.3880 -
Cureus Mar 2022Erythropoietic protoporphyria is a rare skin condition that commonly presents in childhood. We report a case of a 35-year-old Hispanic male with a history of sun...
Erythropoietic protoporphyria is a rare skin condition that commonly presents in childhood. We report a case of a 35-year-old Hispanic male with a history of sun sensitivity, presenting with complaints of immediate burning and itching of the skin on his face and upper extremities upon sun exposure. On examination, there was minimal face erythema and calluses over the knuckles. Laboratory workup demonstrated substantially increased protoporphyrin (over 10 times the upper limit of normal) along with elevated liver enzyme levels. Liver biopsy confirmed stage 4 cirrhosis. Our patient's cutaneous manifestations were the primary complaint that led to the diagnosis of his terminal hepatic illness. We recommend screening for erythropoietic protoporphyria in patients who present with a life-long history of non-blistering, burning and itching of the skin, which begins immediately upon sun exposure.
PubMed: 35449677
DOI: 10.7759/cureus.23253 -
Molecular Genetics and Metabolism Nov 2019The erythropoietic porphyrias are inborn errors of heme biosynthesis with prominent cutaneous manifestations. They include autosomal recessive Congenital Erythropoietic...
The erythropoietic porphyrias are inborn errors of heme biosynthesis with prominent cutaneous manifestations. They include autosomal recessive Congenital Erythropoietic Porphyria (CEP) due to loss-of-function (LOF) mutations in the Uroporphyrinogen III Synthase (UROS) gene, Erythropoietic Protoporphyria (EPP) due to LOF mutations in the ferrochelatase (FECH) gene, and X-Linked Protoporphyria (XLP) due to gain-of-function mutations in the terminal exon of the Aminolevulinic Acid Synthase 2 (ALAS2) gene. During the 11-year period from 01/01/2007 through 12/31/2017, the Mount Sinai Porphyrias Diagnostic Laboratory provided molecular diagnostic testing for one or more of these disorders in 628 individuals, including 413 unrelated individuals. Of these 628, 120 patients were tested for CEP, 483 for EPP, and 331 for XLP, for a total of 934 tests. For CEP, 24 of 78 (31%) unrelated individuals tested had UROS mutations, including seven novel mutations. For EPP, 239 of 362 (66%) unrelated individuals tested had pathogenic FECH mutations, including twenty novel mutations. The IVS3-48 T > C low-expression allele was present in 231 (97%) of 239 mutation-positive EPP probands with a pathogenic FECH mutation. In the remaining 3%, three patients with two different FECH mutations in trans were identified. For XLP, 24 of 250 (10%) unrelated individuals tested had ALAS2 exon 11 mutations. No novel ALAS2 mutations were identified. Among family members referred for testing, 33 of 42 (79%) CEP, 62 of 121 (51%) EPP, and 31 of 81 (38%) XLP family members had the respective family mutation. Mutation-positive CEP, EPP, and XLP patients who had been biochemically tested had marked elevations of the disease-appropriate porphyrin intermediates. These results expand the molecular heterogeneity of the erythropoietic porphyrias by adding a total of 27 novel mutations. The results document the usefulness of molecular testing to confirm the positive biochemical findings in these patients and to identify heterozygous family members.
Topics: Family; Female; Ferrochelatase; Genetic Carrier Screening; Genetic Heterogeneity; Heme; Humans; Male; Molecular Diagnostic Techniques; Mutation; Photosensitivity Disorders; Porphyria, Erythropoietic; Protoporphyria, Erythropoietic; Uroporphyrinogen III Synthetase
PubMed: 30454868
DOI: 10.1016/j.ymgme.2018.08.015