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1.
Exp Dermatol ; 33(9): e15179, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39278731

ABSTRACT

Hidradenitis suppurativa (HS) is a chronic skin disease, characterized by clinical inflammation of the hair follicle with the recurrence of abscesses, nodules, and tunnels. Recently, several studies suggested a role of IL-1 family (IL-1F) cytokines in eliciting and sustaining the disease. The aim of this work is to perform a comprehensive analysis of IL-1F cytokines, soluble inhibitors and receptors in a cohort of HS patients not treated with biological agents. Sixteen patients affected by HS and 16 healthy controls were recruited; clinical data were collected and disease severity evaluated by means of the International HS Severity Score System (IHS4). Serum levels of IL-1F cytokines, inhibitors and receptors were measured using a Multiplex Assays. IL-18 and free IL-18 levels were significantly higher in patients vs controls. Among soluble inhibitors, IL-1Ra, IL-1R2 and ST2/IL-1R4 were significantly increased. IL-18, free IL-18 and IL-33 levels are strongly correlated with IHS4. Also the inhibitors IL-1Ra and IL-18BP show a correlation with IHS4. The data obtained in this study confirm the involvement of IL-1F cytokines in mediating the disease and determining its severity and suggest a possible role for IL-18 as novel serum biomarker of active disease.


Subject(s)
Hidradenitis Suppurativa , Interleukin 1 Receptor Antagonist Protein , Interleukin-18 , Receptors, Interleukin-1 Type II , Severity of Illness Index , Hidradenitis Suppurativa/blood , Humans , Interleukin-18/blood , Male , Adult , Female , Interleukin 1 Receptor Antagonist Protein/blood , Middle Aged , Receptors, Interleukin-1 Type II/blood , Interleukin-1/blood , Interleukin-1 Receptor-Like 1 Protein/blood , Interleukin-33/blood , Case-Control Studies , Young Adult
2.
FEBS J ; 291(5): 965-985, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38037534

ABSTRACT

Starvation resistance is a life-saving mechanism for many organisms facing food availability fluctuation in the natural environment. Different strategies have been episodically identified for some model organisms, the first of which was the ability to suppress metabolic rate. Among the identified strategies, the ability of planarians to shrink their body under fasting conditions and revert the process after feeding (the growth-degrowth process) represents a fascinating mechanism to face long periods of fasting. The growth-degrowth process is strictly related to the capability of planarians to continuously maintain tissue homeostasis and body proportions even in challenging conditions, thanks to the presence of a population of pluripotent stem cells. Here, we take advantage of several previous studies describing the growth-degrowth process and of recent progress in the understanding of planarian homeostasis mechanisms, to identify tissue-selective transcriptional downregulation as a driving strategy for the development of a thrifty phenotype, and the p53 transcription factor as a player in adjusting tissue homeostasis in accordance with food availability.


Subject(s)
Planarians , Animals , Planarians/genetics , Fasting , Down-Regulation , Phenotype , Transcription Factors
3.
PLoS One ; 17(12): e0278966, 2022.
Article in English | MEDLINE | ID: mdl-36508441

ABSTRACT

Microtubule-associated 1B (MAP1B) proteins are expressed at the nervous system level where they control cytoskeleton activity and regulate neurotransmitter release. Here, we report about the identification of a planarian MAP1B factor (DjMap1B) that is enriched in cephalic ganglia and longitudinal nerve cords but not in neoblasts, the plentiful population of adult stem cells present in planarians, thanks to which these animals can continuously cell turnover and regenerate any lost body parts. DjMap1B knockdown induces morphological anomalies in the nervous system and affects neoblast commitment. Our data put forward a correlation between a MAP1B factor and stem cells and suggest a function of the nervous system in non-cell autonomous control of planarian stem cells.


Subject(s)
Planarians , Animals , Planarians/genetics , Stem Cells/metabolism , Nervous System
4.
Open Biol ; 12(12): 220216, 2022 12.
Article in English | MEDLINE | ID: mdl-36541101

ABSTRACT

Cell quiescence appeared early in evolution as an adaptive response to adverse conditions (i.e. nutrient depletion). In metazoans, quiescence has been involved in additional processes like tissue homeostasis, which is made possible by the presence of adult stem cells (ASCs). Cell cycle control machinery is a common hub for quiescence entrance, and evidence indicates a role for p53 in establishing the quiescent state of undamaged cells. Mechanisms responsible for waking up quiescent cells remain elusive, and nutritional stimulus, as a legacy of its original role, still appears to be a player in quiescence exit. Planarians, rich in ASCs, represent a suitable system in which we characterized a quiescent population of ASCs, the dorsal midline cord (DMC) cells, exhibiting unique transcriptional features and maintained quiescent by p53 and awakened upon feeding. The function of DMC cells is puzzling and we speculate that DMC cells, despite retaining ancient properties, might represent a functional drift in which quiescence has been recruited to provide evolutionary advantages.


Subject(s)
Adult Stem Cells , Planarians , Animals , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Stem Cells , Cell Division
5.
Biomolecules ; 11(7)2021 06 26.
Article in English | MEDLINE | ID: mdl-34206807

ABSTRACT

Under physiological conditions, the complex planarian neoblast system is a composite of hierarchically organized stem cell sub-populations with sigma-class neoblasts, including clonogenic neoblasts, endowed with larger self-renewal and differentiation capabilities, thus generating all the other sub-populations and dominating the regenerative process. This complex system responds to differentiated tissue demands, ensuring a continuous cell turnover in a way to replace aged specialized cells and maintain tissue functionality. Potency of the neoblast system can be appreciated under challenging conditions in which these stem cells are massively depleted and the few remaining repopulate the entire body, ensuring animal resilience. These challenging conditions offer the possibility to deepen the relationships among different neoblast sub-populations, allowing to expose uncanonical properties that are negligible under physiological conditions. In this paper, we employ short, sub-lethal 5-fluorouracil treatment to specifically affect proliferating cells passing through the S phase and demonstrate that S-phase slowdown triggers a shift in the transcriptional profile of sigma neoblasts, which reduces the expression of their hallmark sox-P1. Later, some cells reactivate sox-P1 expression, suggesting that some neoblasts in the earlier steps of commitment could modulate their expression profile, reacquiring a wider differentiative potential.


Subject(s)
Fluorouracil/pharmacology , Planarians/cytology , Stem Cells/cytology , Animals , Cell Differentiation , Fluorouracil/metabolism , Planarians/metabolism , Planarians/physiology , Regeneration/physiology , Stem Cells/drug effects , Stem Cells/metabolism , Stem Cells/physiology
6.
Int J Mol Sci ; 22(14)2021 Jul 19.
Article in English | MEDLINE | ID: mdl-34299313

ABSTRACT

With the progress of sequencing technologies, an ever-increasing number of variants of unknown functional and clinical significance (VUS) have been identified in both coding and non-coding regions of the main Breast Cancer (BC) predisposition genes. The aim of this study is to identify a mutational profile of coding and intron-exon junction regions of 12 moderate penetrance genes (ATM, BRIP1, CDH1, CHEK2, NBN, PALB2, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53) in a cohort of 450 Italian patients with Hereditary Breast/Ovarian Cancer Syndrome, wild type for germline mutation in BRCA1/2 genes. The analysis was extended to 5'UTR and 3'UTR of all the genes listed above and to the BRCA1 and BRCA2 known regulatory regions in a subset of 120 patients. The screening was performed through NGS target resequencing on the Illumina platform MiSeq. 8.7% of the patients analyzed is carriers of class 5/4 coding variants in the ATM (3.6%), BRIP1 (1.6%), CHEK2 (1.8%), PALB2 (0.7%), RAD51C (0.4%), RAD51D (0.4%), and TP53 (0.2%) genes, while variants of uncertain pathological significance (VUSs)/class 3 were identified in 9.1% of the samples. In intron-exon junctions and in regulatory regions, variants were detected respectively in 5.1% and in 32.5% of the cases analyzed. The average age of disease onset of 44.4 in non-coding variant carriers is absolutely similar to the average age of disease onset in coding variant carriers for each proband's group with the same cancer type. Furthermore, there is not a statistically significant difference in the proportion of cases with a tumor onset under age of 40 between the two groups, but the presence of multiple non-coding variants in the same patient may affect the aggressiveness of the tumor and it is worth underlining that 25% of patients with an aggressive tumor are carriers of a PTEN 3'UTR-variant. This data provides initial information on how important it might be to extend mutational screening to the regulatory regions in clinical practice.


Subject(s)
Hereditary Breast and Ovarian Cancer Syndrome/genetics , Adult , Age of Onset , Cohort Studies , Female , Genes, BRCA1 , Genes, BRCA2 , Genetic Predisposition to Disease , Genetic Variation , Germ-Line Mutation , Humans , Italy , Middle Aged , PTEN Phosphohydrolase/genetics , Penetrance , Regulatory Sequences, Nucleic Acid
7.
J Biomed Mater Res A ; 109(11): 2322-2333, 2021 11.
Article in English | MEDLINE | ID: mdl-33960131

ABSTRACT

Gravity alterations elicit complex and mostly detrimental effects on biological systems. Among these, a prominent role is occupied by oxidative stress, with consequences for tissue homeostasis and development. Studies in altered gravity are relevant for both Earth and space biomedicine, but their implementation using whole organisms is often troublesome. Here we utilize planarians, simple worm model for stem cell and regeneration biology, to characterize the pathogenic mechanisms brought by artificial gravity alterations. In particular, we provide a comprehensive evaluation of molecular responses in intact and regenerating specimens, and demonstrate a protective action from the space-apt for nanotechnological antioxidant cerium oxide nanoparticles.


Subject(s)
Cerium , Gravity, Altered , Nanoparticles/chemistry , Planarians/metabolism , Regeneration/drug effects , Animals , Cerium/chemistry , Cerium/pharmacology
8.
Biol Cell ; 112(11): 335-348, 2020 Nov.
Article in English | MEDLINE | ID: mdl-32640042

ABSTRACT

BACKGROUND INFORMATION: Planarians are a sound, well-established model system for molecular studies in the field of stem cells, cell differentiation, developmental biology and translational research. Treated stem cell-less planarians produced by X-ray treatment are commonly used to study stem cell transcriptional profile and their role in planarian biological processes. X-ray induces oxidative and DNA damage to differentiated cells, requires expensive radiation machines that are not available in most of the research centres and demand rigorous risk management and dedicated staff. RESULTS: We tested the use of the well-known antimetabolite genotoxic drug 5-fluorouracil which mainly affects proliferating cells in way to demonstrate its use in replacing X-ray treatment. We succeeded in demonstrating ability of high doses of 5-fluorouracil to deplete Dugesia japonica stem cells and in identifying a 5-fluorouracil transiently resistant population of lineage committed stem cells. CONCLUSIONS AND SIGNIFICANCE: Our results encourage the use of 5-fluorouracil-treated planarians as a model system for studying mechanisms of resistance to genotoxicants, planarian stem cell heterogeneity and molecular cascades of tissue aging.


Subject(s)
Aging , Cell Differentiation/drug effects , DNA Damage/drug effects , Fluorouracil/pharmacology , Planarians/drug effects , Stem Cells/drug effects , Animals
9.
Mater Sci Eng C Mater Biol Appl ; 115: 111113, 2020 Oct.
Article in English | MEDLINE | ID: mdl-32600713

ABSTRACT

Owing to the self-renewing reactive oxygen species scavenger capability of cerium oxide nanoparticles (nanoceria), we tested in vivo radioprotective effects on stem cells and tissue regeneration using low-dose irradiated planarians as model system. We treated planarians with nanoceria or gum Arabic, as control, and we analyzed the expression of stem cell molecular markers and tissue regeneration capability, as well as cell death and DNA damage in non-irradiated and in low-dose irradiated animals. Our findings show that nanoceria increase the number of stem cells and tissue regenerative capability, and reduce cell death and DNA damage after low-dose irradiation, suggesting a protective role on stem cells.


Subject(s)
Cerium/pharmacology , Planarians/physiology , Radiation-Protective Agents/pharmacology , Regeneration/drug effects , Animals , DNA Damage/drug effects , Nanoparticles , Planarians/drug effects , Planarians/radiation effects , Radiation, Ionizing , Stem Cells/drug effects , Stem Cells/physiology , Stem Cells/radiation effects
10.
Aquat Toxicol ; 218: 105354, 2020 Jan.
Article in English | MEDLINE | ID: mdl-31734615

ABSTRACT

Increasing microplastics pollution of marine and terrestrial water is a concerning issue for ecosystems and human health. Nevertheless, the interaction of microplastics with freshwater biota is still a poorly explored field. In order to achieve information concerning the uptake, distribution and effect of microplastics in planarians, Dugesia japonica specimens have been fed with mixtures of food and differently shaped and sized plastic particles. Feeding activity and food intake were non-altered by the presence of high concentrations of different types of plastic particles. However, the persistence of microplastic within the planarian body was a function of size/shape, being small spheres (<10 µm in diameter) and short fibers (14 µm large and 5/6 µm length) more persisting than larger spheres and longer fibers which were eliminated almost entirely by ejection in a few hours. Transmission electron microscopy analysis demonstrated that at least part of microplastics was phagocytized by the enterocytes. Chronic exposure to small plastic did not alter the regenerative ability but caused a significant reduction of the gut epithelium thickness and lipid content of enterocytes, together with the induction of apoptotic cell death, modulation of Djgata 4/5/6 expression and reduced growth rate. The ability of microplastic to perturb planarian homeostasis is concerning being them extremely resilient against mechanical and chemical insults and suggests possible harmful effects upon other more susceptible species in freshwater ecosystems.


Subject(s)
Environmental Monitoring/methods , Homeostasis/drug effects , Microplastics/toxicity , Planarians/drug effects , Regeneration/drug effects , Water Pollutants, Chemical/toxicity , Animals , Apoptosis/drug effects , Biota/drug effects , Ecosystem , Enterocytes/drug effects , Enterocytes/ultrastructure , Feeding Behavior/drug effects , Fresh Water/analysis , Humans , Microscopy, Electron, Transmission , Particle Size , Planarians/physiology , Planarians/ultrastructure
11.
Hum Mutat ; 39(12): 2025-2039, 2018 12.
Article in English | MEDLINE | ID: mdl-30204945

ABSTRACT

The widespread use of next generation sequencing for clinical testing is detecting an escalating number of variants in noncoding regions of the genome. The clinical significance of the majority of these variants is currently unknown, which presents a significant clinical challenge. We have screened over 6,000 early-onset and/or familial breast cancer (BC) cases collected by the ENIGMA consortium for sequence variants in the 5' noncoding regions of BC susceptibility genes BRCA1 and BRCA2, and identified 141 rare variants with global minor allele frequency < 0.01, 76 of which have not been reported previously. Bioinformatic analysis identified a set of 21 variants most likely to impact transcriptional regulation, and luciferase reporter assays detected altered promoter activity for four of these variants. Electrophoretic mobility shift assays demonstrated that three of these altered the binding of proteins to the respective BRCA1 or BRCA2 promoter regions, including NFYA binding to BRCA1:c.-287C>T and PAX5 binding to BRCA2:c.-296C>T. Clinical classification of variants affecting promoter activity, using existing prediction models, found no evidence to suggest that these variants confer a high risk of disease. Further studies are required to determine if such variation may be associated with a moderate or low risk of BC.


Subject(s)
BRCA1 Protein/genetics , BRCA2 Protein/genetics , Breast Neoplasms/genetics , Germ-Line Mutation , Promoter Regions, Genetic , 5' Untranslated Regions , Age of Onset , BRCA1 Protein/chemistry , BRCA1 Protein/metabolism , BRCA2 Protein/chemistry , BRCA2 Protein/metabolism , CCAAT-Binding Factor/metabolism , Cell Line, Tumor , Female , Genetic Predisposition to Disease , Humans , MCF-7 Cells , PAX5 Transcription Factor/metabolism , Protein Binding
12.
Genes Chromosomes Cancer ; 55(12): 915-924, 2016 12.
Article in English | MEDLINE | ID: mdl-27328445

ABSTRACT

Triple negative breast cancers (TNBCs) represent about 15-20% of all breast cancer cases and are characterized by a complex molecular heterogeneity. Some TNBCs exhibit clinical and pathological properties similar to BRCA-mutated tumors, without actually bearing a mutation in BRCA genes. This "BRCAness" phenotype may be explained by germline mutations in other genes involved in DNA repair. Although respond to chemotherapy with alkylating agents, they have a high risk of recurrence and progression. Some studies have shown the efficacy of neoadjuvant therapy in TNBC patients with DNA repair defects, but proper biomarkers of DNA repair deficiency are still needed. Here, we investigated if mutations in DNA repair genes may be correlated with anthracyclines/taxanes neoadjuvant therapy response. DNA from 19 TNBC patients undergoing neoadjuvant therapy were subjected to next generation sequencing of a panel of 24 genes in DNA repair and breast cancer predisposition. In this study, 5 of 19 patients (26%) carried a pathogenic mutation in BRCA1, PALB2, RAD51C and two patients carried a probable pathogenic missense variant. Moreover, VUS (Variants of Unknown Significance) in other genes, predicted to be deleterious by in silico tools, were detected in five patients. Germline mutations in DNA repair genes were found to be associated with the group of TNBC patients who responded to therapy. We conclude that a subgroup of TNBC patients have defects in DNA repair genes, other than BRCA1, and such patients respond favourably to neoadjuvant anthracyclines/taxanes therapy. © 2016 Wiley Periodicals, Inc.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/genetics , DNA Repair Enzymes/genetics , Germ-Line Mutation/genetics , Neoadjuvant Therapy , Neoplasm Recurrence, Local/genetics , Triple Negative Breast Neoplasms/genetics , Adult , Aged , BRCA1 Protein/genetics , Case-Control Studies , DNA Repair/drug effects , DNA Repair/genetics , DNA-Binding Proteins/genetics , Fanconi Anemia Complementation Group N Protein , Female , Follow-Up Studies , Genetic Predisposition to Disease , High-Throughput Nucleotide Sequencing , Humans , Middle Aged , Neoplasm Grading , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/pathology , Neoplasm Staging , Nuclear Proteins/genetics , Prognosis , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/pathology , Tumor Suppressor Proteins/genetics
13.
Int J Mol Med ; 35(4): 950-6, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25683334

ABSTRACT

The study of BRCA1 and BRCA2 genes and their alterations has been essential to the understanding of the development of familial breast and ovarian cancers. Many of the variants identified have an unknown pathogenic significance. These include variants which determine alternative mRNA splicing, identified in the intronic regions and those are capable of destroying the splicing ability. The aim of this study was to detect BRCA1/BRCA2 aberrant transcripts resulting from alternative splicing, in women with a known family history and/or early onset of breast and/or ovarian cancer, tested wild-type for BRCA1 and BRCA2. The identification and characterization of aberrant transcripts through the analysis of mRNA levels in blood lymphocytes may help us to recognize families otherwise misclassified as wild-type BRCA1 and BRCA2. Blood samples were collected from 13 women that had a family history of breast and/or ovarian cancer and tested negative for pathogenic mutations in the BRCA1 and BRCA2 genes. Total RNA was analyzed for the presence of BRCA1 and BRCA2 naturally occurring and pathological transcripts using RT-PCR. In 2 out of the 13 samples, 2 alternative transcripts of the BRCA1 gene were identified. These were probably pathogenic as they lacked exon 17 and exon 15, respectively, giving rise to a truncated protein. In addition to these, we identified the Δ17-19 transcript in 1 patient, which gives rise to a protein with an in-frame deletion of 69 amino acids. In conclusion, this study on alternative transcripts of the BRCA1 and BRCA2 genes revealed the presence of isoforms (prevalence of 15%) in blood samples from women with breast and ovarian cancer that were probably pathogenic, that were not detected by conventional methods of mutation screening based on direct sequencing of all coding regions, intron-exons junctions and MLPA analysis.


Subject(s)
Alternative Splicing , Breast Neoplasms/genetics , Genes, BRCA1 , Hereditary Breast and Ovarian Cancer Syndrome/genetics , Adult , Exons , Female , Genes, BRCA2 , Genetic Association Studies , Humans , Middle Aged , Mutation , RNA Isoforms , RNA, Messenger/genetics , Sequence Analysis, DNA , Transcription, Genetic
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