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Article ; Online: Special Focus on Regulated Cell Death: Emerging Mechanisms and Current Perspectives in Biology and Pathology.

Santagostino, Sara Francesca / Radaelli, Enrico

2021 Volume 58, Issue 4, Page(s) 594–595

MeSH term(s)	Animals ; Biology ; Regulated Cell Death
Language	English
Publishing date	2021-02-12
Publishing country	United States
Document type	Editorial
ZDB-ID	188012-3
ISSN	1544-2217 ; 0300-9858
ISSN (online)	1544-2217
ISSN	0300-9858
DOI	10.1177/0300985820985326
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Article ; Online: Preconception and developmental DEHP exposure alter liver metabolism in a sex-dependent manner in adult mouse offspring.

Robles-Matos, Nicole / Radaelli, Enrico / Simmons, Rebecca A / Bartolomei, Marisa S

Toxicology

2023 Volume 499, Page(s) 153640

Abstract: Environmental exposure to endocrine disrupting chemicals (EDCs) during critical periods of development is associated with an increased risk of metabolic diseases, including hepatic steatosis and obesity. Di-2-ethylhexyl-phthalate (DEHP) is an EDC ... ...

Abstract	Environmental exposure to endocrine disrupting chemicals (EDCs) during critical periods of development is associated with an increased risk of metabolic diseases, including hepatic steatosis and obesity. Di-2-ethylhexyl-phthalate (DEHP) is an EDC strongly associated with these metabolic abnormalities. DEHP developmental windows of susceptibility are unknown yet have important public health implications. The purpose of this study was to identify these windows of susceptibility and determine whether developmental DEHP exposure alters hepatic metabolism later in life. Dams were exposed to control or feed containing human exposure relevant doses of DEHP (50 μg/kg BW/d) and high dose DEHP (10 mg/kg BW/d) from preconception until weaning or only exposed to DEHP during preconception. Post-weaning, all offspring were fed a control diet throughout adulthood. Using the Metabolon Untargeted Metabolomics platform, we identified 148 significant metabolites in female adult livers that were altered by preconception-gestation-lactation DEHP exposure. We found a significant increase in the levels of acylcarnitines, diacylglycerols, sphingolipids, glutathione, purines, and pyrimidines in DEHP-exposed female livers compared to controls. These changes in fatty acid oxidation and oxidative stress-related metabolites were correlated with hepatic changes including microvesicular steatosis, hepatocyte swelling, inflammation. In contrast to females, we observed fewer metabolic alterations in male offspring, which were uniquely found in preconception-only low dose DEHP exposure group. Although we found that preconception-gestational-lactation exposure causes the most liver pathology, we surprisingly found preconception exposure linked to an abnormal liver metabolome. We also found that two doses exhibited non-monotonic DEHP-induced changes in the liver. Collectively, these findings suggest that metabolic changes in the adult liver of offspring exposed periconceptionally to DHEP depends on the timing of exposure, dose, and sex.
MeSH term(s)	Animals ; Female ; Male ; Mice ; Diethylhexyl Phthalate/toxicity ; Endocrine Disruptors/toxicity ; Fatty Liver ; Lactation ; Prenatal Exposure Delayed Effects
Chemical Substances	Diethylhexyl Phthalate (C42K0PH13C) ; Endocrine Disruptors
Language	English
Publishing date	2023-10-06
Publishing country	Ireland
Document type	Journal Article
ZDB-ID	184557-3
ISSN	1879-3185 ; 0300-483X
ISSN (online)	1879-3185
ISSN	0300-483X
DOI	10.1016/j.tox.2023.153640
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Article ; Online: Restricted Sensitivity of FJ-C Staining to Assess Neuronal Degeneration and Death in Preclinical Mouse Studies

Santagostino, Sara Francesca / Spinazzi, Marco / Radaelli, Enrico

Veterinary Pathology. 2021 July, v. 58, no. 4 p.643-649

2021

Abstract: Fluorescein-derived fluorochromes and anionic dyes such as Fluoro-Jade (FJ) stains have been introduced to facilitate recognition of dying neurons in tissue sections. However, the definition of what is really detected by FJ-based stains and its ... ...

Abstract	Fluorescein-derived fluorochromes and anionic dyes such as Fluoro-Jade (FJ) stains have been introduced to facilitate recognition of dying neurons in tissue sections. However, the definition of what is really detected by FJ-based stains and its sensitivity in the detection of neuronal cell death is unclear. In our work, we evaluated the outcome of FJ-C staining in mouse brains from 4 different well-characterized models of neurodegeneration. Neuronal degeneration and loss were highlighted with high sensitivity by FJ-C stain in mice with dysfunctional γ-secretase in the glutamatergic neurons and in mice affected by acute cerebral ischemia. Histopathologically, acute eosinophilic necrosis or “red dead” neurons were associated with FJ-C staining in both settings. Conversely, in mice affected by chronic cerebral microinfarcts due to tumor lysis syndrome as well as in a model of mitochondrial encephalopathy, FJ-C staining failed to detect neuronal death. Histopathologically, these models were characterized by extensive neuronal vacuolation associated with fading neurons (“ghost cells”). Therefore, contrary to the widespread belief that FJ-C stain has high affinity for all degenerating neurons regardless of the underlying cell death mechanism, we observed restricted sensitivity of the technique to specific conditions of neuronal cell death. As such, complementary techniques are essential to evaluate the presence of neurodegeneration in the absence of a positive FJ-C signal.
Keywords	animal pathology ; cell death ; death ; encephalopathy ; fluorescent dyes ; histopathology ; ischemia ; mice ; mitochondria ; models ; necrosis ; neoplasms ; neurodegenerative diseases ; neurons ; Fluoro-Jade C ; neurodegeneration ; neuronal cell death ; mouse models
Language	English
Dates of publication	2021-07
Size	p. 643-649.
Publishing place	SAGE Publications
Document type	Article ; Online
ZDB-ID	188012-3
ISSN	1544-2217 ; 0300-9858
ISSN (online)	1544-2217
ISSN	0300-9858
DOI	10.1177/0300985820985290
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Article ; Online: Restricted Sensitivity of FJ-C Staining to Assess Neuronal Degeneration and Death in Preclinical Mouse Studies.

Santagostino, Sara Francesca / Spinazzi, Marco / Radaelli, Enrico

Veterinary pathology

2021 Volume 58, Issue 4, Page(s) 643–649

Abstract	Fluorescein-derived fluorochromes and anionic dyes such as Fluoro-Jade (FJ) stains have been introduced to facilitate recognition of dying neurons in tissue sections. However, the definition of what is really detected by FJ-based stains and its sensitivity in the detection of neuronal cell death is unclear. In our work, we evaluated the outcome of FJ-C staining in mouse brains from 4 different well-characterized models of neurodegeneration. Neuronal degeneration and loss were highlighted with high sensitivity by FJ-C stain in mice with dysfunctional γ-secretase in the glutamatergic neurons and in mice affected by acute cerebral ischemia. Histopathologically, acute eosinophilic necrosis or "red dead" neurons were associated with FJ-C staining in both settings. Conversely, in mice affected by chronic cerebral microinfarcts due to tumor lysis syndrome as well as in a model of mitochondrial encephalopathy, FJ-C staining failed to detect neuronal death. Histopathologically, these models were characterized by extensive neuronal vacuolation associated with fading neurons ("ghost cells"). Therefore, contrary to the widespread belief that FJ-C stain has high affinity for all degenerating neurons regardless of the underlying cell death mechanism, we observed restricted sensitivity of the technique to specific conditions of neuronal cell death. As such, complementary techniques are essential to evaluate the presence of neurodegeneration in the absence of a positive FJ-C signal.
MeSH term(s)	Animals ; Brain/pathology ; Fluorescent Dyes ; Mice ; Nerve Degeneration/pathology ; Nerve Degeneration/veterinary ; Organic Chemicals ; Staining and Labeling/veterinary
Chemical Substances	Fluorescent Dyes ; Organic Chemicals
Language	English
Publishing date	2021-01-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	188012-3
ISSN	1544-2217 ; 0300-9858
ISSN (online)	1544-2217
ISSN	0300-9858
DOI	10.1177/0300985820985290
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Article: Spontaneous pulmonary co-metastasis of hepatoblastoma arising within a hepatocellular carcinoma in an aged C57BL/6J mouse.

Castiglioni, Vittoria / Radaelli, Enrico

Journal of toxicologic pathology

2018 Volume 31, Issue 3, Page(s) 195–199

Abstract: Murine hepatoblastoma (HB) is a rare spontaneous tumor with controversial histogenesis. It mainly occurs in aged males, frequently in close association with preexisting hepatocellular neoplasms. The present work describes a spontaneous HB arising within ... ...

Abstract	Murine hepatoblastoma (HB) is a rare spontaneous tumor with controversial histogenesis. It mainly occurs in aged males, frequently in close association with preexisting hepatocellular neoplasms. The present work describes a spontaneous HB arising within a hepatocellular carcinoma (HCC) in a 22-month-old male C57BL/6J mouse. The mouse also developed pulmonary co-metastases with either tumor components physically associated within the same metastatic foci. Microscopically, the HB consisted of a densely cellular neoplastic growth composed of palisades and perivascular pseudorosettes of poorly differentiated primitive cells, with a scant amount of cytoplasm, elongated hyperchromatic nuclei, and a high mitotic rate, whereas the hepatocellular carcinoma was composed of solid areas of neoplastic hepatocytes. Both in primary tumors and their metastases, β-catenin immunohistochemistry revealed a strong nucleocytoplasmic signal in HB cells, while neoplastic hepatocytes displayed a delicate membranous staining pattern. These findings suggest that the Wnt/β-catenin oncogenic pathway is upregulated in murine HB but not in the co-existing HCC, thus providing some insights into their divergent pathogenesis. Coexisting murine HB and HCC have been demonstrated to be completely distinct entities including origin, mutational landscape, and molecular profile. In this context, they might be regarded as collision tumors because of their intimate association, unique histologic features, and distinct immunohistochemical patterns. Nevertheless, the nature of their coevolution and progression to a co-metastatic phenotype reflects a close interdependence and support the overall idea that HB's origin and progression might be promoted by not otherwise specified paracrine stimuli provided by the concurrent hepatocellular tumor (the so called "interaction theory").
Language	English
Publishing date	2018-06-23
Publishing country	Japan
Document type	Case Reports
ZDB-ID	2128461-1
ISSN	1881-915X ; 0914-9198
ISSN (online)	1881-915X
ISSN	0914-9198
DOI	10.1293/tox.2017-0067
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Article ; Online: Palisading granulomatous dermatitis and panniculitis (palisading granuloma) of dogs.

Lund, Michael / Mauldin, Elizabeth A / Radaelli, Enrico / Bradley, Charles W

Veterinary pathology

2021 Volume 58, Issue 6, Page(s) 1091–1099

Abstract: Palisading granulomatous dermatitis and panniculitis is recognized in various cutaneous inflammatory lesions secondary to presumed collagen damage. Cutaneous nodules with a palisading arrangement of histiocytes surrounding foci of collagen degeneration ... ...

Abstract	Palisading granulomatous dermatitis and panniculitis is recognized in various cutaneous inflammatory lesions secondary to presumed collagen damage. Cutaneous nodules with a palisading arrangement of histiocytes surrounding foci of collagen degeneration have been clinically termed palisading granuloma in dogs. Study aims were to characterize the cellular infiltrate of canine palisading granuloma and document salient clinical features. Inclusion criteria were met for 36 dogs and encompassed nodular dermal and subcutaneous histiocyte-predominant cellular infiltrates targeting and enveloping collagen fibers/necrotic foci with palisading configurations. Infectious causes were ruled out via standard histochemical stains and/or clinical data. Medical records were reviewed for signalment, clinical features, treatment, outcome, and comorbidities. Immunohistochemistry (IBA1, CD204, E-cadherin) and Masson's trichrome stain were used to assess histiocytic populations and dermal collagen, respectively. The histiocytes had moderate or strong immunolabeling for IBA1 and CD204 in 36/36 dogs (100%) and mild positive immunolabeling for E-cadherin in 3/36 dogs (8%). Alteration of collagen was graded as moderate or strong in 32/36 dogs (89%) and mild in 3/36 dogs (8%). Large breeds predominated with 30/36 dogs (83%) being ≥23 kg. Focal nodules were identified in 31/36 dogs (86%). The head/face were involved in 19/36 dogs (53%) and the extremities in 18/36 dogs (50%). Lesions from the 5/36 dogs (14%) with multiple nodules contained prominent eosinophilic infiltrates. Following excision, there was no evidence of recurrence. In conclusion, palisading granulomas are a distinct, non-neoplastic, histiocyte-predominant inflammatory condition in dogs associated with altered dermal collagen and favorable prognosis.
MeSH term(s)	Animals ; Autoimmune Diseases/veterinary ; Dermatitis/veterinary ; Dog Diseases ; Dogs ; Granuloma/veterinary ; Histiocytes ; Panniculitis/veterinary
Language	English
Publishing date	2021-07-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	188012-3
ISSN	1544-2217 ; 0300-9858
ISSN (online)	1544-2217
ISSN	0300-9858
DOI	10.1177/03009858211030525
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Article: Post Mortem

Assenmacher, Charles-Antoine / Lanza, Matthew / Tarrant, James C / Gardiner, Kristin L / Blankemeyer, Eric / Radaelli, Enrico

Animals : an open access journal from MDPI

2022 Volume 12, Issue 23

Abstract: Routine handling and manipulation of laboratory mice are integral components of most preclinical studies. Any type of handling and manipulation may cause stress and result in physical harm to mice, potentially leading to unintended consequences of ... ...

Abstract	Routine handling and manipulation of laboratory mice are integral components of most preclinical studies. Any type of handling and manipulation may cause stress and result in physical harm to mice, potentially leading to unintended consequences of experimental outcomes. Nevertheless, the pathological effects of these interventions are poorly documented and assumed to have a negligible effect on experimental variables. In that context, we provide a comprehensive
Language	English
Publishing date	2022-11-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606558-7
ISSN	2076-2615
ISSN	2076-2615
DOI	10.3390/ani12233234
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Article ; Online: Inquiry Concerning Which Polyclonal Goat Antibody for Detection of FLAG-tag in Formalin-Fixed and Paraffin-Embedded Specimens.

Radaelli, Enrico / Riva, Matteo

The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society

2017 Volume 65, Issue 4, Page(s) 253

MeSH term(s)	Animals ; Formaldehyde ; Goats ; Immunohistochemistry ; Mice ; Paraffin Embedding ; Tissue Fixation
Chemical Substances	Formaldehyde (1HG84L3525)
Language	English
Publishing date	2017-03-14
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	218208-7
ISSN	1551-5044 ; 0022-1554
ISSN (online)	1551-5044
ISSN	0022-1554
DOI	10.1369/0022155416688199
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Article ; Online: Palisading granulomatous dermatitis and panniculitis (palisading granuloma) of dogs

Lund, Michael / Mauldin, Elizabeth A. / Radaelli, Enrico / Bradley, Charles W.

Veterinary Pathology. 2021 Nov., v. 58, no. 6 p.1091-1099

2021

Abstract	Palisading granulomatous dermatitis and panniculitis is recognized in various cutaneous inflammatory lesions secondary to presumed collagen damage. Cutaneous nodules with a palisading arrangement of histiocytes surrounding foci of collagen degeneration have been clinically termed palisading granuloma in dogs. Study aims were to characterize the cellular infiltrate of canine palisading granuloma and document salient clinical features. Inclusion criteria were met for 36 dogs and encompassed nodular dermal and subcutaneous histiocyte-predominant cellular infiltrates targeting and enveloping collagen fibers/necrotic foci with palisading configurations. Infectious causes were ruled out via standard histochemical stains and/or clinical data. Medical records were reviewed for signalment, clinical features, treatment, outcome, and comorbidities. Immunohistochemistry (IBA1, CD204, E-cadherin) and Masson’s trichrome stain were used to assess histiocytic populations and dermal collagen, respectively. The histiocytes had moderate or strong immunolabeling for IBA1 and CD204 in 36/36 dogs (100%) and mild positive immunolabeling for E-cadherin in 3/36 dogs (8%). Alteration of collagen was graded as moderate or strong in 32/36 dogs (89%) and mild in 3/36 dogs (8%). Large breeds predominated with 30/36 dogs (83%) being ≥23 kg. Focal nodules were identified in 31/36 dogs (86%). The head/face were involved in 19/36 dogs (53%) and the extremities in 18/36 dogs (50%). Lesions from the 5/36 dogs (14%) with multiple nodules contained prominent eosinophilic infiltrates. Following excision, there was no evidence of recurrence. In conclusion, palisading granulomas are a distinct, non-neoplastic, histiocyte-predominant inflammatory condition in dogs associated with altered dermal collagen and favorable prognosis.
Keywords	animal pathology ; cadherins ; collagen ; dermatitis ; dogs ; excision ; face ; granuloma ; histiocytes ; immunohistochemistry ; prognosis ; dermatopathology ; dog ; granulomatous dermatitis ; inflammation ; macrophages ; skin ; trauma
Language	English
Dates of publication	2021-11
Size	p. 1091-1099.
Publishing place	SAGE Publications
Document type	Article ; Online
ZDB-ID	188012-3
ISSN	1544-2217 ; 0300-9858
ISSN (online)	1544-2217
ISSN	0300-9858
DOI	10.1177/03009858211030525
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Mechanisms of Regulated Cell Death: Current Perspectives

Santagostino, Sara Francesca / Assenmacher, Charles-Antoine / Tarrant, James C. / Adedeji, Adeyemi O. / Radaelli, Enrico

Veterinary Pathology. 2021 July, v. 58, no. 4 p.596-623

2021

Abstract: Balancing cell survival and cell death is fundamental to development and homeostasis. Cell death is regulated by multiple interconnected signaling pathways and molecular mechanisms. Regulated cell death (RCD) is implicated in fundamental processes such ... ...

Abstract	Balancing cell survival and cell death is fundamental to development and homeostasis. Cell death is regulated by multiple interconnected signaling pathways and molecular mechanisms. Regulated cell death (RCD) is implicated in fundamental processes such as organogenesis and tissue remodeling, removal of unnecessary structures or cells, and regulation of cell numbers. RCD can also be triggered by exogenous perturbations of the intracellular or extracellular microenvironment when the adaptive processes that respond to stress fail. During the past few years, many novel forms of non-apoptotic RCD have been identified, and the characterization of RCD mechanisms at a molecular level has deepened our understanding of diseases encountered in human and veterinary medicine. Given the complexity of these processes, it has become clear that the identification of RCD cannot be based simply on morphologic characteristics and that descriptive and diagnostic terms presently used by pathologists—such as individual cell apoptosis or necrosis—appear inadequate and possibly misleading. In this review, the current understanding of the molecular machinery of each type of non-apoptotic RCD mechanisms is outlined. Due to the continuous discovery of new mechanisms or nuances of previously described processes, the limitations of the terms apoptosis and necrosis to indicate microscopic findings are also reported. In addition, the need for a standard panel of biomarkers and functional tests to adequately characterize the underlying RCD and its role as a mechanism of disease is considered.
Keywords	animal pathology ; apoptosis ; biomarkers ; cell viability ; homeostasis ; humans ; necrosis ; organogenesis ; anoikis ; autophagic cell death ; entosis ; ferroptosis ; immunogenic cell death ; lysosomes ; pathology ; mitochondrial transmembrane permeability-driven necroptosis ; neutrophil extracellular traps ; parthanatos ; pyroptosis ; regulated cell death
Language	English
Dates of publication	2021-07
Size	p. 596-623.
Publishing place	SAGE Publications
Document type	Article ; Online
ZDB-ID	188012-3
ISSN	1544-2217 ; 0300-9858
ISSN (online)	1544-2217
ISSN	0300-9858
DOI	10.1177/03009858211005537
Database	NAL-Catalogue (AGRICOLA)

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