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Article ; Online: Sex difference in liver diseases: How preclinical models help to dissect the sex-related mechanisms sustaining NAFLD and hepatocellular carcinoma.

Smiriglia, Alfredo / Lorito, Nicla / Serra, Marina / Perra, Andrea / Morandi, Andrea / Kowalik, Marta Anna

iScience

2023 Volume 26, Issue 12, Page(s) 108363

Abstract: Only a few preclinical findings are confirmed in the clinic, posing a critical issue for clinical development. Therefore, identifying the best preclinical models can help to dissect molecular and mechanistic insights into liver disease pathogenesis while ...

Abstract	Only a few preclinical findings are confirmed in the clinic, posing a critical issue for clinical development. Therefore, identifying the best preclinical models can help to dissect molecular and mechanistic insights into liver disease pathogenesis while being clinically relevant. In this context, the sex relevance of most preclinical models has been only partially considered. This is particularly significant in NAFLD and HCC, which have a higher prevalence in men when compared to pre-menopause women but not to those in post-menopausal status, suggesting a role for sex hormones in the pathogenesis of the diseases. This review gathers the sex-relevant findings and the available preclinical models focusing on both
Language	English
Publishing date	2023-10-30
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2023.108363
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Article ; Online: Sex difference in liver diseases

Alfredo Smiriglia / Nicla Lorito / Marina Serra / Andrea Perra / Andrea Morandi / Marta Anna Kowalik

iScience, Vol 26, Iss 12, Pp 108363- (2023)

How preclinical models help to dissect the sex-related mechanisms sustaining NAFLD and hepatocellular carcinoma

2023

Abstract: Summary: Only a few preclinical findings are confirmed in the clinic, posing a critical issue for clinical development. Therefore, identifying the best preclinical models can help to dissect molecular and mechanistic insights into liver disease ... ...

Abstract	Summary: Only a few preclinical findings are confirmed in the clinic, posing a critical issue for clinical development. Therefore, identifying the best preclinical models can help to dissect molecular and mechanistic insights into liver disease pathogenesis while being clinically relevant. In this context, the sex relevance of most preclinical models has been only partially considered. This is particularly significant in NAFLD and HCC, which have a higher prevalence in men when compared to pre-menopause women but not to those in post-menopausal status, suggesting a role for sex hormones in the pathogenesis of the diseases. This review gathers the sex-relevant findings and the available preclinical models focusing on both in vitro and in vivo studies and discusses the potential implications and perspectives of introducing the sex effect in the selection of the best preclinical model. This is a critical aspect that would help to tailor personalized therapies based on sex.
Keywords	Natural sciences ; Biological sciences ; Cancer ; Science ; Q
Language	English
Publishing date	2023-12-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The density of hepatic autonomic innervation differs between compensatory and direct hyperplasia rat models.

Trucas, Marcello / Kowalik, Marta Anna / Boi, Marianna / Serra, Maria Pina / Perra, Andrea / Quartu, Marina

Journal of the peripheral nervous system : JPNS

2022 Volume 28, Issue 1, Page(s) 98–107

Abstract: To contribute to the knowledge of the autonomic innervation in liver regeneration, here we investigate the distribution of tyrosine hydroxylase (TH)- and choline acetyltransferase (ChAT)-like immunoreactive (LI) nerve fibers, to indicate noradrenergic ... ...

Abstract	To contribute to the knowledge of the autonomic innervation in liver regeneration, here we investigate the distribution of tyrosine hydroxylase (TH)- and choline acetyltransferase (ChAT)-like immunoreactive (LI) nerve fibers, to indicate noradrenergic and cholinergic nerves, respectively, in rats under different conditions of liver damage and repair. By immunohistochemistry and assessment of nerve fiber density, three models of induced hepatic regeneration were examined: the carbon tetrachloride (CCl
MeSH term(s)	Rats ; Animals ; Hyperplasia ; Nerve Fibers ; Immunohistochemistry
Language	English
Publishing date	2022-11-23
Publishing country	United States
Document type	Case Reports ; Research Support, Non-U.S. Gov't
ZDB-ID	1364009-4
ISSN	1529-8027 ; 1085-9489
ISSN (online)	1529-8027
ISSN	1085-9489
DOI	10.1111/jns.12521
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Article: Potential use of TG68 - A novel thyromimetic - for the treatment of non-alcoholic fatty liver (NAFLD)-associated hepatocarcinogenesis.

Caddeo, Andrea / Serra, Marina / Sedda, Francesca / Bacci, Andrea / Manera, Clementina / Rapposelli, Simona / Columbano, Amedeo / Perra, Andrea / Kowalik, Marta Anna

Frontiers in oncology

2023 Volume 13, Page(s) 1127517

Abstract: Introduction: Several lines of evidence suggest that the thyroid hormone signaling pathway is altered in patients with NAFLD and that pharmacological strategies to target the thyroid hormone/thyroid hormone nuclear receptor axis (TH/THR) in the liver ... ...

Abstract	Introduction: Several lines of evidence suggest that the thyroid hormone signaling pathway is altered in patients with NAFLD and that pharmacological strategies to target the thyroid hormone/thyroid hormone nuclear receptor axis (TH/THR) in the liver may exert beneficial effects. In this study, we investigated the effect of TG68, a novel THRβ agonist, on rat hepatic fat accumulation and NAFLD-associated hepatocarcinogenesis. Methods: Male rats given a single dose of diethylnitrosamine (DEN) and fed a high fat diet (HFD) were co-treated with different doses of TG68. Systemic and hepatic metabolic parameters, immunohistochemistry and hepatic gene expression were determined to assess the effect of TG68 on THRβ activation. Results: Irrespectively of the dose, treatment with TG68 led to a significant reduction in liver weight, hepatic steatosis, circulating triglycerides, cholesterol and blood glucose. Importantly, a short exposure to TG68 caused regression of DEN-induced preneoplastic lesions associated with a differentiation program, as evidenced by a loss of neoplastic markers and reacquisition of markers of differentiated hepatocytes. Finally, while an equimolar dose of the THRβ agonist Resmetirom reduced hepatic fat accumulation, it did not exert any antitumorigenic effect. Discussion: The use of this novel thyromimetic represents a promising therapeutic strategy for the treatment of NAFLD-associated hepatocarcinogenesis.
Language	English
Publishing date	2023-02-23
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2023.1127517
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Article: Animal Models: A Useful Tool to Unveil Metabolic Changes in Hepatocellular Carcinoma.

Serra, Marina / Columbano, Amedeo / Perra, Andrea / Kowalik, Marta Anna

Cancers

2020 Volume 12, Issue 11

Abstract: Hepatocellular carcinoma (HCC) is one the most frequent and lethal human cancers. At present, no effective treatment for advanced HCC exist; therefore, the overall prognosis for HCC patients remains dismal. In recent years, a better knowledge of the ... ...

Abstract	Hepatocellular carcinoma (HCC) is one the most frequent and lethal human cancers. At present, no effective treatment for advanced HCC exist; therefore, the overall prognosis for HCC patients remains dismal. In recent years, a better knowledge of the signaling pathways involved in the regulation of HCC development and progression, has led to the identification of novel potential targets for therapeutic strategies. However, the obtained benefits from current therapeutic options are disappointing. Altered cancer metabolism has become a topic of renewed interest in the last decades, and it has been included among the core hallmarks of cancer. In the light of growing evidence for metabolic reprogramming in cancer, a wide number of experimental animal models have been exploited to study metabolic changes characterizing HCC development and progression and to further expand our knowledge of this tumor. In the present review, we discuss several rodent models of hepatocarcinogenesis, that contributed to elucidate the metabolic profile of HCC and the implications of these changes in modulating the aggressiveness of neoplastic cells. We also highlight the apparently contrasting results stemming from different animal models. Finally, we analyze whether these observations could be exploited to improve current therapeutic strategies for HCC.
Language	English
Publishing date	2020-11-10
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers12113318
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Article ; Online: Diverse MicroRNAs-mRNA networks regulate the priming phase of mouse liver regeneration and of direct hyperplasia.

Pal, Rajesh / Kowalik, Marta Anna / Serra, Marina / Migliore, Cristina / Giordano, Silvia / Columbano, Amedeo / Perra, Andrea

Cell proliferation

2022 Volume 55, Issue 4, Page(s) e13199

Abstract: Objectives: Adult hepatocytes are quiescent cells that can be induced to proliferate in response to a reduction in liver mass (liver regeneration) or by agents endowed with mitogenic potency (primary hyperplasia). The latter condition is characterized ... ...

Abstract	Objectives: Adult hepatocytes are quiescent cells that can be induced to proliferate in response to a reduction in liver mass (liver regeneration) or by agents endowed with mitogenic potency (primary hyperplasia). The latter condition is characterized by a more rapid entry of hepatocytes into the cell cycle, but the mechanisms responsible for the accelerated entry into the S phase are unknown. Materials and methods: Next generation sequencing and Illumina microarray were used to profile microRNA and mRNA expression in CD-1 mice livers 1, 3 and 6 h after 2/3 partial hepatectomy (PH) or a single dose of TCPOBOP, a ligand of the constitutive androstane receptor (CAR). Ingenuity pathway and DAVID analyses were performed to identify deregulated pathways. MultiMiR analysis was used to construct microRNA-mRNA networks. Results: Following PH or TCPOBOP we identified 810 and 527 genes, and 102 and 10 miRNAs, respectively, differentially expressed. Only 20 genes and 8 microRNAs were shared by the two conditions. Many miRNAs targeting negative regulators of cell cycle were downregulated early after PH, concomitantly with increased expression of their target genes. On the contrary, negative regulators were not modified after TCPOBOP, but Ccnd1 targeting miRNAs, such as miR-106b-5p, were downregulated. Conclusions: While miRNAs targeting negative regulators of the cell cycle are downregulated after PH, TCPOBOP caused downregulation of miRNAs targeting genes required for cell cycle entry. The enhanced Ccnd1 expression may explain the more rapid entry into the S phase of mouse hepatocytes following TCPOBOP.
MeSH term(s)	Animals ; Hepatocytes/metabolism ; Hyperplasia/pathology ; Liver/pathology ; Liver Regeneration/genetics ; Mice ; MicroRNAs/genetics ; MicroRNAs/metabolism ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Receptors, Cytoplasmic and Nuclear/genetics ; Receptors, Cytoplasmic and Nuclear/metabolism
Chemical Substances	MicroRNAs ; RNA, Messenger ; Receptors, Cytoplasmic and Nuclear
Language	English
Publishing date	2022-02-17
Publishing country	England
Document type	Journal Article
ZDB-ID	1064202-x
ISSN	1365-2184 ; 0008-8730 ; 0960-7722
ISSN (online)	1365-2184
ISSN	0008-8730 ; 0960-7722
DOI	10.1111/cpr.13199
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Article: Indium(II) Chloride as a Precursor in the Synthesis of Ternary (Ag-In-S) and Quaternary (Ag-In-Zn-S) Nanocrystals.

Kowalik, Patrycja / Bujak, Piotr / Penkala, Mateusz / Maroń, Anna M / Ostrowski, Andrzej / Kmita, Angelika / Gajewska, Marta / Lisowski, Wojciech / Sobczak, Janusz W / Pron, Adam

Chemistry of materials : a publication of the American Chemical Society

2022 Volume 34, Issue 2, Page(s) 809–825

Abstract: A new indium precursor, namely, indium(II) chloride, was tested as a precursor in the synthesis of ternary Ag-In-S and quaternary Ag-In-Zn-S nanocrystals. This new precursor, being in fact a dimer of ... ...

Abstract	A new indium precursor, namely, indium(II) chloride, was tested as a precursor in the synthesis of ternary Ag-In-S and quaternary Ag-In-Zn-S nanocrystals. This new precursor, being in fact a dimer of Cl
Language	English
Publishing date	2022-01-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	1500399-1
ISSN	1520-5002 ; 0897-4756
ISSN (online)	1520-5002
ISSN	0897-4756
DOI	10.1021/acs.chemmater.1c03800
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Article ; Online: Multi-Organ Morphological Findings in a Humanized Murine Model of Sickle Cell Trait.

Trucas, Marcello / Burattini, Sabrina / Porcu, Susanna / Simbula, Michela / Ristaldi, Maria Serafina / Kowalik, Marta Anna / Serra, Maria Pina / Gobbi, Pietro / Battistelli, Michela / Perra, Andrea / Quartu, Marina

International journal of molecular sciences

2023 Volume 24, Issue 13

Abstract: Sickle cell disease (SCD) is caused by the homozygous beta-globin gene mutation that can lead to ischemic multi-organ damage and consequently reduce life expectancy. On the other hand, sickle cell trait (SCT), the heterozygous beta-globin gene mutation, ... ...

Abstract	Sickle cell disease (SCD) is caused by the homozygous beta-globin gene mutation that can lead to ischemic multi-organ damage and consequently reduce life expectancy. On the other hand, sickle cell trait (SCT), the heterozygous beta-globin gene mutation, is still considered a benign condition. Although the mechanisms are not well understood, clinical evidence has recently shown that specific pathological symptoms can also be recognized in SCT carriers. So far, there are still scant data regarding the morphological modifications referable to possible multi-organ damage in the SCT condition. Therefore, after genotypic and hematological characterization, by conventional light microscopy and transmission electron microscopy (TEM), we investigated the presence of tissue alterations in 13 heterozygous Townes mice, one of the best-known animal models that, up to now, was used only for the study of the homozygous condition. We found that endothelial alterations, as among which the thickening of vessel basal lamina, are ubiquitous in the lung, liver, kidney, and spleen of SCT carrier mice. The lung shows the most significant alterations, with a distortion of the general tissue architecture, while the heart is the least affected. Collectively, our findings contribute novel data to the histopathological modifications at microscopic and ultrastructural levels, underlying the heterozygous beta-globin gene mutation, and indicate the translational suitability of the Townes model to characterize the features of multiple organ involvement in the SCT carriers.
MeSH term(s)	Mice ; Animals ; Sickle Cell Trait/genetics ; Disease Models, Animal ; Anemia, Sickle Cell/genetics ; Anemia, Sickle Cell/diagnosis ; Kidney ; beta-Globins/genetics
Chemical Substances	beta-Globins
Language	English
Publishing date	2023-06-21
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms241310452
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Article: Emerging Role of the Pentose Phosphate Pathway in Hepatocellular Carcinoma.

Kowalik, Marta Anna / Columbano, Amedeo / Perra, Andrea

Frontiers in oncology

2017 Volume 7, Page(s) 87

Abstract: In recent years, there has been a revival of interest in metabolic changes of cancer cells as it has been noticed that malignant transformation and metabolic reprogramming are closely intertwined. The pentose phosphate pathway (PPP) is one of the ... ...

Abstract	In recent years, there has been a revival of interest in metabolic changes of cancer cells as it has been noticed that malignant transformation and metabolic reprogramming are closely intertwined. The pentose phosphate pathway (PPP) is one of the fundamental components of cellular metabolism crucial for cancer cells. This review will discuss recent findings regarding the involvement of PPP enzymes in several types of cancer, with a focus on hepatocellular carcinoma (HCC). We will pay considerable attention to the involvement of glucose-6-phosphate dehydrogenase, the rate-limiting enzyme of the PPP. Subsequently, we discuss the inhibition of the PPP as a potential therapeutic strategy against cancer, in particular, HCC.
Language	English
Publishing date	2017-05-11
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2017.00087
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Article ; Online: Obesity-associated deterioration of the hippocampus is partially restored after weight loss.

Liśkiewicz, Arkadiusz D / Liśkiewicz, Daniela / Marczak, Łukasz / Przybyła, Marta / Grabowska, Konstancja / Student, Sebastian / Dębiec, Magdalena / Sługocka, Anna / Lewin-Kowalik, Joanna

Brain, behavior, and immunity

2021 Volume 96, Page(s) 212–226

Abstract: Objective: Obesity is a multidimensional condition that is treatable by the restoration of a lean phenotype; however, some obesity-related outcomes may persist after weight normalization. Among the organs of the human body, the brain possesses a ... ...

Abstract	Objective: Obesity is a multidimensional condition that is treatable by the restoration of a lean phenotype; however, some obesity-related outcomes may persist after weight normalization. Among the organs of the human body, the brain possesses a relatively low regenerative capacity and could retain perturbations established as a result of developmental obesity. Calorie restriction (CR) or a restricted ketogenic diet (KD) are successfully used as weight loss approaches, but their impact on obesity-related effects in the brain have not been previously evaluated. Methods: We performed a series of experiments in a rat model of developmental obesity induced by a 12-week cafeteria diet, followed by CR to implement weight loss. First, we assessed the impact of obesity on neurogenesis (BrdU incorporation into the hippocampus), cognitive function (water maze), and concomitant changes in hippocampal protein expression (GC/MS-MS, western blot). Next, we repeated these experiments in a rat model of weight loss induced by CR. We also measured mitochondrial enzyme activity in rats after weight loss during the fed or fasting state. This study was extended by additional experiments with restricted KD used as a weight loss approach in order to compare the efficacy of two different nutritional interventions used in the treatment of obesity on hippocampal functions. By using a modified version of the water maze we evaluated cognitive abilities in rats subjected to weight loss by CR or a restricted KD. Results: In this study, obesity affected metabolic processes, upregulated hippocampal NF-κB, and induced proteomic differences which were associated with impaired cognition and neurogenesis. Weight loss improved neurogenesis and enhanced cognition. While the expression pattern of some proteins persisted after weight loss, most of the changes appeared de novo revealing metabolic adjustment by overactivation of citrate synthase and downregulation of ATP synthase. As a consequence of fasting, the activity of these enzymes indicated hippocampal adaptation to negative energy balance during the weight loss phase of CR. Moreover, the effects on cognitive abilities measured after weight loss were negatively correlated with the animal weight measured at the final stage of weight gain. This was alleviated by KD, which improved cognition when used as a weight loss approach. Conclusions: The study shows that cognition and mitochondrial metabolism in the hippocampus are affected by CR- or KD-induced weight loss.
MeSH term(s)	Animals ; Caloric Restriction ; Hippocampus ; Obesity/complications ; Proteomics ; Rats ; Weight Loss
Language	English
Publishing date	2021-06-02
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639219-2
ISSN	1090-2139 ; 0889-1591
ISSN (online)	1090-2139
ISSN	0889-1591
DOI	10.1016/j.bbi.2021.05.030
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