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Article: Molecular and functional anticancer effects of GLP/G9a inhibition by UNC0646 in MeWo melanoma cells.

Filiú-Braga, Luma Dayane de Carvalho / Silva-Carvalho, Amanda Évelin / Sousa, Marielly Reis Resende / Carvalho, Juliana Lott / Saldanha-Araujo, Felipe

Heliyon

2024 Volume 10, Issue 5, Page(s) e27085

Abstract: In recent years, histone methyltransferases (HMTs) have emerged as important therapeutic targets in cancer due to their oncogenic role. Herein, we used the GLP/G9a inhibitor UNC0646 to assess whether the inhibition of such HMTs could induce cell death in ...

Abstract	In recent years, histone methyltransferases (HMTs) have emerged as important therapeutic targets in cancer due to their oncogenic role. Herein, we used the GLP/G9a inhibitor UNC0646 to assess whether the inhibition of such HMTs could induce cell death in MeWo melanoma cells. Furthermore, we investigated the cellular and molecular mechanisms involved in the observed cell death events. Finally, we performed a functional genomics analysis of 480 melanoma samples to characterize G9a/GLP involvement in melanoma. Interestingly, after UNC0646 treatment, MeWo cells underwent apoptosis, followed by loss of mitochondrial membrane potential and the generation of reactive oxygen species (ROS). Furthermore, MeWo cells treated with UNC0646 showed cell cycle arrest and inhibition of proliferation. At the molecular level, UNC0646 treatment increased the transcriptional levels of
Language	English
Publishing date	2024-02-24
Publishing country	England
Document type	Journal Article
ZDB-ID	2835763-2
ISSN	2405-8440
ISSN	2405-8440
DOI	10.1016/j.heliyon.2024.e27085
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Article ; Online: Anti-inflammatory effect evaluation of naringenin and its incorporation into a chitosan-based film for transdermal delivery.

Quintão, Wanessa S C / Silva-Carvalho, Amandda E / Hilgert, Leandro A / Gratieri, Tais / Cunha-Filho, Marcilio / Saldanha-Araújo, Felipe / Gelfuso, Guilherme M

International journal of pharmaceutics

2022 Volume 627, Page(s) 122231

Abstract: Naringenin is a bioflavonoid mainly found in citrus fruits. It presents many pharmacological benefits, including a remarkable anti-inflammatory activity, but its oral bioavailability is poor. To overcome this drawback, this work proposes a transdermal ... ...

Abstract	Naringenin is a bioflavonoid mainly found in citrus fruits. It presents many pharmacological benefits, including a remarkable anti-inflammatory activity, but its oral bioavailability is poor. To overcome this drawback, this work proposes a transdermal administration of such bioflavonoid, considering its use in the chronic treatment of inflammatory conditions. For this, it aims to develop a chitosan-based film that guarantees a consistent transdermal delivery of the drug. First, naringenin's in vitro anti-inflammatory effect on T-cell proliferation was evaluated, followed by research on the modulation of gene expression for inflammatory factors in peripheral blood mononuclear cells. Chitosan films were then prepared and characterized. Afterward, naringenin release profile from a selected film was determined as well as the drug permeation across porcine skin provided by the film. Naringenin induced the expression of the anti-inflammatory factors IL-10 and TGF-β1 while inhibiting the expression of the pro-inflammatory cytokine IL-1β and limiting T-cell proliferation. The chitosan film was successfully developed, and the drug was progressively released to the physiological media following both first order and Korsmeyer-Peppas kinetics. When topically applied, the chitosan film guaranteed a constant and continuous diffusion of naringenin across the skin over 72 h. Indeed, the permeation flux of naringenin was 0.30 ± 0.01 µg/cm
MeSH term(s)	Swine ; Animals ; Administration, Cutaneous ; Chitosan/pharmacology ; Transforming Growth Factor beta1/metabolism ; Leukocytes, Mononuclear ; Interleukin-10/metabolism ; Flavanones/pharmacology ; Skin/metabolism ; Pharmaceutical Preparations/metabolism ; Drug Delivery Systems
Chemical Substances	Chitosan (9012-76-4) ; naringenin (HN5425SBF2) ; Transforming Growth Factor beta1 ; Interleukin-10 (130068-27-8) ; Flavanones ; Pharmaceutical Preparations
Language	English
Publishing date	2022-09-24
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	428962-6
ISSN	1873-3476 ; 0378-5173
ISSN (online)	1873-3476
ISSN	0378-5173
DOI	10.1016/j.ijpharm.2022.122231
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Article ; Online: Senescence on Dental Pulp Cells: Effects on Morphology, Migration, Proliferation, and Immune Response.

de Farias, Jade Ormondes / da Costa Sousa, Maurício Gonçalves / Martins, Danilo César Mota / de Oliveira, Mayara Alves / Takahashi, Isadora / de Sousa, Larissa Barbosa / da Silva, Ingrid Gracielle Martins / Corrêa, José Raimundo / Silva Carvalho, Amandda Évelin / Saldanha-Araújo, Felipe / Rezende, Taia Maria Berto

Journal of endodontics

2024 Volume 50, Issue 3, Page(s) 362–369

Abstract: Introduction: Evidence indicates that senescence can affect essential dental pulp functions, such as defense capacity and repair, consequently affecting the successes of conservative endodontic treatments. This study aims to evaluate the effects of ... ...

Abstract	Introduction: Evidence indicates that senescence can affect essential dental pulp functions, such as defense capacity and repair, consequently affecting the successes of conservative endodontic treatments. This study aims to evaluate the effects of senescence on the morphology, migration, proliferation, and immune response of human dental pulp cells. Methods: Cells were treated with doxorubicin to induce senescence, confirmed by β-galactosidase staining. Morphological changes, cellular proliferation, and migration were evaluated by scanning electron microscopy, trypan blue cells, and the scratch method, respectively. Modifications in the immune response were evaluated by measuring the genes for pro-inflammatory cytokines tumor necrosis factor alpha and interleukin (IL)-6 and anti-inflammatory cytokines transforming growth factor beta 1 and IL-10 using the real time polymerase chain reaction assay. Results: An increase in cell size and a decrease in the number of extensions were observed in senescent cells. A reduction in the proliferative and migratory capacity was also found in senescent cells. In addition, there was an increase in the gene expression of inflammatory cytokines tumor necrosis factor alpha and IL-6 and a decrease in the gene expression of IL-10 and transforming growth factor beta-1, suggesting an exacerbated inflammatory situation associated with immunosuppression. Conclusions: Cellular senescence is possibly a condition that affects prognoses of conservative endodontic treatments, as it affects primordial cellular functions related to this treatment.
MeSH term(s)	Humans ; Dental Pulp/metabolism ; Cell Differentiation ; Interleukin-10/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Cytokines/metabolism ; Cell Proliferation ; Interleukin-6/metabolism ; Immunity ; Cellular Senescence ; Cells, Cultured
Chemical Substances	Interleukin-10 (130068-27-8) ; Tumor Necrosis Factor-alpha ; Cytokines ; Interleukin-6
Language	English
Publishing date	2024-01-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	752412-2
ISSN	1878-3554 ; 0099-2399
ISSN (online)	1878-3554
ISSN	0099-2399
DOI	10.1016/j.joen.2023.12.009
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Article ; Online: Regulatory T-Cell Enhancement, Expression of Adhesion Molecules, and Production of Anti-Inflammatory Factors Are Differentially Modulated by Spheroid-Cultured Mesenchymal Stem Cells.

Silva-Carvalho, Amandda Évelin / da Silva, Ingrid Gracielle Martins / Corrêa, José Raimundo / Saldanha-Araujo, Felipe

International journal of molecular sciences

2022 Volume 23, Issue 22

Abstract: The culture of mesenchymal stem cells (MSCs) as spheroids promotes a more physiological cellular behavior, as it more accurately reflects the biological microenvironment. Nevertheless, mixed results have been found regarding the immunosuppressive ... ...

Abstract	The culture of mesenchymal stem cells (MSCs) as spheroids promotes a more physiological cellular behavior, as it more accurately reflects the biological microenvironment. Nevertheless, mixed results have been found regarding the immunosuppressive properties of spheroid-cultured MSCs (3D-MSCs), the mechanisms of immunoregulation of 3D-MSCs being scarcely described at this point. In the present study, we constructed spheroids from MSCs and compared their immunosuppressive potential with that of MSCs cultured in monolayer (2D-MSCs). First, we evaluated the ability of 2D-MSCs and 3D-MSCs to control the activation and proliferation of T-cells. Next, we evaluated the percentage of regulatory T-cells (Tregs) after the co-culturing of peripheral blood mononuclear cells (PBMCs) with 2D-MSCs and 3D-MSCs. Finally, we investigated the expression of adhesion molecules, as well as the expressions of several anti-inflammatory transcripts in 2D-MSCs and 3D-MSCs maintained in both inflammatory and non-inflammatory conditions. Interestingly, our data show that several anti-inflammatory genes are up-regulated in 3D-MSCs, and that these cells can control T-cell proliferation. Nevertheless, 2D-MSCs are more efficient in suppressing the immune cell proliferation. Importantly, contrary to what was observed in 3D-MSCs, the expressions of ICAM-1 and VCAM-1 are significantly upregulated in 2D-MSCs exposed to an inflammatory environment. Furthermore, only 2D-MSCs are able to promote the enhancement of Tregs. Taken together, our data clearly show that the immunosuppressive potential of MSCs is significantly impacted by their shape, and highlights the important role of cell-cell adhesion molecules for optimal MSC immunomodulatory function.
MeSH term(s)	T-Lymphocytes, Regulatory ; Leukocytes, Mononuclear ; Mesenchymal Stem Cells/metabolism ; Cell Adhesion Molecules/genetics ; Cell Adhesion Molecules/metabolism ; Anti-Inflammatory Agents/metabolism
Chemical Substances	Cell Adhesion Molecules ; Anti-Inflammatory Agents
Language	English
Publishing date	2022-11-18
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/ijms232214349
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Article ; Online: Ibrutinib topical delivery for melanoma treatment: The effect of nanostructured lipid carriers' composition on the controlled drug skin deposition.

Albuquerque, Lucas F F / Lins, Fernanda V / Bispo, Elizabete C I / Borges, Ellyêssa N / Silva, Mateus T / Gratieri, Taís / Cunha-Filho, Marcílio / Alonso, Antonio / Carvalho, Juliana L / Saldanha-Araujo, Felipe / Gelfuso, Guilherme M

Colloids and surfaces. B, Biointerfaces

2024 Volume 237, Page(s) 113875

Abstract: Melanoma is responsible for more than 80% of deaths related to skin diseases. Ibrutinib (IBR), a Bruton's tyrosine kinase inhibitor, has been proposed to treat this type of tumor. However, its low solubility, extensive first-pass effect, and severe ... ...

Abstract	Melanoma is responsible for more than 80% of deaths related to skin diseases. Ibrutinib (IBR), a Bruton's tyrosine kinase inhibitor, has been proposed to treat this type of tumor. However, its low solubility, extensive first-pass effect, and severe adverse reactions with systemic administration affect therapeutic success. This study proposes developing and comparing the performance of two compositions of nanostructured lipid carriers (NLCs) to load IBR for the topical management of melanomas in their early stages. Initially, the effectiveness of IBR on melanoma proliferation was evaluated in vitro, and the results confirmed that the drug reduces the viability of human melanoma cells by inducing apoptosis at a dose that does not compromise dermal cells. Preformulation tests were then conducted to characterize the physical compatibility between the drug and the selected components used in NLCs preparation. Sequentially, two lipid compositions were used to develop the NLCs. Formulations were then characterized and subjected to in vitro release and permeation tests on porcine skin. The NLCs containing oleic acid effectively controlled IBR release over 24 h compared to the NLCs composed of pomegranate seed oil. Furthermore, the nanoparticles acted as permeation enhancers, increasing the fluidity of the lipids in the stratum corneum, as determined by EPR spectroscopy, which stimulated the IBR penetration more profoundly into the skin. However, the NLCs composition also influenced the permeation promotion factor. Thus, these findings emphasize the importance of the composition of NLCs in controlling and increasing the skin penetration of IBR and pave the way for future advances in melanoma therapy.
MeSH term(s)	Animals ; Swine ; Humans ; Melanoma/drug therapy ; Drug Carriers/chemistry ; Skin ; Nanostructures/chemistry ; Nanoparticles/chemistry ; Lipids/chemistry ; Particle Size ; Adenine/analogs & derivatives ; Piperidines
Chemical Substances	ibrutinib (1X70OSD4VX) ; Drug Carriers ; Lipids ; Adenine (JAC85A2161) ; Piperidines
Language	English
Publishing date	2024-03-22
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1500523-9
ISSN	1873-4367 ; 0927-7765
ISSN (online)	1873-4367
ISSN	0927-7765
DOI	10.1016/j.colsurfb.2024.113875
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Article ; Online: Commentary: Mesenchymal Stem Cells: A New Piece in the Puzzle of COVID-19 Treatment.

Carvalho, Juliana Lott / Silva-Carvalho, Amandda Evelin / Garcez, Emãnuella Melgaço / Saldanha-Araujo, Felipe

Frontiers in immunology

2021 Volume 12, Page(s) 682195

MeSH term(s)	COVID-19/drug therapy ; Coronavirus Infections ; Humans ; Mesenchymal Stem Cells ; SARS-CoV-2
Language	English
Publishing date	2021-04-29
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.682195
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Article ; Online: The immunosuppressive mechanisms of mesenchymal stem cells are differentially regulated by platelet poor plasma and fetal bovine serum supplemented media.

Silva-Carvalho, Amandda Évelin / Neves, Francisco Assis Rocha / Saldanha-Araujo, Felipe

International immunopharmacology

2020 Volume 79, Page(s) 106172

Abstract: Purpose: Mesenchymal Stem Cells (MSCs) can interact with and modulate the functions of all immune cells, suppressing both the innate and adaptive immune responses. Currently, most of the in vitro studies which have led to the description of MSC ... ...

Abstract	Purpose: Mesenchymal Stem Cells (MSCs) can interact with and modulate the functions of all immune cells, suppressing both the innate and adaptive immune responses. Currently, most of the in vitro studies which have led to the description of MSC properties have resulted from MSC culture in the presence of fetal bovine serum (FBS), in spite of the recognition of FBS limitations and attempts to substitute this component from the MSC media. Methods: Herein, we compare FBS and Platelet Poor Plasma (PPP) as MSC media supplements, according to Adipose-derived MSC (AMSC) phenotype, proliferation and immunoregulatory mechanisms. Results: Interestingly, despite maintaining the classic phenotypic profile of MSCs, PPP cultured AMSCs showed impaired proliferative potential. Furthermore, our results clearly show that AMSC culture with PPP leads to decreased expression of soluble immunosuppressive factors, which resulted in decreased capacity of inducing regulatory T-cells (Tregs) generation by these cells. In contrast, PPP supplementation promoted enhanced VCAM-1 and ICAM-1 expression on AMSC surface. Therefore, AMSCs cultured with PPP showed limited potential to produce soluble immunomodulatory factors, indicating a reduced capacity to control the immune system thought paracrine activity. Conclusion: Overall, our data sheds light on the importance of culture media supplementation for MSC immunomodulatory behavior, as well as serving as an alert regarding the complexity of replacing FBS in MSC culture.
MeSH term(s)	Animals ; Blood Platelets/cytology ; Cattle ; Cell Culture Techniques ; Cell Differentiation ; Cell Proliferation ; Cells, Cultured ; Culture Media/metabolism ; Humans ; Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/metabolism ; Mesenchymal Stem Cells/pathology ; Plasma/metabolism
Chemical Substances	Culture Media
Language	English
Publishing date	2020-01-08
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2043785-7
ISSN	1878-1705 ; 1567-5769
ISSN (online)	1878-1705
ISSN	1567-5769
DOI	10.1016/j.intimp.2019.106172
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Article: The Inflammatory Status of Soluble Microenvironment Influences the Capacity of Melanoma Cells to Control T-Cell Responses.

Bogéa, Gabriela Muller Reche / Silva-Carvalho, Amandda Évelin / Filiú-Braga, Luma Dayane de Carvalho / Neves, Francisco de Assis Rocha / Saldanha-Araujo, Felipe

Frontiers in oncology

2022 Volume 12, Page(s) 858425

Abstract: The development of immunotherapeutic approaches for the treatment of melanoma requires a better understanding of immunoescape mechanisms of tumor cells and how they interact with other tumor-resident cell types. Here, we evaluated how the conditioned ... ...

Abstract	The development of immunotherapeutic approaches for the treatment of melanoma requires a better understanding of immunoescape mechanisms of tumor cells and how they interact with other tumor-resident cell types. Here, we evaluated how the conditioned media of resting (rCM) and immune-activated PBMCs (iCM) influence the ability of a metastatic melanoma cell line (MeWo) to control T-cells function. MeWo cells were expanded in RPMI, rCM, or iCM and the secretome generated after cell expansion was identified as MeSec (RPMI), niSec (non-inflammatory), or iSec (inflammatory secretome), respectively. Then, the immunomodulatory potential of such secretomes was tested in PHA-activated PBMCs. iCM induced higher levels of IFN-γ and IL-10 in treated melanoma cells compared to rCM, as well as higher
Language	English
Publishing date	2022-03-28
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2022.858425
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Article ; Online: Transcriptional deregulation of

Costa, Daniel Freitas da / Filiú-Braga, Luma Dayane de Carvalho / Silva-Carvalho, Amandda Évelin / Schiavinato, Josiane Lilian / Vasconcelos, Maria Catarina Cals de / Figueiredo-Pontes, Lorena Lôbo de / Lucena-Araujo, Antonio Roberto / Saldanha-Araujo, Felipe

Leukemia & lymphoma

2022 , Page(s) 1–5

Language	English
Publishing date	2022-08-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	1042374-6
ISSN	1029-2403 ; 1042-8194
ISSN (online)	1029-2403
ISSN	1042-8194
DOI	10.1080/10428194.2022.2116935
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Article: The Peptide Salamandrin-I Modulates Components Involved in Pyroptosis and Induces Cell Death in Human Leukemia Cell Line HL-60.

Silva-Carvalho, Amandda Évelin / Oliveira, Nakaly Natiely de / Machado, Julia Viana Lafetá / Moreira, Daniel Carneiro / Brand, Guilherme Dotto / Leite, José Roberto S A / Plácido, Alexandra / Eaton, Peter / Saldanha-Araujo, Felipe

Pharmaceutics

2023 Volume 15, Issue 7

Abstract: Amphibian secretions have been extensively investigated for the production of bioactive molecules. Salamandrin-I is an antioxidant peptide, isolated from the skin secretion of the fire salamander, that has induced no toxicity in microglia or erythrocytes. ...

Abstract	Amphibian secretions have been extensively investigated for the production of bioactive molecules. Salamandrin-I is an antioxidant peptide, isolated from the skin secretion of the fire salamander, that has induced no toxicity in microglia or erythrocytes. Importantly, the administration of antioxidants may constitute an adequate therapeutic approach to cancer treatment. Here, with the purpose of better characterizing the therapeutic potential of salamandrin-I, we investigated whether this antioxidant peptide also exerts anticancer activity, using the human leukemia cell line HL-60 as a cancer model. Salamandrin-I treatment induced a significant reduction in HL-60 proliferation, which was accompanied by cell cycle arrest. Furthermore, the peptide-induced cell death showed a significant increase in the LDH release in HL-60 cells. The cellular toxicity exerted by salamandrin-I is possibly related to pyroptosis, since the HL-60 cells showed loss of mitochondrial membrane potential and hyperexpression of inflammasome components following the peptide treatment. This is the first demonstration of the anticancer potential of the salamandrin-I peptide. Such results are important, as they offer relevant insights into the field of cancer therapy and allow the design of future bioactive molecules using salamandrin-I as a template.
Language	English
Publishing date	2023-07-01
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527217-2
ISSN	1999-4923
ISSN	1999-4923
DOI	10.3390/pharmaceutics15071864
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