Phytochemical frontiers and molecular targets in liver cancer: A systematic bibliometric curation of natural compounds for HCC therapy (2015–2025) Fábio Rodrigues Ferreira Seiva, Milena Cremer de Souza, Wesley Ladeira Caputo, Maria Luisa Gonçalves Agneis, Matheus Ribas de Almeida, et al. Biomedicine and Pharmacotherapy, 2026 Hepatocellular carcinoma (HCC) is an aggressive malignancy with limited treatment options. While natural products offer a vast chemical space for drug discovery, the literature at the oncology-phytochemistry interface remains fragmented. This study provides a high-resolution bibliometric curation to map research trends and pharmacological hotspots in HCC therapy over the last decade. A systematic search was conducted via Scopus for studies published between 2015 and 2025. Following manual curation of 1477 eligible articles, VOSviewer and the Bibliometrix R-package were utilized for analysis. A distinctive feature was the integration of taxonomic validation and manual text mining to ensure high accuracy of botanical and phytochemical data. Our findings reveal an exponential growth in scientific production, led by China, the USA, and India. The editorial landscape spans over 400 journals and 90 publishers, such as Elsevier, Frontiers, MDPI and Wiley. Phytomedicine and Journal of Ethnopharmacology were the most prolific journals. We identified over 700 distinct phytochemicals, notably quercetin, curcumin, and resveratrol, and approximately 600 plant species. Thematic clustering demonstrated that these compounds modulate critical cellular events, including apoptosis, oxidative stress, cell-cycle checkpoints, epithelial-mesenquimal transition, and distinct but complementary signaling pathway, such as Bax-Bcl-2, PI3K/Akt, mTOR, VEGF, SIRT1/NRF2, MAPK/ERK, CHOP and GRP78, and also different classes of miRNAs. Nanotechnology-based delivery systems emerged as a major trend to overcome bioavailability challenges. This bibliometric curation provides a mapping of the field, identifying critical thematic transitions and current knowledge gaps. The systematic cataloging of authors, institutions, publishers, journals, and phytochemicals offers a foundation for prioritizing molecules in future trials, providing objective insights for drug discovery and potential novel targeted therapies for HCC.
Ethanolic Extract of Stachys byzantina Leaf: Optimization of Ultrasonic Probe-Assisted Extraction and Characterization Sthefany Lorena Gemaque Dias, Djéssica Tatiane Raspe, Oscar de Oliveira Santos Júnior, Maria Luisa Gonçalves Agneis, Fabio Rodrigues Ferreira Seiva, Vitor Augusto dos Santos Garcia, Lúcio Cardozo-Filho, Camila da Silva Plants, 2025 The present study aimed to apply ultrasonic probe-assisted extraction (UPAE) using ethanol as a solvent to separate compounds from Stachys byzantina leaves. Experimental tests were carried out to investigate the influence of temperature (T) (30, 45 and 60 °C), ultrasonic amplitude (UA) (30, 60 and 90%) and extraction time (ET) (10, 15 and 20 min) on the extraction yield (EY). The extracts obtained at different extraction times were characterized for compound profile, soluble protein content, and antioxidant potential. The cytotoxic effect of the extract was also evaluated. The greatest mass recovery (19.8 wt%) was verified at the highest levels of the variables. The total phenolic compound content and antioxidant potential increased with the application of extraction times of 5 to 20 min, at 60 °C and UA of 90%. The extracts contained ~25 wt% of soluble protein. The extracts showed a predominance of chlorogenic, protocatechuic, and syringic acids. Nicotinic acid was also detected in the extracts, with levels ranging from 11.91 to 13.86 mg/100 g. The fatty acid profile indicated the presence of lauric, palmitic and linolenic acids in higher concentrations, with quantification of squalene, α-tocopherol and β-sitosterol. The ethanolic extract of Stachys byzantina showed no cytotoxic effect on HaCaT cells at concentrations up to 200 µg/mL, maintaining cell viability above 70% after 48 h of exposure.
Melatonin promotes cytotoxicity while reducing cell motility and antioxidant defenses in ovarian cancer cell lines Henrique Spaulonci Silveira, Roberta Carvalho Cesário, Vinicius Augusto Simão, Fernando Guimarães, Fábio Rodrigues Ferreira Seiva, Debora Aparecida P.C. Zuccari, Glaura Scantamburlo Alves Fernandes, Milena Cremer de Souza, Russel J. Reiter, Luiz Gustavo de Almeida Chuffa Toxicology Reports, 2025 Ovarian cancer (OC), a highly recurrent and fatal tumor, poses diagnostic challenges due to generic symptoms and chemoresistance. Melatonin (Mel) is an indoleamine acting against tumor progression and exhibiting pro-oxidative actions in tumor cells. This in vitro study explores the impact of Mel on antioxidant defenses of OC cells (high-grade SKOV-3 and low-grade CAISMOV-24 lines), focusing on its receptor-dependent and -independent effects. Cell viability was evaluated through MTT assay and antioxidant system was assessed in supernatants by measuring glutathione (GS), reduced (GSH) and oxidized (GSSG) glutathione, catalase (CAT), glutathione S-transferase (GST), and superoxide dismutase (SOD). Mel accumulated intracellularly and exerted cytotoxic effects, reducing cell viability in both cell lines. Notably, Mel independently of its membrane receptors, inhibited migration and invasion, thus showing its anti-tumoral potential. By investigating melatonin's actions, we observed an impact on the antioxidant system primarily through the reduced activity of CAT and the GS axis. The modulation of these antioxidants by Mel demonstrates its multifaceted role in OC, emphasizing its therapeutic potential. We also demonstrated, for the first time, the theoretical ability of Mel to bind to CAT, which may be responsible for the reduction in enzyme activity. This study provides novel insights into Mel's receptor-independent actions and supports its potential as an adjuvant therapeutic agent in OC.
Pesticide exposome reveals oxidative stress and immune response disruptions in occupationally exposed women with breast cancer Juliana Maria Bitencourt de Morais Valentim, Luciana Pizzatti, Carolina Coradi, Isabella Cristina Cazagranda, Bruna Fadel, Beatriz Geovana Leite Vacario, Shaiane Carla Gaboardi, Matheus Iago Oliveira Coletto, Rodrigo Kern, Wander Rogério Pavanelli, Daniel Rech, Maria Luiza Ferreira dos Santos, Leonardo Foti, Allan Henrique Depieri Cataneo, Guilherme Ferreira Silveira, Juliano Bordignon, Fábio Rodrigues Ferreira Seiva, Carolina Panis Scientific Reports, 2025 Rural women are at a higher risk of developing breast cancer, but the molecular mechanisms involved remain poorly understood. This study investigates the impact of chronic pesticide exposure on systemic and tissue-level protein expressions in women diagnosed with breast cancer. Plasma and tumor samples were collected from 215 women diagnosed with breast cancer; among them, 128 patients were occupationally exposed (n = 128) and 87 patients were not occupationally exposed (87) were analyzed for further studies. High-throughput proteomic analyses of plasma revealed distinct protein expression profiles between the groups, primarily associated with inflammation, oxidative stress, and immune deregulation. Validation analysis showed that cytokines such as IL-1β, IL-12, IL-17A, and TNF-α were significantly reduced in both plasma and tumor samples from exposed patients compared to unexposed women. This reduction in cytokines, coupled with decreased tumor-infiltrating leukocytes (TILs) and CTLA-4 overexpression, suggests pesticide-induced immune compromise. Circulating IL-12 levels were significantly reduced in younger, eutrophic, and at menacme exposed patients. Pesticide exposure also influenced nitrosative stress production, leading to reduced NOx levels in plasma and impaired iNOS expression in TILs. These results suggest a potential link between pesticide exposure and the pathophysiology of breast cancer, offering new insights into the underlying molecular mechanisms.
Oral disintegration films based on agar-agar with incorporation of hydroalcoholic extract of Hibiscus sabdariffa seeds Jecielly de Oliveira Dias, Rosemary Aparecida de Carvalho, Aline Nunes, Rodrigo Henrique dos Santos Garcia, Giovana de Menezes Rodrigues, Cristiana Maria Pedroso Yoshida, Camila da Silva, Fabio Rodrigues Ferreira Seiva, Giuseppina Pace Pereira Lima, Silvia Maria Martelli, Vitor Augusto dos Santos Garcia International Journal of Biological Macromolecules, 2025
Effect of Drying Methods on Bioactivity of Pyrostegia venusta Extracts: Antioxidant Assays, Cytotoxicity, and Computational Approaches Milena Cremer de Souza, Letícia Bertini, Julia Estrella Szmaruk, Matheus Ribas de Almeida, Maria Luisa G. Agneis, Roberta Carvalho Cesário, Wesley Ladeira Caputo, Christiane Luciana da Costa, Vitor Augusto dos Santos Garcia, Fábio R. F. Seiva Pharmaceuticals, 2025 Background/Objectives: Pyrostegia venusta (Cipó-de-São-João), a native Brazilian Cerrado plant, is rich antioxidant phytochemicals. The efficacy of herbal extracts, particularly their phenolic content and antioxidant potential, is influenced by the extraction method used. This study investigated the effects of two drying methods, hot-air oven drying and freeze-drying, on the antioxidant activity, cytotoxicity, and molecular interactions of aqueous extracts from the flowers and leaves of P. venusta. Methods: antioxidant capacity was assessed using DPPH, FRAP, and Folin–Ciocalteu assays; phenolic profiles were characterized by UHPLC; and cytotoxicity was evaluated via the MTT assay in HaCaT human keratinocyte cells. Additionally, in silico ADMET predictions were conducted to assess pharmacokinetics and potential toxicity, followed by molecular docking to evaluate interactions with the proliferation markers Ki-67 and PCNA. Results: freeze-dried extracts, particularly from the flowers, contained higher concentrations of phenolic compounds and exhibited superior antioxidant activity compared to hot-air oven-dried extracts. UHPLC analysis identified a range of bioactive phenolics including caffeic, chlorogenic, gallic, ferulic, and p-coumaric acids, quercetin, and anthocyanidins such as pelargonidin-3-O-glucoside and peonidin-3-O-glucoside, with distinct compositional differences between leaves and flowers. ADMET analysis revealed generally favorable pharmacokinetic properties for most compounds. Docking simulations indicated that multiple phenolics showed synergistic interactions with Ki-67 and PCNA. Conclusions: our findings highlight freeze-drying as the optimal method for preserving bioactive compounds in P. venusta and support the therapeutic potential of its flower extracts. The evidence supports the notion that the biological effects of P. venusta are driven by synergism among multiple constituents rather than isolated compounds.
Production and characterization of ora-pro-nóbis and agar-agar based edible leathers (Snack-films): a new plant-based food option Tiago de Freitas Pereira, Rosemary Aparecida de Carvalho, Cristiana Maria Pedroso Yoshida, Rodrigo Henrique dos Santos Garcia, Pricila Veiga-Santos, Maria Luisa Gonçalves Agneis, Fábio Rodrigues Ferreira Seiva, Silvia Maria Martelli, Danielle Marques Vilela, Vitor Augusto dos Santos Garcia Journal of the Indian Chemical Society, 2025 The present study aimed to produce and characterize edible leathers based on ora-pro-nóbis leaf puree (OLP), with concentrations ranging from 30 to 60 g/100 g of ELFM (edible leather forming mass) and agar-agar (3 g/100 g ELFM), using the tape casting technique. The edible leathers were dried in an oven and evaluated for their physicochemical parameters (Aw, moisture, pH, protein content, and hygroscopicity), optical properties (color and browning index), structural characteristics (thickness and SEM), mechanical properties, and spectroscopic profile (NMR). Regardless of the OLP concentration used, it was possible to form leathers from ora-pro-nóbis leaves and agar-agar. Color characteristics were not significantly affected in terms of lightness (L) and chroma a. However, significant differences were observed for chroma b* and C*. The physicochemical stability of the leathers was confirmed by their low water activity (< 0.8) and moisture content (< 7.8 %). Increasing OLP levels resulted in higher protein content (6.8 – 8.9 g/100 g w.b.) and thickness (0.3 – 0.5 mm), which positively impacted puncture resistance and indicated a more cohesive structure. SEM analysis revealed heterogeneous surfaces and internal structures, with discontinuity zones attributed to compounds in the OLP. NMR results confirmed the presence of hemicellulose, lignin, cellulose, and amino acids, reinforcing the nutritional value of the leathers. Additionally, total phenolic content (680 – 830 mg GAE/g edible leathers) and ABTS•+ (1.272 – 1.499 μmol Trolox eq./ 100 g edible leathers) increased with higher OLP content, demonstrating the product’s functional potential. The incorporation of ora-pro-nóbis puree into edible leather formulations contributed to improvements in the nutritional, functional, and structural aspects of the final product. Thus, the developed edible leathers are a promising alternative for using non-conventional vegetables, contributing to innovation in functional and sustainable food products. • Edible leathers were made with ora-pro-nóbis puree and agar-agar using tape casting. • Formulations with 30–60% puree had good structural integrity. • More ora-pro-nóbis increased protein content. •SEM and NMR showed structural complexity and bioactives. • Antioxidant activity and phenolics rose with puree concentration. • All samples showed cell viability above 70%, indicating safety.
Melatonin changes energy metabolism and reduces oncogenic signaling in ovarian cancer cells Henrique Spaulonci Silveira, Roberta Carvalho Cesário, Renan Aparecido Vígaro, Leticia Barbosa Gaiotte, Maira Smaniotto Cucielo, Fernando Guimarães, Fábio Rodrigues Ferreira Seiva, Debora Aparecida P.C. Zuccari, Russel J. Reiter, Luiz Gustavo de Almeida Chuffa Molecular and Cellular Endocrinology, 2024
Maternal protein restriction combined with postnatal sugar consumption alters liver proteomic profile and metabolic pathways in adult male offspring rats Isabelle Tenori Ribeiro, Matheus Naia Fioretto, Sérgio Alexandre Alcantara dos Santos, Ketlin Thassiani Colombelli, Luiz Marcos Frediani Portela, Marcus Vinicius Niz Alvarez, Pedro de Magalhães Padilha, Aislan Quintiliano Delgado, Marcus Vinicius Lage Silva Giaculi Marques, José Roberto Bosqueiro, Fábio Rodrigues Ferreira Seiva, Luís Fernando Barbisan, Antonio Marcus de Andrade Paes, Elena Zambrano, Luis Antonio Justulin Molecular and Cellular Endocrinology, 2024
The proteomic landscape of ovarian cancer cells in response to melatonin Roberta Carvalho Cesário, Leticia Barbosa Gaiotte, Maira Smaniotto Cucielo, Henrique Spaulonci Silveira, Lucilene Delazari dos Santos, Debora Aparecida Pires de Campos Zuccari, Fábio Rodrigues Ferreira Seiva, Russel J. Reiter, Luiz Gustavo de Almeida Chuffa Life Sciences, 2022
Melatonin-loaded nanocarriers: New horizons for therapeutic applications Luiz Gustavo de Almeida Chuffa, Fábio Rodrigues Ferreira Seiva, Adriana Alonso Novais, Vinícius Augusto Simão, Virna Margarita Martín Giménez, Walter Manucha, Debora Aparecida Pires de Campos Zuccari, Russel J. Reiter Molecules, 2021
COVID-19: The question of genetic diversity and therapeutic intervention approaches David Livingstone Alves Figueiredo, João Paulo Bianchi Ximenez, Fábio Rodrigues Ferreira Seiva, Carolina Panis, Rafael dos Santos Bezerra, Adriano Ferrasa, Alessandra Lourenço Cecchini, Alexandra Ivo de Medeiros, Ana Marisa Fusco Almeida, Anelisa Ramão, Angelica Beate Winter Boldt, Carla Fredrichsen Moya, Chung Man Chin, Daniel de Paula, Daniel Rech, Daniela Fiori Gradia, Danielle Malheiros, Danielle Venturini, Eliandro Reis Tavares, Emerson Carraro, Enilze Maria de Souza Fonseca Ribeiro, Evani Marques Pereira, Felipe Francisco Tuon, Franciele Aní Caovilla Follador, Glaura Scantamburlo Alves Fernandes, Hélito Volpato, Ilce Mara de Syllos Cólus, Jaqueline Carvalho de Oliveira, Jean Henrique da Silva Rodrigues, Jean Leandro dos Santos, Jeane Eliete Laguila Visentainer, Juliana Cristina Brandi, Juliana Mara Serpeloni, Juliana Sartori Bonini, Karen Brajão de Oliveira, Karine Fiorentin, Léia Carolina Lucio, Ligia Carla Faccin-Galhardi, Lirane Elize Defante Ferreto, Lucy Megumi Yamauchi Lioni, Marcia Edilaine Lopes Consolaro, Marcelo Ricardo Vicari, Marcos Abdo Arbex, Marcos Pileggi, Maria Angelica Ehara Watanabe, Maria Antônia Ramos Costa, Maria José S. Mendes Giannini, Marla Karine Amarante, Najeh Maissar Khalil, Quirino Alves de Lima Neto, Roberto H. Herai, Roberta Losi Guembarovski, Rogério N. Shinsato, Rubiana Mara Mainardes, Silvana Giuliatti, Sueli Fumie Yamada-Ogatta, Viviane Knuppel de Quadros Gerber, Wander Rogério Pavanelli, Weber Claudio da Silva, Maria Luiza Petzl-Erler, Valeria Valente, Christiane Pienna Soares, Luciane Regina Cavalli, Wilson Araujo Silva Jr Genetics and Molecular Biology, 2021
Influence of N-acetylcysteine on oxidative stress in slow-twitch soleus muscle of heart failure rats Paula F. Martinez, Camila Bonomo, Daniele M. Guizoni, Silvio A. Oliveira Junior, Ricardo L. Damatto, Marcelo D.M. Cezar, Aline R.R. Lima, Luana U. Pagan, Fabio R. Seiva, Denise C. Fernandes, Francisco R.M. Laurindo, Ethel L.B. Novelli, Luiz S. Matsubara, Leonardo A.M. Zornoff, Katashi Okoshi, Marina P. Okoshi Cellular Physiology and Biochemistry, 2015
Ovarian cancer: New therapies, potential risk factors and prognostic values for improving survival outcomes in women Handbook on Ovarian Cancer Risk Factors Therapies and Prognosis, 2015
Rutin ameliorates glycemic index, lipid profile and enzymatic activities in serum, heart and liver tissues of rats fed with a combination of hypercaloric diet and chronic ethanol consumption Indian Journal of Biochemistry and Biophysics, 2014
Melatonin and their protective role on oxidative cell damage: Interplay between oxidative stress and tumorigenesis New Developments in Melatonin Research, 2013
Taurine attenuates cardiac remodeling after myocardial infarction Lidiane P. Ardisson, Bruna P.M. Rafacho, Priscila P. Santos, Heloísa Assalin, Andréa F. Gonçalves, Paula S. Azevedo, Marcos F. Minicucci, Bertha F. Polegato, Katashi Okoshi, Julio Sergio Marchini, Luis F. Barbisan, Ana Angélica H. Fernandes, Fabio R.F. Seiva, Sergio A.R. Paiva, Leonardo A.M. Zornoff International Journal of Cardiology, 2013
Combined effects of age and diet-induced obesity on biochemical parameters and cardiac energy metabolism in rats Indian Journal of Biochemistry and Biophysics, 2013
Ventricular remodeling induced by tissue vitamin A deficiency in rats Paula S. Azevedo, Marcos F. Minicucci, Fernanda Chiuso-Minicucci, Luis A. Justulin Jr, Luiz S. Matsubara, Beatriz B. Matsubara, Ethel Novelli, Fabio Seiva, Giovanna Ebaid, Alvaro O. Campana, Leonardo A.M. Zornoff, Sergio A.R. Paiva Cellular Physiology and Biochemistry, 2010
Diet compounds, glycemic index and obesity-related cardiac effects Yeda S. Diniz, Regina M. Burneiko, Fabio R.F. Seiva, Flávia Q.A. Almeida, Cristiano Machado Galhardi, José Luiz V.B. Novelli Filho, Fernanda Mani, Ethel L.B. Novelli International Journal of Cardiology, 2008
