Eduarda Fernandes

The strong α-glucosidase inhibitory activity exhibited by myricetin against both yeast-derived and human enzymes further substantiates the therapeutic potential of polyphenols in diabetes management.

The synthesis of chalcones commonly relies on the Claisen–Schmidt condensation, an attractive reaction owing to its operational simplicity and favorable atom economy. However, its application to acetophenones bearing multiple hydroxy substituents can be problematic, often requiring hydroxy protection and subsequent deprotection, thereby diminishing the sustainability advantages of the approach. In this work, density functional theory (DFT) calculations were performed at the CAM-B3LYP/6-311++G(d,p) level to provide a qualitative electronic rationale for the factors that may account for this limitation. The nucleophilic behavior of the starting species was examined under basic, acidic, and metal-assisted conditions, using molecular models both with and without the hydroxy groups to evaluate the hypothesis that competing nucleophilic sites could interfere with the desired condensation and hinder the reaction. The results indicated that strong basic conditions favor extensive phenol deprotonation, generating several competing nucleophiles. In this situation, the resulting phenolate species were more nucleophilic than the corresponding enolates, favoring undesired reaction pathways. Coordination of lithium or calcium to the two phenolate groups decreased their nucleophilicity but failed to suppress the unwanted reactivity of the remaining phenolate. In contrast, under acidic conditions, the enol species exhibited greater nucleophilic character than the phenolic groups, providing no support for the proposed competition between phenolates and enolates as the sole explanation for the unsuccessful reaction. Nevertheless, the acidic environment may facilitate isomerization of the bischalcone products, which could subsequently promote degradation and/or undesired cyclization processes. Taken together, experimental and computational results indicate that the failure of the reaction arises from multiple competing factors rather than from a single mechanistic limitation. Among the conditions investigated, the acid-mediated pathway appears to be the most promising starting point for further optimization of the synthesis of polyhydroxylated bischalcones.

Passiflora edulis seeds are frequently discarded as agro-industrial residues despite being a source of bioactive compounds such as piceatannol (PIC). Their valorization through ethanolic extraction aligns with circular economy principles and enables the investigation of antioxidant, anti-inflammatory, and antidiabetic potential relevant to metabolic disorders associated with oxidative stress, inflammation, and impaired glucose homeostasis. Therefore, this study compared the biological activities and toxicological profiles of P. edulis seed ethanol extract (PESE) and PIC using in vitro and in vivo assays, including human and nonhuman models, and hyperglycemia induced during embryogenesis. The zebrafish procedures were approved by the Animal Use Ethics Committee (CEUA; protocol No. 13/2022). LC–MS identified PIC among the main constituents of PESE, which exhibited a high total phenolic content and relevant antioxidant capacity. PIC showed greater antioxidant potency than PESE against DPPH•, HOCl, and O2•–. It also inhibited α-amylase and α-glucosidase, with IC50 values of 11.8 and 3.1 μg/mL, respectively, outperforming acarbose against α-glucosidase, and activated glucokinase. In contrast, PESE inhibited PTP1B (IC50 = 29.8 μg/mL), an effect not observed with PIC alone. Both samples reduced ROS production in human neutrophils, with PIC displaying high potency in the luminol assay (IC50 = 0.12 μg/mL). In zebrafish embryos, PESE was less embryotoxic than PIC, with LC50 values of 39.3 and 6.2 μg/mL, respectively. In the hyperglycemic zebrafish model, both samples significantly reduced total free glucose and oxidant activity (p ≤ 0.05) and induced distinct antioxidant gene-expression responses: PESE upregulated nfe2l2a, sod1, sod2, and cat, whereas PIC upregulated nfe2l2a, gpx1a, and cat. These findings demonstrate that PESE and PIC act through multiple complementary mechanisms to counteract hyperglycemia and oxidative stress, highlighting the therapeutic potential of an underutilized byproduct while emphasizing the importance of developmental toxicity assessment for the safe advancement of plant-derived agents.

Osteosarcoma (OS) is the most frequent primary bone malignancy, with stagnant therapeutic progress. The current chemotherapy treatment shows limited efficacy in disseminating metastasis, and its recurrent use is associated with high systemic toxicity. Moreover, the absence of effective therapeutic strategies along with low complexity models for drug screen analysis hinders therapeutic progress. Herein, by developing a three-dimensional (3D) OS model, we found that compared to two-dimensional (2D) OS culture, the 3D spheroid model exhibited upregulation of pro-tumorigenic genes (IL6, OPN, and MMP2), as well as 3D-exclusive activation of TGF-β1 and p-ERK1/2. Additionally, we report the anticancer potential of robinetin, which successfully suppressed pro-tumorigenic genes and downregulated TGF-β1 and p-ERK1/2, demonstrating antitumor efficacy at a similar magnitude as doxorubicin while exhibiting low toxicity toward a healthy mesenchymal 3D system. In a scaffold-based 3D model with bone-mimicking stiffness, robinetin treatment suppressed pro-tumorigenic genes related to tumor invasiveness (FN1, OPN, IL6, and MMP2) and decreased the viability of OS cells upon exposure to TGF-β1. This study highlights robinetin as a promising candidate for selective OS therapy while emphasizing the reliability of advanced 3D OS models for anticancer drug screening and translational research.

Purpose of Review: This review provides an overview of adipose tissue plasticity and adipogenesis as central processes regulating adipose tissue expansion, remodeling, and metabolic function in health and obesity, highlighting their relevance as potential therapeutic targets. Recent Findings: Adipogenesis is a tightly regulated process involving the differentiation of adipose progenitor cells into mature adipocytes through coordinated transcriptional cascades, primarily driven by peroxisome proliferator–activated receptor (PPAR)γ and CCAAT/enhancer–binding protein (C/EBP) family members. This process is further modulated by multiple signaling pathways, including wingless–related integration site (Wnt), bone morphogenetic proteins (BMPs), and insulin signaling, which collectively regulate adipocyte differentiation and metabolic function. Under physiological conditions, the adipose tissue exhibits remarkable plasticity, with adipogenesis supporting lipid buffering capacity and tissue renewal. In obesity, however, chronic nutrient excess and hormonal dysregulation impair this process, favoring adipocyte hypertrophy, hypoxia, and chronic inflammation. These alterations disrupt adipokine secretion and promote ectopic lipid deposition, thereby contributing to metabolic disorders, including insulin resistance and cardiometabolic disease. Summary: Adipose tissue plasticity and adipogenesis are critical determinants of metabolic health. Dysregulation of these processes underlies adipose tissue dysfunction and contributes to the development of obesity-related comorbidities. Targeting adipogenesis and promoting healthy adipose tissue remodeling represent promising strategies for restoring metabolic homeostasis and mitigating obesity-associated diseases.

Selective inhibition of COX‐2 is considered one of the best strategies for treating chronic inflammatory diseases. However, the currently available options still have significant side effects due to exacerbated selectivity. Bis ‐chalcone derivatives have shown promising anti‐inflammatory properties with reduced side effects. In this study, a family of polyhydroxylated bis ‐chalcones was synthesized and tested in vitro for their ability to inhibit human COX‐2 and COX‐1 and to assess selectivity. To further understand their mechanism of action, inhibitory kinetic analysis and in silico molecular docking calculations were performed. The results showed that bis ‐chalcone 31 , with hydroxy groups at positions 3′ and 4′ of the B rings and three hydroxy groups at the center, was the most active. It was recognized as a mixed‐type inhibitor with balanced selectivity. With molecular docking, it was observed that this substitution pattern provided bis ‐chalcone 31 with additional bulk that hindered its access to the active pocket of COX‐1 over COX‐2. Also, compound 31 establishes additional hydrogen bonds within the COX‐2 pocket that bis ‐chalcone 30 did not, therefore explaining the selectivity and superior potency of bis ‐chalcone 31 . In conclusion, bis ‐chalcone 31 with multiple hydroxy groups in its structure shows promising properties for the design of new COX‐2 selective inhibitors.

Background/Objectives: Osteosarcoma treatment options remain limited due to tumor metastasis and the toxicity of conventional chemotherapy, warranting new therapeutic strategies. A well-founded strategy is the use of flavonoids, a class of phytochemicals possessing pharmaceutical properties that contribute to anticancer effects, including antioxidant and anti-inflammatory properties. This study aimed to evaluate the anticancer potential of flavonoids in osteosarcoma and investigate their interaction with doxorubicin. Methods: In this study, five flavonoids were screened for cytotoxicity and selectivity across four osteosarcoma cell lines and healthy fibroblasts (MRC-5). The interaction between myricetin and doxorubicin was assessed using a fixed-ratio combination approach. Cell migration and invasion were evaluated using cell exclusion/wound healing and 2D co-culture assays. EMT-related gene expressions were assessed by RT-qPCR. Antitumor activity was evaluated in vivo using a chick chorioallantoic membrane (CAM) xenograft model. Results: Myricetin emerged as the most selective compound, exhibiting cytotoxicity against osteosarcoma cells while sparing MRC-5 fibroblasts. Notably, myricetin synergized with doxorubicin (ratio 69:1), enhancing its cytotoxicity and significantly reducing osteosarcoma cell migration in vitro. Myricetin downregulated SNAI1 and MMP9, suggesting modulation of epithelial–mesenchymal transition (EMT)-related pathways. Complementarily, in the CAM xenograft model, myricetin reduced xenograft tumor size, confirming its anticancer activity in vivo. Conclusions: Collectively, these findings emphasize the anticancer potential of myricetin in osteosarcoma through inhibition of the SNAI1/MMP-9 signaling axis.

Over the past two decades, the search for safe and effective COX-2 inhibitors has spurred extensive research on flavonoids. Within this context, synthetic flavonoid dimers have emerged as a promising subclass with potential anti-inflammatory activity. To investigate whether dimerization enhances their potency and selectivity, novel A-fused bis-chalcones and A-fused bis-flavones were synthesized and evaluated for their inhibitory activity against isolated human COX-1 and COX-2 enzymes, as well as their effects on prostaglandin E₂ production in whole human blood. Interestingly, the most active compound identified was a monomeric chalcone sharing the same substitution pattern as the top-performing bis-chalcone, suggesting that key structural features drive activity regardless of dimerization. While the dimeric nature of bis-chalcones did not enhance COX-2 inhibition or selectivity in this study, these results provide valuable insights into structure-activity relationships. Furthermore, all active compounds against the isolated enzyme showed reduced potency in whole blood, possibly due to plasma protein binding limiting bioavailability. This study highlights the importance of rational design for further development of dimeric flavonoids, in particular strategies aimed at optimizing bioavailability.