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Simple Summary: The occurrence of resistance to the standard treatment for estrogen receptor-positive (ER+) (Luminal A) breast cancer emphasizes the search for new molecules. In recent years, the interest in multi-target drugs has been growing, and they have even been identified as future therapeutic strategies. In line with this, this study aims to understand the anti-cancer action and multi-target potential of three new steroidal aromatase inhibitors (AIs): 7α-methylandrost-4-en-17-one (6), 7α-methylandrost-4-ene-3,17-dione (10a) and androsta-4,9(11)-diene-3,17-dione (13). We report new compounds that are able to impair the growth of sensitive and resistant ER+ breast cancer cells by acting as AIs, ER modulators and AR agonists, which is a therapeutic advantage over the current drugs applied in clinic. Therefore, this study is a breakthrough on drug discovery as it allows the discovery of new multi-target drugs for the treatment of ER+ breast cancer. Background/Objectives: Endocrine therapies that comprise anti-estrogens and aromatase inhibitors (AIs) are the standard treatment for estrogen receptor-positive (ER+) (Luminal A) breast cancer—the most prevalent subtype. However, the emergence of resistance restricts their success by causing tumor relapse and re-growth, which demands a switch towards other therapeutic approaches in order to minimize or overcome resistance. Indeed, this clinical limitation highlights the search for new molecules to improve cancer treatment. Recently, strategies that address multiple targets have been emerging, and multi-target drugs have the potential to become the future anti-cancer molecules. Our group has been searching for new multi-target compounds, and as part of this, our study aims to understand the anti-cancer and multi-target potential of three new steroidal aromatase inhibitors (AIs): 7α-methylandrost-4-en-17-one (6), 7α-methylandrost-4-ene-3,17-dione (10a) and androsta-4,9(11)-diene-3,17-dione (13). Methods: Their in vitro actions and molecular mechanisms were elucidated in a sensitive ER+ aromatase-overexpressing breast cancer cell line, MCF-7aro cells, as well as in an AI-resistant ER+ breast cancer cell line, LTEDaro cells. Results: All the new AIs (10 µM) prevented the proliferation of MCF-7aro cells by arresting cell cycle progression. Interestingly, all AIs (10 µM) act as androgen receptor (AR) agonists and modulate ER levels, synthesis and signaling to induce the apoptosis of ER+ breast cancer cells. Additionally, these new AIs (10 µM) also re-sensitize resistant cells by promoting apoptosis, offering a therapeutic benefit. Conclusions: Overall, new steroidal polypharmacological compounds have been discovered that, by acting as AIs, ER modulators and AR agonists, impair ER+ breast cancer cell growth. Overall, this study is a breakthrough on drug discovery as it presents new molecules with appealing anti-cancer properties and multi-target action for the treatment of ER+ breast cancer. [ABSTRACT FROM AUTHOR]

Background/Objectives: Côa Valley, located in the northeast of Portugal, harbors more than 500 medicinal plant species. Among them, four species stand out due to their traditional uses: Equisetum ramosissimum Desf. (hemorrhages, urethritis, hepatitis), Rumex scutatus L. subsp. induratus (Boiss. and Reut.) Malag. (inflammation, constipation), Geranium purpureum Vill., and Geranium lucidum L. (pain relief, gastric issues). Given their rich ethnomedicinal history, we evaluated their protective effects on an in vitro model of metabolic dysfunction-associated steatotic liver disease (MASLD). Methods: Decoction (D) and hydroalcoholic (EtOH80%) extracts were prepared and chemically characterized. Their safety profile and effects on lipid accumulation were assessed in palmitic acid (PA)-treated HepG2 cells using resazurin, sulforhodamine B, and Nile Red assays. Results: Chemical analysis revealed diverse phenolic compounds, particularly kaempferol derivatives in E. ramosissimum. All extracts showed minimal cytotoxicity at 25–50 µg/mL. At 100 µg/mL, only E. ramosissimum extracts maintained high cell viability. In the lipotoxicity model, E. ramosissimum decoction demonstrated the most potent effect, significantly reducing PA-induced neutral lipid accumulation in a dose-dependent manner, while other extracts showed varying degrees of activity. Conclusions: These findings highlight E. ramosissimum's decoction, rich in kaempferol derivatives, as particularly effective in reducing lipid accumulation in this MASLD cell model while also providing a comprehensive characterization of traditionally used plants from the Côa Valley region. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a chronic eczematous inflammatory disease that may arise from environmental, genetic, and immunological factors. Despite the efficacy of current treatment options such as corticosteroids, such approaches are mainly focused on symptom relief and may present certain undesirable side effects. In recent years, isolated natural compounds, oils, mixtures, and/or extracts have gained scientific attention because of their high efficiency and moderate to low toxicity. Despite their promising therapeutic effects, the applicability of such natural healthcare solutions is somewhat limited by their instability, poor solubility, and low bioavailability. Therefore, novel nanoformulation-based systems have been designed to overcome these limitations, thus enhancing the therapeutic potential, by promoting the capacity of these natural drugs to properly exert their action in AD-like skin lesions. To the best of our knowledge, this is the first literature review that has focused on summarizing recent nanoformulation-based solutions loaded with natural ingredients, specifically for the management of AD. We suggest that future studies should focus on robust clinical trials that may confirm the safety and effectiveness of such natural-based nanosystems, thus paving the way for more reliable AD treatments. [ABSTRACT FROM AUTHOR]

Skin tissue has a crucial role in protecting the human body from external harmful agents, preventing wounds that frequently demand proper healing approaches. The ethnobotanical knowledge of specific regions with further investigation on their medicinal plants has been paramount to create new and effective therapeutical agents, including for dermatological purposes. This review attempts, for the first time, to investigate the traditional applications of Lamiaceae medicinal plants that are already used by local communities in the Iberian Peninsula in wound healing. Henceforward, Iberian ethnobotanical surveys were reviewed, and the information about the traditional wound healing practices of Lamiaceae was comprehensively summarized. Afterwards, the scientific validation of each Lamiaceae species was exhaustively checked. From this, eight out of twenty-nine Lamiaceae medicinal plants were highlighted by their wound-related pharmacological evidence and are in-depth presented in this review. We suggest that future studies should focus on the isolation and identification of the active molecules of these Lamiaceae, followed by robust clinical trials that may confirm the security and effectiveness of such natural-based approaches. This will in turn pave the way for more reliable wound healing treatments. [ABSTRACT FROM AUTHOR]

Lavandula pedunculata (Mill.) Cav., Mentha cervina L. and Thymus mastichina (L.) L. subsp. mastichina are representative species of the Côa Valley's flora, a Portuguese UNESCO World Heritage Site. L. pedunculata and T. mastichina are traditionally used to preserve olives and to aromatize bonfires on Saint John's Eve, while M. cervina is mainly used as a spice for river fish dishes. Despite their traditional uses, these aromatic plants are still undervalued, and literature regarding their bioactivity, especially anticancer, is scarce. In this work, the morphology of secretory structures was assessed by scanning electron microscopy (SEM), and the composition of essential oils (EOs) was characterized by gas chromatography-mass spectrometry (GC-MS). The study proceeded with cytotoxic evaluation of EOs in tumor and non-tumor cells with the cell death mechanism explored in glioblastoma (GB) cells. L. pedunculata EO presented the most pronounced cytotoxic/antiproliferative activity against tumor cells, with moderate cytotoxicity against non-tumor cells. Whereas, M. cervina EO exhibited a slightly lower cytotoxic effect against tumor cells and did not affect the viability of non-tumor cells. Meanwhile, T. mastichina EO did not induce a strong cytotoxic effect against GB cells. L. pedunculata and M. cervina EOs lead to cell death by inducing apoptosis in a dose-dependent manner. The present study suggests that L. pedunculata and M. cervina EOs have a strong cytotoxic and antiproliferative potential to be further studied as efficient antitumor agents. [ABSTRACT FROM AUTHOR]

Around 70–85% of all breast cancer (BC) cases are estrogen receptor-positive (ER+). The third generation of aromatase inhibitors (AIs) is the first-line treatment option for these tumors. Despite their therapeutic success, they induce several side effects and resistance, which limits their efficacy. Thus, it is crucial to search for novel, safe and more effective anti-cancer molecules. Currently, multi-target drugs are emerging, as they present higher efficacy and lower toxicity in comparison to standard options. Considering this, this work aimed to investigate the anti-cancer properties and the multi-target potential of the compound 1α,2α-epoxy-6-methylenandrost-4-ene-3,17-dione (Oxy), also designated by Oxymestane-D1, a derivative of Exemestane, which we previously synthesized and demonstrated to be a potent AI. For this purpose, it was studied for its effects on the ER+ BC cell line that overexpresses aromatase, MCF-7aro cells, as well as on the AIs-resistant BC cell line, LTEDaro cells. Oxy reduces cell viability, impairs DNA synthesis and induces apoptosis in MCF-7aro cells. Moreover, its growth-inhibitory properties are inhibited in the presence of ERα, ERβ and AR antagonists, suggesting a mechanism of action dependent on these receptors. In fact, Oxy decreased ERα expression and activation and induced AR overexpression with a pro-death effect. Complementary transactivation assays demonstrated that Oxy presents ER antagonist and AR agonist activities. In addition, Oxy also decreased the viability and caused apoptosis of LTEDaro cells. Therefore, this work highlights the discovery of a new and promising multi-target drug that, besides acting as an AI, appears to also act as an ERα antagonist and AR agonist. Thus, the multi-target action of Oxy may be a therapeutic advantage over the three AIs applied in clinic. Furthermore, this new multi-target compound has the ability to sensitize the AI-resistant BC cells, which represents another advantage over the endocrine therapy used in the clinic, since resistance is a major drawback in the clinic. [ABSTRACT FROM AUTHOR]

Light-harvesting complexes in natural photosynthetic systems, such as those in purple bacteria, consist of photo-reactive chromophores embedded in densely packed "antenna" systems organized in well-defined nanostructures. In the case of purple bacteria, the chromophore antennas are composed of natural J-aggregates such as bacteriochlorophylls and carotenoids. Inspired by the molecular composition of such biological systems, we create a library of organic materials composed of densely packed J-aggregates in a polymeric matrix, in which the matrix mimics the optical role of a protein scaffold. This library of organic materials shows polaritonic properties which can be tuned from the visible to the infrared by choice of the model molecule. Inspired by the molecular architecture of the light-harvesting complexes of Rhodospirillum molischianum bacteria, we study the light–matter interactions of J-aggregate-based nanorings with similar dimensions to the analogous natural nanoscale architectures. Electromagnetic simulations show that these nanorings of J-aggregates can act as resonators, with subwavelength confinement of light while concentrating the electric field in specific regions. These results open the door to bio-inspired building blocks for metamaterials from visible to infrared in an all-organic platform, while offering a new perspective on light–matter interactions at the nanoscale in densely packed organic matter in biological organisms including photosynthetic organelles. [ABSTRACT FROM AUTHOR]

Optical Tamm states (OTS) are confined optical modes that can occur at the interface between two highly reflective structures. However, due to the strong reflectance required, their implementation with highly processable and metal-free flexible materials has proven challenging. Herein, we develop the first structure supporting OTS based only on organic polymeric materials, demonstrating a photonic platform based on non-critical, widely available and easily processable materials. The structures fabricated present large areas and consist of a narrowband multi-layered polymeric distributed Bragg reflector (DBR) followed by a thin film of J-aggregate molecular excitonic material that can act as a highly reflective surface within a narrowband range. We take advantage of the narrowband spectral response of the DBR and of the reflective molecular layer to tune the OTS band by varying the periodicity of the multilayer, opening the door for the fabrication of OTS structures based on lightweight integrable excitonic devices with cost-effective procedures. [ABSTRACT FROM AUTHOR]

The classical synthesis, followed by purification of the steroidal A-ring Δ1-olefin, 5 α-androst-1-en-17-one ( 5), from the Δ1-3-keto enone, (5 α,17 β)-3-oxo-5-androst-1-en-17-yl acetate ( 1), through a strategy involving the reaction of Δ1-3-hydroxy allylic alcohol, 3 β-hydroxy-5 α-androst-1-en-17 β-yl acetate ( 2), with SOCl2, was revisited in order to prepare and biologically evaluate 5 as aromatase inhibitor for breast cancer treatment. Surprisingly, the followed strategy also afforded the isomeric Δ2-olefin 6 as a by-product, which could only be detected on the basis of NMR analysis. Optimization of the purification and detection procedures allowed us to reach 96% purity required for biological assays of compound 5. The same synthetic strategy was applied, using the Δ4-3-keto enone, 3-oxoandrost-4-en-17 β-yl acetate ( 8), as starting material, to prepare the potent aromatase inhibitor Δ4-olefin, androst-4-en-17-one ( 15). Unexpectedly, a different aromatase inhibitor, the Δ3,5-diene, androst-3,5-dien-17-one ( 12), was formed. To overcome this drawback, another strategy was developed for the preparation of 15 from 8. The data now presented show the unequal reactivity of the two steroidal A-ring Δ1- and Δ4-3-hydroxy allylic alcohol intermediates, 3 β-hydroxy-5 α-androst-1-en-17 β-yl acetate ( 2) and 3 β-hydroxyandrost-4-en-17 β-yl acetate ( 9), towards SOCl2, and provides a new strategy for the preparation of the aromatase inhibitor 12. Additionally, a new pathway to prepare compound 15 was achieved, which avoids the formation of undesirable by-products. [ABSTRACT FROM AUTHOR]

Different hormonal therapies are used for estrogen receptor positive (ER) breast cancers, being the third-generation of aromatase inhibitors (AIs), an effective alternative to the classical tamoxifen. AIs inhibit the enzyme aromatase, which is responsible for catalyzing the conversion of androgens to estrogens. In this study, it was evaluated the effects of several steroidal AIs, namely 3β-hydroxyandrost-4-en-17-one ( 1), androst-4-en-17-one ( 12), 4α,5α-epoxyandrostan-17-one ( 13a) and 5α-androst-2-en-17-one ( 16), on cell proliferation, cell cycle progression and cell death in an ER aromatase-overexpressing human breast cancer cell line (MCF-7aro). All AIs induced a decrease in cell proliferation and these anti-proliferative effects were due to a disruption in cell cycle progression and cell death, by apoptosis. AIs 1 and 16 caused cell cycle arrest in G/G, while AIs 12 and 13a induced an arrest in G/M. Moreover, it was observed that these AIs induced apoptosis by different pathways, since AIs 1, 12 and 13a activated the apoptotic mitochondrial pathway, while AI 16 induced apoptosis through activation of caspase-8. These results are important for the elucidation of the cellular effects of steroidal AIs on breast cancer cells and will also highlight the importance of AIs as inducers of apoptosis in hormone-dependent breast cancers. [ABSTRACT FROM AUTHOR]