Search Results (35)

The microwave-aided racemic synthesis of six 5-hydroxy-5-vinyl-2-cyclopentenone-type natural products was achieved. A key reaction involving the construction of the α-keto vinyl carbinol function was realized by applying a Mislow–Evans rearrangement of an allylic sulfoxide, which was prepared by conjugate addition of cyclopentane-1,3-dione-derived enolate to alkynyl sulfoxide to afford 5-hydroxy-3-methoxy-5-vinyl-2-cyclopentenone (1). From the common intermediate 1, five other congeneric natural products were synthesized. Full article

Background: Indole-3-carbinol is an indole derivative which is commonly present in vegetables, which belong to Brassicaceae family and has many medicinal properties. This study aimed to investigate the antioxidant impact of indole-3-carbinol on damages caused by Fenton reaction substrates to lipid membranes (lipid peroxidation) of porcine kidneys and ovaries. Methods: Antioxidant effect of indole-3-carbinol was assessed using Lipid Peroxidation Assay. As damaging agents were used Fenton reaction substrates, i.e., FeSO₄ at 11 different concentrations and H₂O₂. The concentrations of indole-3-carbinol were 0.0, 20.0, 10.0, 5.0, 1.0 and 0.5 mM. Results: Comparative analysis showed higher lipid peroxidation levels in kidney than ovary homogenates at 600–18.75 μM FeSO₄. Indole-3-carbinol significantly reduced LPO in porcine ovary homogenates at higher FeSO₄ concentrations (1200–300 μM) in a concentration-dependent manner, while antioxidant effects in kidney homogenates were observed across a broader FeSO₄ range (1200–18.75 μM). Notably, at the lowest FeSO₄ concentrations (4.687–2.343 μM), high doses of indole-3-carbinol (20.0 and 10.0 mM) induced pro-oxidant effects in both tissues. Furthermore, indole-3-carbinol at these concentrations exhibited potential pro-oxidant activity even in samples without added Fenton reaction substrates. Conclusions: Indole-3-carbinol has dose-dependent antioxidant effects in porcine ovary and kidney homogenates under high oxidative stress, reducing Fenton reaction-induced lipid peroxidation. However, high doses of indole-3-carbinol exhibited pro-oxidant effects at lower prooxidant concentration and under basal conditions (i.e., without addition of prooxidant), highlighting the importance of dose and oxidative conditions in its potential therapeutic use. Full article

In the realm of click-type reactions and their application to bioorthogonal chemistry in living organisms, metal-free [3+2] cycloadditions involving mesoionic rings and strained cycloalkynes have gained increasing attention and potentiality in recent years. While there has been a significant accretion of experimental data, biological assays, and assessments of reaction mechanisms, some pieces of the tale are still missing. For instance, which structural and/or stereoelectronic effects are actually interlocked and which remain unplugged. With the advent of data-driven methods, including machine learning simulations, quantitative estimations of relevant observables and their correlations will explore better the chemical space of these transformations. Here we unveil a series of linear relationships, such as Hammett-type correlations, as well as deviations of linearity, using the case study of phenylsydnone (and its 4-aryl-substituted derivatives) with a highly reactive bicyclo[6.1.0]nonyne carbinol. Through accurate estimation of activation barriers and prediction of rate constants, our findings further increase the significance of integrating strain release and electronic effects in organic reactivity. Moreover, such results could pave the way to use mesoionics cycloadditions as probes for measuring the extent of delocalization-assisted strain release, which can be applied to related reactions involving dipoles and strained rings. Full article

Background: Glioblastoma (GBM) is a highly aggressive brain tumor characterized by rapid cell proliferation, invasive behavior, and chemoresistance. The aryl hydrocarbon receptor (AhR) is implicated in chemoresistance and immune evasion, making it a promising therapeutic target. Natural compounds such as flavonoids have gained attention for their anti-inflammatory, antioxidant, and anticancer properties. Among them, naringenin, a citrus-derived flavonoid, exerts antiproliferative, pro-apoptotic, and immunomodulatory effects. Objectives: This study investigated the antiglioma effects of the flavonoid naringenin on the viability, growth, and migration of glioma cells and its potential role as an AhR modulator. Methods: Human (U87) and rat (C6) glioma cell lines were exposed to naringenin (10–300 µM) alone or in combination with the AhR agonist indole-3-carbinol (50 µM) for 24 to 48 h. Cell viability, scratch wound, and cell migration assays were performed. The expression of inflammatory markers was also analyzed by RT-qPCR. Results: Naringenin exerted dose- and time-dependent inhibition of cell viability and migration. The treatment decreased the gene expression of interleukin-6 (IL-6) and chemokine (CCL2), alongside increased tumor necrosis factor-alpha (TNF-α) expression, an effect reversed by the AhR agonist. Conclusions: These findings highlight naringenin’s potential as an antiglioma agent and its role in AhR signaling. Full article

The aryl hydrocarbon receptor (AhR) is an environmentally sensitive transcription factor (TF) historically associated with carcinogenesis initiation via the activation of numerous carcinogens. Nowadays, the AhR has been attributed to multiple endogenous functions to maintain cellular homeostasis. Moreover, crosstalk, often reciprocal, has been found between the AhR and several other TFs, particularly estrogen receptors (ERs) and nuclear factor erythroid 2-related factor-2 (Nrf2). Adequate modulation of these signaling pathways seems to be an attractive strategy for cancer chemoprevention. Several naturally occurring and synthetically modified AhR or ER ligands and Nrf2 modulators have been described. Sulfur-containing derivatives of glucosinolates, such as indole-3-carbinol (I3C), and stilbene derivatives are particularly interesting in this context. I3C and its condensation product, 3,3′-diindolylmethane (DIM), are classic examples of blocking agents that increase drug-metabolizing enzyme activity through activation of the AhR. Still, they also affect multiple essential signaling pathways in preventing hormone-dependent cancer. Resveratrol is a competitive antagonist of several classic AhR ligands. Its analogs, with ortho-methoxy substituents, exert stronger antiproliferative and proapoptotic activity. In addition, they modulate AhR activity and estrogen metabolism. Their activity seems related to a number of methoxy groups introduced into the stilbene structure. This review summarizes the data on the chemopreventive potential of these classes of phytochemicals, in the context of AhR and its crosstalk modulation. Full article

Cacalol (C), a sesquiterpene isolated from Psacalium decompositum, has demonstrated anti-inflammatory and antioxidant activities. Its cytotoxic, antiproliferative, and pro-apoptotic effects have been previously shown in an in vitro breast cancer model. A derivative, cacalol acetate (CA), shows potential in regulating these processes, which has not been previously reported. This study focused on an in vitro cervical cancer model, assessing CA’s antiproliferative, pro-apoptotic, cytostatic, and anti-migratory activities using the HeLa cell line. The natural anticancer agent indole-3-carbinol (I3C) was used as a control for comparison. CA demonstrated significant antitumor activities, including inhibiting cell growth, inducing apoptosis, arresting cells in the G2 phase of the cell cycle, and inhibiting cell migration. These effects were notably greater compared to I3C. I3C, while following a similar trend, did not induce Cas-3 expression, suggesting a different apoptotic pathway. Neither CA nor I3C increased p62 and LC3B levels, indicating they do not stimulate autophagy marker expression. Both compounds inhibited HeLa cell migration and induced cell cycle arrest. Despite both holding promise as anticancer agents for cervical cancer, CA’s lower cytotoxicity and stronger regulation of tumor phenotypes make it a more promising agent compared to I3C. Full article

Brain-derived neurotrophic factor (BDNF) and its downstream tropomyosin receptor kinase B (TrkB) signaling pathway play pivotal roles in the resilience and action of antidepressant drugs, making them prominent targets in psychiatric research. Oxidative stress (OS) contributes to various neurological disorders, including neurodegenerative diseases, stroke, and mental illnesses, and exacerbates the aging process. The nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant responsive element (ARE) serves as the primary cellular defense mechanism against OS-induced brain damage. Thus, Nrf2 activation may confer endogenous neuroprotection against OS-related cellular damage; notably, the TrkB/phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway, stimulated by BDNF-dependent TrkB signaling, activates Nrf2 and promotes its nuclear translocation. However, insufficient neurotrophin support often leads to the downregulation of the TrkB signaling pathway in brain diseases. Thus, targeting TrkB activation and the Nrf2-ARE system is a promising therapeutic strategy for treating neurodegenerative diseases. Phytochemicals, including indole-3-carbinol (I3C) and its metabolite, diindolylmethane (DIM), exhibit neuroprotective effects through BDNF’s mimetic activity; Akt phosphorylation is induced, and the antioxidant defense mechanism is activated by blocking the Nrf2-kelch-like ECH-associated protein 1 (Keap1) complex. This review emphasizes the therapeutic potential of I3C and its derivatives for concurrently activating neuronal defense mechanisms in the treatment of neurodegenerative diseases. Full article

During the harvesting of the broccoli plant, the leaves are discarded, being considered a by-product that may be up to 47% of total broccoli biomass, representing a large amount of wasted material. The use of broccoli leaves is of great interest in the sense that this wasted material is rich in health promoter compounds, such as isothiocyanates. In this study, C57BL/6J mice ingested 790 mg/kg broccoli leaf flour, and the presence of glucosinolates and isothiocyanates in the plasma, liver, kidney, adipose tissue, faeces and urine was analysed at 1, 2, 4, 8, 12 and 24 h post-ingestion. In plasma, only glucoerucin (GE), glucobrassicin (GB), sulforaphane (SFN) and indol-3-carbinol (I3C) were detected, and all four compounds peaked between 4 and 8 h after ingestion. The compounds SFN, SFN-glutathione (SFN-GSH), SFN–cysteine (SFN-CYS) and SFN-N-acetyl-cysteine (SFN-NAC) were excreted in faeces at high levels, while glucoraphanin (GR), the precursor of SFN, was not detected in any biological samples other than urine. In the liver, the compounds GE, SFN-CYS, SFN-NAC and I3C were detected, while in the kidney, only GE, GB and SFN-GSH were present. None of the glucosinolates and isothiocyanates analysed were detected in fat tissue. These results demonstrate that glucosinolates and their derivatives were absorbed into the bloodstream and were bioavailable after ingestion of powdered broccoli leaves. Full article

High mortality rates in ovarian cancer have been linked to recurrence, metastasis, and chemoresistant disease, which are known to involve not only genetic changes but also epigenetic aberrations. In ovarian cancer, adipose-derived stem cells from the omentum (O-ASCs) play a crucial role in supporting the tumor and its tumorigenic microenvironment, further propagating epigenetic abnormalities and dissemination of the disease. Epigallocatechin gallate (EGCG), a DNA methyltransferase inhibitor derived from green tea, and Indole-3-carbinol (I3C), a histone deacetylase inhibitor from cruciferous vegetables, carry promising effects in reprograming aberrant epigenetic modifications in cancer. Therefore, we demonstrate the action of these diet-derived compounds in suppressing the growth of 3D ovarian cancer spheroids or organoids as well as post-treatment cancer recovery through proliferation, migration, invasion, and colony formation assays when compared to the synthetic epigenetic compound Panobinostat with or without standard chemotherapy. Finally, given the regulatory role of the secretome in growth, metastasis, chemoresistance, and relapse of disease, we demonstrate that natural epigenetic compounds can regulate the secretion of protumorigenic growth factors, cytokines, extracellular matrix components, and immunoregulatory markers in human ovarian cancer specimens. While further studies are needed, our results suggest that these treatments could be considered in the future as adjuncts to standard chemotherapy, improving efficiency and patient outcomes. Full article

Rapeseed oil is the third most consumed culinary oil in the world. It is well-known for its high content of unsaturated fatty acids, especially polyunsaturated fatty acids, which make it of great nutritional value. There is increasing evidence that a diet rich in unsaturated fatty acids offers health benefits. Although the consumption of rapeseed oil cuts across many areas around the world, the nutritional elements of rapeseed oil and the exact efficacy of the nutrients remain unclear. In this review, we systematically summarized the latest studies on functional rapeseed components to ascertain which component of canola oil contributes to its function. Apart from unsaturated fatty acids, there are nine functional components in rapeseed oil that contribute to its anti-microbial, anti-inflammatory, anti-obesity, anti-diabetic, anti-cancer, neuroprotective, and cardioprotective, among others. These nine functional components are vitamin E, flavonoids, squalene, carotenoids, glucoraphanin, indole-3-Carbinol, sterols, phospholipids, and ferulic acid, which themselves or their derivatives have health-benefiting properties. This review sheds light on the health-benefiting effects of rapeseed oil in the hope of further development of functional foods from rapeseed. Full article

3-3′-Diindolylmethane (DIM) is a biologically active dimer derived from the endogenous conversion of indole-3-carbinol (I3C), a naturally occurring glucosinolate found in many cruciferous vegetables (i.e., Brassicaceae). DIM was the first pure androgen receptor antagonist isolated from the Brassicaceae family and has been recently investigated for its potential pharmacological use in prostate cancer prevention and treatment. Interestingly, there is evidence that DIM can also interact with cannabinoid receptors. In this context, by considering the well-known involvement of the endocannabinoid system in prostate cancer, we have pharmacologically characterized the properties of DIM on both CB₁ and CB₂ cannabinoid receptors in two human prostate cancer cell lines: PC3 (androgen-independent/androgen receptor negative) and LNCaP (androgen-dependent). In the PC3 cell line, DIM was able to activate CB₂ receptors and potentially associated apoptotic pathways. On the other hand, although DIM was also able to activate CB₂ receptors in the LNCaP cell line, no apoptotic effects were observed. Our evidence confirms that DIM is a CB₂ receptor ligand and, moreover, it has a potential anti-proliferative effect on androgen-independent/androgen receptor-negative prostate cancer cells. Full article

Indole-3-carbinol (I3C) is a natural product contained in vegetables belonging to the Brassicaceae family and has been studied in recent decades for its biological and pharmacological properties. Herein, we will analyze: (1) the biosynthetic processes and synthetic procedures through which I3C and its main derivatives have been obtained; (2) the characteristics that lead to believe that both I3C and its derivatives are responsible for several important activities—in particular, antitumor and antiviral, through insights concerning in vitro assays and in vivo tests; (3) the mechanisms of action of the most important compounds considered; (4) the potential social impact that the enhancement of the discussed molecules can have in the prevention and treatment of the pathologies’ examined field—first of all, those related to respiratory tract disorders and cancer. Full article

Glucosinolates, specialized metabolites of the Brassicales including Brassica crops and Arabidopsis thaliana, have attracted considerable interest as chemical defenses and health-promoting compounds. Their biological activities are mostly due to breakdown products formed upon mixing with co-occurring myrosinases and specifier proteins, which can result in multiple products with differing properties, even from a single glucosinolate. Whereas product profiles of aliphatic glucosinolates have frequently been reported, indole glucosinolate breakdown may result in complex mixtures, the analysis of which challenging. The aim of this study was to assess the breakdown of indole glucosinolates in A. thaliana root and rosette homogenates and to test the impact of nitrile-specifier proteins (NSPs) on product profiles. To develop a GC-MS-method for quantification of carbinols and nitriles derived from three prominent indole glucosinolates, we synthesized standards, established derivatization conditions, determined relative response factors and evaluated applicability of the method to plant homogenates. We show that carbinols are more dominant among the detected products in rosette than in root homogenates of wild-type and NSP1- or NSP3-deficient mutants. NSP1 is solely responsible for nitrile formation in rosette homogenates and is the major NSP for indolic nitrile formation in root homogenates, with no contribution from NSP3. These results will contribute to the understanding of the roles of NSPs in plants. Full article

Current studies show that approximately one-third of all cancer-related deaths are linked to diet and several cancer forms are preventable with balanced nutrition, due to dietary compounds being able to reverse epigenetic abnormalities. An appropriate diet in cancer patients can lead to changes in gene expression and enhance the efficacy of therapy. It has been demonstrated that nutraceuticals can act as powerful antioxidants at the cellular level as well as anticarcinogenic agents. This review is focused on the best studies on worldwide-available plant-derived nutraceuticals: curcumin, resveratrol, sulforaphane, indole-3-carbinol, quercetin, astaxanthin, epigallocatechin-3-gallate, and lycopene. These compounds have an enhanced effect on epigenetic changes such as histone modification via HDAC (histone deacetylase), HAT (histone acetyltransferase) inhibition, DNMT (DNA methyltransferase) inhibition, and non-coding RNA expression. All of these nutraceuticals are reported to positively modulate the epigenome, reducing cancer incidence. Furthermore, the current review addresses the issue of the low bioavailability of nutraceuticals and how to overcome the drawbacks related to their oral administration. Understanding the mechanisms by which nutraceuticals influence gene expression will allow their incorporation into an “epigenetic diet” that could be further capitalized on in the therapy of cancer. Full article

The natural product indole-3-carbinol (I3C) and its major digestive product 3,3′-diindolylmethane (DIM) have shown clinical promise in multiple forms of cancer including breast cancer. In this study, we explored the calcium channel activity of DIM, its synthetic derivative 3,3′-Diindolylmethanone (DIM-one) and related I3C and DIM-one analogs. For the first time, DIM, DIM-one and analog IX were identified as selective blockers for T-type Ca_V3.3 (IC₅₀s DIM 2.09 µM; DIM-one 9.07 µM) while compound IX inhibited both Ca_V3.2 (6.68 µM) and Ca_V3.3 (IC₅₀ = 3.05 µM) using a FLIPR cell-based assay to measure inhibition of T-type calcium channel window current. Further characterization of DIM by electrophysiology revealed it inhibited inward Ca²⁺ current through Ca_V3.1 (IC₅₀ = 8.32 µM) and Ca_V3.3 (IC₅₀ = 9.63 µM), while IX partially blocked Ca_V3.2 and Ca_V3.3 inward Ca²⁺ current. In contrast, DIM-one preferentially blocked Ca_V3.1 inward Ca²⁺ current (IC₅₀ = 1.53 µM). The anti-proliferative activities of these compounds revealed that oxidation of the methylene group of DIM shifted the selectivity of DIMs from breast cancer cell line MCF-7 to colon cancer cell line HT-29. Full article