Cytoskeletons are dynamic and multifunctional cellular frameworks composed of microtubules, actin filaments, and intermediate filaments [...]

Glioblastoma is one of the most highly aggressive types of brain tumor in adults. With limited treatment options, current therapies remain insufficient due to its invasiveness and immune evasion, highlighting the urgent need for new treatments. Bifunctional molecules targeting multiple aspects of the disease could be promising to overcome drug resistance and tumor heterogeneity. Metformin has demonstrated protective effects against brain tumors but requires high doses for efficacy, making it of great interest for molecular optimization. In this context, we synthesized a series of nine metformin-phenolic molecules, combining the metformin guanidine framework with phenolic acids, which have well-established properties in inhibiting cancer cell migration and adhesion. Their impact on cytotoxicity, reactive oxygen species inhibition, and signaling pathways was investigated for glioma cell lines and stem cells. Two of these hybrids, 5a and 5h, particularly enhanced cytotoxicity in glioblastoma cells, selectively targeting cancer cells while sparing healthy ones. Their mechanism of action differed significantly from metformin. Unlike metformin, which mainly triggers metabolic stress, the hybrids broadly inhibit RTK-MAPK-PI3K signaling, leading to cell cycle arrest and apoptosis. The results suggest that these compounds could offer a more effective and synergistic approach for glioblastoma treatment.

Tau protein displays a key role in promoting tubulin assembly and microtubule stabilization. Alterations in Tau expression have been implicated in many pathologies, including neurodegenerative disorders and, more recently, certain forms of cancer such as glioblastoma, where aberrant Tau expression has been reported. The exploration and development of novel Tau-targeting agents remain in a vibrant field of research due to the urgent need for effective treatments against these Tau-dependent diseases. This review focuses on flavonoids and their role in modulating Tau function. We will begin with an overview of flavonoid classes and structures. Subsequently, we examine how flavonoids influence Tau function through both direct and indirect mechanisms, alongside key pathological Tau alterations, including liquid-liquid phase separation and aggregation. Flavonoids show promise in inhibiting Tau aggregation, but their low bioavailability limits therapeutic use. In this regard, we will outline many approaches to overcome this issue through structural modifications and nano-delivery systems to improve targeting and release of flavonoids in tissue. Finally, we highlight recent advances in the rational design of Tau-targeting agents based on flavonoid scaffolds, with particular emphasis on thiazoloflavonoids explored in GBM models. Our synthesis of current knowledge positions flavonoids as a versatile chemical platform, offering a viable path for Tau-directed therapies in neurodegenerative and oncogenic contexts.

Growing evidence has unveiled the pathological significance of Tau in many cancers, including the most aggressive and lethal brain tumor glioblastoma multiform (GBM). In this regard, we have recently examined the structure–activity relationship of a new series of seventeen 2-aminothiazole-fused to flavonoid hybrid compounds (TZF) on Tau-overexpressing GBM cells. Here, we evaluated the anticancer activities of the two lead compounds 2 and 9 using multi-cellular spheroids (MCSs) which represent an easy 3D human cell model to mimic GBM organization, physical constraints and drug penetration. The two compounds reduced cell evasion from spheroids up to three times, especially for Tau-expressing cells. As a first step towards a therapeutic approach, we quantified the effects of these compounds on MCS growth using two complementary protocols: single and repeated treatments. A single injection with compound 9 slowed down the growth of MCSs formed with U87 shCTRL cells by 40% at 10 µM. More interestingly, multiple treatment with compound 9 slowed the growth of U87 shCTRL spheroids by 40% at a concentration of 5 µM, supporting the increased bioavailability of compound 9 within MCSs. In conclusion, compound 9 deserves particular attention as promising candidate for specifically targeting Tau-expressing cancers such as GBM.

Chalcones constitute an important group of natural compounds abundant in fruits and comestible plants. They are a subject of increasing interest because of their biological activities including antidiabetic and anti-obesity effects. The simple chalcone structural scaffold can be modified at multiple sites with different chemical moieties. Here we generated an artificial chalcone, i.e., 3,5-dimethyl-2,4,6-trimethoxychalcone (TriMetChalc), derived from 2′,4′-Dihydroxy-6′-methoxy-3′,5′-dimethylchalcone (DMC). DMC is the major compound of Cleistocalyx operculatus, a plant widely used in Asia for its anti-hyperglycemic activity. Using ob/ob mice as an obesity model, we ported that, after 3 weeks of per os administration, TriMetChalc modified food intake through the specific activation of brain structures dedicated to the regulation of energy balance. TriMetChalc also decreased weight gain, glucose intolerance and hepatic steatosis. Moreover, through extensive liver lipidomic analysis, we identified TriMetChalc-induced modifications that could contribute to improving the liver status of the animals. Hence, TriMetChalc is a chalcone derivative capable of reducing food intake and addition of glucose intolerance, and hepatic steatosis in a mouse model of obesity. In light of these results, we believe that TriMetChalc action deserves to be more deeply evaluated over longer treatment periods and/or in combination with other chalcones with protective effects on the liver.

Chalcones constitute an important group of natural compounds abundant in fruits and comestible plants. They are a subject of increasing interest because of their biological activities, including anti-diabetic and anti-obesity effects. The simple chalcone structural scaffold can be modified at multiple sites with different chemical moieties. Here, we generated an artificial chalcone, i.e., 3,5-dimethyl-2,4,6-trimethoxychalcone (TriMetChalc), derived from 2′,4′-Dihydroxy-6′-methoxy-3′,5′-dimethylchalcone (DMC). DMC is a major compound of Cleistocalyx operculatus, a plant widely used in Asia for its anti-hyperglycemic activity. Using ob/ob mice as an obesity model, we report that, after 3 weeks of per os administration, TriMetChalc modified food intake through the specific activation of brain structures dedicated to the regulation of energy balance. TriMetChalc also decreased weight gain, glucose intolerance, and hepatic steatosis. Moreover, through extensive liver lipidomic analysis, we identified TriMetChalc-induced modifications that could contribute to improving the liver status of the animals. Hence, TriMetChalc is a chalcone derivative capable of reducing food intake and the addition of glucose intolerance and hepatic steatosis in a mouse model of obesity. In light of these results, we believe that TriMetChalc action deserves to be more deeply evaluated over longer treatment periods and/or in combination with other chalcones with protective effects on the liver.

The development of new and effective antimicrobial compounds is urgent due to the emergence of resistant bacteria. Natural plant flavonoids are known to be effective molecules, but their activity and selectivity have to be increased. Based on previous aurone potency, we designed new aurone derivatives bearing acetamido and amino groups at the position 5 of the A ring and managing various monosubstitutions at the B ring. A series of 31 new aurone derivatives were first evaluated for their antimicrobial activity with five derivatives being the most active (compounds 10, 12, 15, 16, and 20). The evaluation of their cytotoxicity on human cells and of their therapeutic index (TI) showed that compounds 10 and 20 had the highest TI. Finally, screening against a large panel of pathogens confirmed that compounds 10 and 20 possess large spectrum antimicrobial activity, including on bioweapon BSL3 strains, with MIC values as low as 0.78 µM. These results demonstrate that 5-acetamidoaurones are far more active and safer compared with 5-aminoaurones, and that benzyloxy and isopropyl substitutions at the B ring are the most promising strategy in the exploration of new antimicrobial aurones.

Tau protein has been described for several decades as a promoter of tubulin assembly into microtubules. Dysregulation or alterations in Tau expression have been related to various brain cancers, including the highly aggressive and lethal brain tumor glioblastoma multiform (GBM). In this respect, Tau holds significant promise as a target for the development of novel therapies. Here, we examined the structure–activity relationship of a new series of seventeen 2-aminothiazole-fused to flavonoid hybrid compounds (TZF) on Tau binding, Tau fibrillation, and cellular effects on Tau-expressing cancer cells. By spectrofluorometric approach, we found that two compounds, 2 and 9, demonstrated high affinity for Tau and exhibited a strong propensity to inhibit Tau fibrillation. Then, the biological activity of these compounds was evaluated on several Tau-expressing cells derived from glioblastoma. The two lead compounds displayed a high anti-metabolic activity on cells related to an increased fission of the mitochondria network. Moreover, we showed that both compounds induced microtubule bundling within newly formed neurite-like protrusions, as well as with defection of cell migration. Taken together, our results provide a strong experimental basis to develop new potent molecules targeting Tau-expressing cancer cells, such as GBM.

Hemiindigoids comprise a range of natural and synthetic scaffolds that share the same aromatic hydrocarbon backbone as well as promising biological and optical properties. The encouraging therapeutic potential of these scaffolds has been unraveled by many studies over the past years and uncovered representants with inspiring pharmacophoric features such as the acetylcholinesterase inhibitor donezepil and the tubulin polymerization inhibitor indanocine. In this review, we summarize the last advances in the medicinal potential of hemiindigoids, with a special attention to molecular design, structure-activity relationship, ligand-target interactions, and mechanistic explanations covering their effects. As their strong fluorogenic potential and photoswitch behavior recently started to be highlighted and explored in biology, giving rise to the development of novel fluorescent probes and photopharmacological agents, we also discuss these properties in a medicinal chemistry perspective.

Chlordecone (CLD), an obsolete insecticide, used in the French West Indies between 1972 and 1993, is persistent in the environment but can be dechlorinated either chemically or under the action of microorganisms. Therefore, if soil remediation programs based on these processes are implemented in areas still contaminated today, those will see their concentrations of dechlorinated derivatives increase and these compounds will be also found in freshwater by streaming, leaching and erosion processes. The purpose of the present study was to evaluate, at environmental concentrations, the toxic effects of mixtures of chlordecone and a three-chlorine substituted byproduct. A hydra clone, which has been confirmed to be Hydra vulgaris Pallas, 1766 has been retained for bioassays where the toxicity has been evaluated by regeneration capacity during exposure. Exposure to mixtures is complex to investigate by classical methods, therefore, an experimental design associated to a mathematical model has been used to predict the effects of all the mixtures and to detect the toxic influence of each compound. The predictive model is discussed regarding the stochastic “endocrine disruptor effect” of CLD. At probable environmental concentrations of the compounds in the mixture, results show that impairment of regeneration capacity is explained mostly by the presence of CLD in the mixtures and support the implementation of remediation programs aimed at dechlorination of this persistent organochlorine pesticide.

Pyomelanin is a brown-black phenolic polymer and results from the oxidation of homogentisic acid (HGA) in the L-tyrosine pathway. As part of the research for natural and active ingredients issued from realistic bioprocesses, this work re-evaluates the HGA pigment and makes an updated inventory of its syntheses, microbial pathways, and properties, with tracks and recent advances for its large-scale production. The mechanism of the HGA polymerization is also well documented. In alkaptonuria, pyomelanin formation leads to connective tissue damage and arthritis, most probably due to the ROS issued from HGA oxidation. While UV radiation on human melanin may generate degradation products, pyomelanin is not photodegradable, is hyperthermostable, and has other properties better than L-Dopa melanin. This review aims to raise awareness about the potential of this pigment for various applications, not only for skin coloring and protection but also for other cells, materials, and as a promising (semi)conductor for bioelectronics and energy.

Alzheimer's disease is a neurodegenerative disorder that causes a progressive deterioration of memory and intellectual capacities. It causes irreversible lesions in the brain and leads to a decline in cognitive functions. New non-drug approaches should, therefore, be explored to slow the progression of the disease. We previously demonstrated the biological activities of a plant composition, designated as AT000. This herbal extract contains a plant heretofore unlisted in the European Pharmacopoeia. In this study, we substituted this plant with camphor leaves and studied the antioxidant, anti-inflammatory and neuroprotective activities in vitro of this new formulation, designated as AT00X. The chemical composition of the AT00X extract using gas chromatography was also evaluated. Results showed significant antioxidant and anti-inflammatory activity with 224010 equivalents of Trolox, an increase in the resistance of control blood to free radical attack up to 54.21% by KRL assay and an anti-inflammatory ratio of 99.13. The extract significantly improves neuronal survival and decreases ROS production at 5 μg/ml. It also stimulates neurite network reconstitution at 10 µg/ml. It can, therefore, be concluded that AT00X extract is an effective therapeutic agent for cognitive deficits caused by Alzheimer's disease. Keywords: Alzheimer’s disease, medicinal plants, amyloid beta, oxidative stress, inflammation.

Despite being extensively studied for several decades, the microtubule-associated protein Tau has not finished revealing its secrets. For long, Tau has been known for its ability to promote microtubule assembly. A less known feature of Tau is its capability to bind to cancer-related protein kinases, suggesting a possible role of Tau in modulating microtubule-independent cellular pathways that are associated with oncogenesis. With the intention of finding new therapeutic targets for cancer, it appears essential to examine the interaction of Tau with these kinases and their consequences. This review aims at collecting the literature data supporting the relationship between Tau and cancer with a particular focus on glioblastoma tumors in which the pathological significance of Tau remains largely unexplored. We will first treat this subject from a mechanistic point of view showing the pivotal role of Tau in oncogenic processes. Then, we will discuss the involvement of Tau in dysregulating critical pathways in glioblastoma. Finally, we will outline promising strategies to target Tau protein for the therapy of glioblastoma.

In chlordecone (CLD)-contaminated soils of the French West Indies, if microbial remediation or a physicochemical remediation process, e.g., in situ chemical reduction, is implemented, concentrations of degradation byproducts, such as hydrochlordecones, are expected to increase in the ecosystems. To study their impact in mixtures with CLD, bioassays were carried out. They consisted in evaluating the regenerative capacity of hydra polyps, from a clone whose phylogenetic analysis confirmed that it belonged to the species Hydra vulgaris Pallas, 1766. Hydra gastric sections were exposed to CLD alone or CLD plus dechlorinated byproducts (CLD-BP) for 96 h to assess regeneration. Based on chromatographic analysis, the CLD-BP mix was composed of the 5-monohydrochlordecone isomer (CAS nomenclature), four dihydrochlordecone isomers, and one trihydrochlordecone isomer representing 50%, 47%, and 3% of the total chromatographic area, respectively. A total of 18 mixtures of CLD and CLD-BP were tested. Six environmental concentrations of CLD (2.10-4 μM to 4.10-2 μM) and a similar range of CLD-BP were used. Results from exposures to CLD alone showed the following: (i) a significant decrease in the regenerative capacity of hydra, except at the lowest concentration (2.10-4 μM); (ii) a concentration-independent deleterious effect. The regeneration scores obtained after the exposure to the addition of CLD-BP were not significantly different from those obtained after exposure to CLD alone. Using an experimental design, a modeling of the regeneration scores of hydra exposed to mixtures is proposed. Interpreted carefully, since they are limited to only one type of bioassay, the present results suggest that the situation in the aquatic environments should not become worse in terms of toxicity, if soil remediation programs resulting in the formation of hydrochlordecones are put in place.

Sunscreen oil-in-water emulsions containing few ingredients and two EU-authorized organic filters had been developed in an eco-friendly approach. Based on their photostability, spectroscopic features, and the lack of data on toxicity, BEMT (UVA/B range; bis-ethylhexyloxyphenol methoxyphenyl triazine) and DHHB (UVA; diethylamino hydroxybenzoylhexyl benzoate) were selected and incorporated at minimal concentrations to reduce the risk of impact on human health and coastal marine ecosystems. Despite the inconclusive results previously reported, the use of the w-soluble and largely available Na-lignosulfonate (LiS) had been reconsidered with success. Since BEMT and DHHB alone or in combination were not able to higher the sun protection factor (SPF) value at 50, results showed that it becomes possible by supplementing with LiS at 5% (w/w), ensuring stability, antiradical property, and a non-toxicity of the sun emulsion. After defining the range doses for the three components, minimizing concentrations was achieved by experimental design studies using a response surface methodology in which SPF values before and after irradiation has been considered. Consequently, an SPF30 and SPF50 emulsions containing only 9 and 12% total filter respectively and 5% LiS each had been developed. This high boosting effect led to discussions on how LiS interacts, suggesting the involvement of J aggregation, the formation of LiS micelles that would partly encapsulate the o-soluble filters, and the mode of adsorption at the solid-liquid interface of the poly(methyl-methacrylate) plate or the skin.

Pyomelanin is a polymer of homogentisic acid synthesized by microorganisms. This work aimed to develop a production process and evaluate the quality of the pigment. Three procedures have been elaborated and optimized, (1) an HGA-Mn 2+ chemical autoxidation (Pyo CHEM yield 0.317 g/g substrate), (2) an induced bacterial culture of Halomonas titanicae through the 4-hydroxyphenylacetic acid-1-hydroxylase route (Pyo BACT , 0.55 g/L), and (3) a process using a recombinant laccase extract with the highest level produced (Pyo ENZ , 1.25 g/g substrate) and all the criteria for a large-scale prototype. The chemical structures had been investigated by 13 C solid-state NMR (CP-MAS) and FTIR. C ar –C ar bindings predominated in the three polymers, C ar –O–C ar (ether) linkages being absent, proposing mainly C 3 -C 6 (α-bindings) and C 4 -C 6 (β-bindings) configurations. This work highlighted a biological decarboxylation by the laccase or bacterial oxidase(s), leading to the partly formation of gentisyl alcohol and gentisaldehyde that are integral parts of the polymer. By comparison, Pyo ENZ exhibited an M w of 5,400 Da, was hyperthermostable, non-cytotoxic even after irradiation, scavenged ROS induced by keratinocytes, and had a highly DPPH-antioxidant and Fe 3+ -reducing activity. As a representative pigment of living cells and an available standard, Pyo ENZ might also be useful for applications in extreme conditions and skin protection.

The biological activities of berberine, a natural plant molecule, are known to be affected by structural modifications, mostly at position 9 and/or 13. A series of new 13-substituted berberine derivatives were synthesized and evaluated in term of antimicrobial activity using various microorganisms associated to human diseases. Contrarily to the original molecule berberine, several derivatives were found strongly active in microbial sensitivity tests against Mycobacterium, Candida albicans and Gram-positive bacteria, including naïve or resistant Bacillus cereus, Staphylococcus aureus and Streptococcus pyogenes with minimal inhibitory concentration (MIC) of 3.12 to 6.25 µM. Among the various Gram-negative strains tested, berberine’s derivatives were only found active on Helicobacter pylori and Vibrio alginolyticus (MIC values of 1.5–3.12 µM). Cytotoxicity assays performed on human cells showed that the antimicrobial berberine derivatives caused low toxicity resulting in good therapeutic index values. In addition, a mechanistic approach demonstrated that, contrarily to already known berberine derivatives causing either membrane permeabilization, DNA fragmentation or interacting with FtsZ protein, active derivatives described in this study act through inhibition of the synthesis of peptidoglycan or RNA. Overall, this study shows that these new berberine derivatives can be considered as potent and safe anti-bacterial agents active on human pathogenic microorganisms, including ones resistant to conventional antibiotics.

Abstract Pyomelanin is a polymer of homogentisic acid synthesized by microorganisms. This work aimed to develop a production process and evaluate the quality of the pigment. Three procedures have been elaborated and optimized, (1) an HGA-Mn2+ chemical autoxidation (PyoCHEM yield 0.317 g/g substrate), (2) an induced bacterial culture of Halomonas titanicae through the 4-hydroxyphenylacetic acid-1-hydroxylase route (PyoBACT, 0.55 g/L), and (3) a process using a recombinant laccase with the highest level produced (PyoENZ, 1.25 g/g substrate) and all the criteria for a large-scale prototype. The chemical structures had been investigated by 13C solid-state NMR (CP-MAS) and FTIR. Car-Car bindings predominated in the three polymers, Car-O-Car (ether) linkages being absent, proposing mainly C3-C6 (β-bindings) and C4-C6 (α-bindings) configurations. This work highlighted a biological decarboxylation by the laccase or bacterial oxidase(s), leading to the partly formation of gentisyl alcohol and gentisaldehyde that are integral parts of the polymer. By comparison, PyoENZ exhibited an Mw of 5,700 Da, was hyperthermostable, non-cytotoxic even after irradiation, scavenged ROS induced by keratinocytes, and had a highly DPPH-antioxidant and Fe3+-reducing activity. As a representative pigment of living cells and an available standard, PyoENZ might also be useful for applications in extreme conditions and skin protection.

Chlordecone (CLD) is an organochlorine pesticide widely used in the past to control pest insects in banana plantations in the French West Indies. Due to its persistence in the environment, CLD has contaminated the soils where it has been spread, as well as the waters, and is still present in them. The objective of our study was to evaluate the effects of chronic exposure to environmentally relevant CLD concentrations in an animal model, the freshwater hydra ( Hydra circumcincta ). In a multi-marker approach, we have studied the expression of some target stress genes, the morphology, and the asexual reproduction rates. Our data showed that exposure to low concentrations of chlordecone leads to (i) a modulation of the expression of target genes involved in oxidative stress, detoxification, and neurobiological processes, and (ii) morphological damages and asexual reproduction impairment. We have observed non-monotonic dose-response curves, which agree with endocrine-disrupting chemical effects. Thus, “U-shaped” dose-response curves were observed for SOD, GRed, Hym355, and potentially GST gene expressions; inverted “U-shaped” curves for GPx and CYP1A gene expressions and reproductive rates; and a biphasic dose-response curve for morphological damages. Therefore, in the range of environmental concentrations tested, very low concentrations of CLD can produce equally or more important deleterious effects than higher ones. Finally, to our knowledge, this study is the first one to fill the lack of knowledge concerning the effects of CLD in Hydra circumcincta and confirms that this diploblastic organism is a pertinent freshwater model in the risk assessment.