Publications

Abstract Thymus capitatus is a Mediterranean endemic plant commonly known as Zaitra in northern Morocco. As T. capitatus is widely used in traditional medicine and food, this present work aims to investigate the chemical compositions and biological activities of the T. capitatus leaves essential oil (TcLEO), acetonic (TcLAE), and methanolic extract (TcLME). The spectrophotometric determination demonstrated that T. capitatus is a natural source rich in phenolic contents (TPC) and flavonoid contents (TFC) and that TcLME revealed the highest TPC and TFC than TcLAE and TcLEO. The LC-MS analysis of phenolic compounds showed that paraben acid was predominant in both TcLME and TcLAE, followed by cinnamic acid and p-hydroxybenzoic acid. GC-MS analysis of the TcLEO revealed the presence of a total of 10 compounds, which were predominated by carvacrol. The antioxidant activity by ORAC was observed to be significantly higher in TcLEO and TcLAE than in TcLME. All samples used to assess DNA degradation effectively prevented DNA oxidation and, at the same time, had a prooxidant effect. The genotoxicity test showed that the T. capitatus were devoid of any mutagenic activity. Concerning antifungal activity, all samples were able to inhibit the growth of all microorganisms tested at low concentrations. TcLAE showed higher activity than TcLME, and in general, dermatophytes were more susceptible, being Microsporum canis the most sensitive one. Overall, the results obtained from this study confirm the wide uses of T. capitatus. Furthermore, the finding results suggest that the T. capitatus essential oil and extracts can be highly useful for pharmaceutical industries.

Abstract Parkinson's disease (PD) is an incurable neurodegenerative movement disorder. PD affects 2% of the population above 65 years old; however, with the growing number of senior citizens, PD prevalence is predicted to increase in the following years. Pathologically, PD is characterized by dopaminergic cell neurodegeneration in the substantia nigra, resulting in decreased dopamine levels in the nigrostriatal pathway, triggering motor symptoms. Although the pathological mechanisms leading to PD are still unclear, large evidence indicates that oxidative stress plays an important role, not only because it increases with age which is the most significant risk factor for PD development, but also as a result of alterations in several processes, particularly mitochondria dysfunction. The modulation of oxidative stress, especially using dietary mitochondriotropic antioxidants, represents a promising approach to prevent or treat PD. Although most mitochondria-targeted antioxidants with beneficial effects in PD-associated models have failed to show any therapeutic benefit in clinical trials, several questions remain to be clarified. Hereby, we review the role played by oxidative stress in PD pathogenesis, emphasizing mitochondria as reactive oxygen species (ROS) producers and as targets for oxidative stress-related dysfunctional mechanisms. In addition, we also describe the importance of using dietary-based mitochondria-targeted antioxidants as a valuable strategy to counteract the deleterious effects of ROS in pre-clinical and/or clinical trials of PD, pointing out their significance to slow, and possibly halt, the progression of PD.

Abstract Over the years, literature reported inumerous applications of electrochemical and surface plasmon resonance (SPR) immunoassays for biosensing but, so far, the combination of the two methods in the same sensing spot for analytical purposes is much less explored and discussed. The aim of this Review is to highlight the great potential of electrochemistry combined-SPR (eSPR) as analytical tool for screening chemically and biologically relevant (bio)molecules by combining the unique features of SPR integrated with electrochemical readout.In the first part of the Review, we describe the urgent need of innovative methods for screening clinical biological markers (General Introduction), briefly discuss general concepts of SPR and electrochemical sensing (Concepts behind eSPR biosensors) and highlight the hyphenation of two methods to developed combined biosensing systems (Set-up configuration and eSPR principles). Firstly, we briefly give an overview of the setup for implementation of eSPR technique and discuss some relevant experimental conditions to perform the combined optical and electrochemical measurements. Then, the principles and fundamentals of eSPR biosensors are presented and described. We also present representative examples of eSPR biosensors in the literature (Applications of eSPR biosensors).In the second part, we review studies on how combined electrical and plasmonic detection contributed to the biosensing field, in particular, for the successful screening of clinically relevant biomolecules, namely proteins (Detection of proteins), nucleic acids (Detection of nucleic acids), small size chemical species (Detection of small molecules) and cells (Living-cell Analysis).Finally, we discuss the current limitations of eSPR biosensors performance and suggest possible ways to overcome these limitations (Limitations and optimization) and then we explore aspects about the development of the method and its applications and discuss areas of likely future growth (Conclusions and perspectives). (c) 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Abstract UV-based advanced oxidation processes (AOPs) (UV/H2O2 and UV/S2O82-) with a titanium(IV)-doped carbon dot, TiP-CD, as a catalyst were developed for the decomposition of Remazol Brilliant Blue R (Reactive Blue 19), an anthraquinone textile dye (at T = 25 degrees C and pH = 7). The Ti-CD, with marked catalytic UV properties, was successfully synthesized by the one-pot hydrothermal procedure, using L-cysteine as carbon precursor, ethylenediamine as nitrogen source, PEG (polyethylene glycol) as a capping agent, and titanium(IV) isopropoxide (precursor of TiO2 doping). Contrary to azo dyes (methyl orange, orange II sodium salt, and reactive black 5), which achieved complete degradation in a time interval less than 30 min in the developed AOP systems (UV/H2O2, UV/S2O82-, and UV/TiO2), the RBB-R showed relatively low degradation rates and low discoloration rate constants. In the presence of the catalyzer, the reaction rate significantly increased, and the pseudo-first-order rate constants for the RBB-R discoloration were UV/3.0 mM H2O2/TIP-CD-0.0330 min(-1) and UV/1.02 mM S2O82-/TIP-CD-0.0345 min(-1).

Abstract The absence of disease modifying drugs in Parkinson's disease therapy urges for new chemical entities acting on relevant PD-associated biological targets. As a result, developing selective and reversible inhibitors targeting MAO-B is still a desirable line of therapeutic research. Within this framework, a small library of chromone derivatives was synthesized and screened towards human monoamine oxidases. Structural modifications on the chromone 3-phenylcarboxamide resulted in potent MAO-B inhibitors with an improved drug-like profile, and for the first time we obtained potent and selective chromone 2-phenylcarboxamides acting in the low nanomolar range. Compounds 5-hydroxy-4-oxo-N-phenyl-4H-chromene-3-carboxamide (38) (IC50 = 13.0 nM) and N-(4-chlorophenyl)-5-hydroxy-4-oxo-4H-chromene-3-carboxamide (41) (IC50 = 8.3 nM) stood out as reversible, potent, selective and non-cytotoxic MAO-B inhibitors bearing a favourable drug-like profile. Both compounds displayed cytoprotective effects towards iron(III) oxidative stressor.

Abstract The present work aimed at developing a novel water-in-oleogel emulsion using a mixture of gamma-oryzanol and phytosterols as gelator. The gelator network was severely affected by the presence of water, with single beta-sitosterol crystals being the main contributors to the self-standing ability of the emulsions. X-ray analyses have shown sharp crystallographic reflections for anhydrous and hemihydrated beta-sitosterol crystals, independently of the gelator concentrations and water-in-oleogel ratios. The samples with higher water content have shown additional reflections that could be traced back to monohydrated beta-sitosterol crystals, but these were not present after 7 days. The rheological analysis has revealed the impact of the emulsion composition on their strength. Foreseeing their use for the co-delivery of bioactive compounds, we added beta-carotene and epigallocatechin gallate to the emulsions. We confirmed their viability toward the incorporation of bioactives in their free-form, constituting a proof of concept for the fortification of lipid-rich foods with both oil and water-soluble bioactive compounds.

Abstract A system of dimethyl ester of 3,3 ''''-bisdecyl[2,2 ':5 ',2 '':5 '',2 ''':5 ''',2 '''':5 '''',2 ''''']sexithiophene-5,5 '''''-dicarboxylic acid, with polyethylene oxide, copolymer (ST) and [6,6]phenyl-C61-butyric acid methyl ester (PCBM) is of photochemical interest. A focus is on dynamics within the ST/PCBM donor/acceptor system as a solution and as a film by means of fluorescence spectroscopy, cyclic voltammetry, and atomic force microscopy. ST forms intra-molecular rod-coil aggregates in the solution and terraces of aggregates in the film. ST/PCBM fluorescence spectra from the solution:film result in a spectral red shift of 60 nm and intensity decrease with a ratio of 17:8, respectively. The fluorescence decay times tau(1) increase with increasing PCBM concentration from 17.0 to 25.5 ps and from 5.8 to 19 ps in the solutions and the films, respectively. Interestingly, the decay time tau(2) result for the solutions and for the films to be on average 491 ps and 78 ps, describing the slower and the faster overall process, respectively. HOMO/LUMO levels for ST and PCBM are - 7.27 eV/- 4.42 eV and - 6.68 eV/- 4.43 eV, respectively. Excitation energy transfer between ST and PCBM is observed as radiative quenching and static quenching through the disaggregation of the ST aggregates by PCBM molecules.

Abstract Polypharmacology is a new trend in amyotrophic lateral sclerosis (ALS) therapy and an effective way of addressing a multifactorial etiology involving excitotoxicity, mitochondrial dysfunction, oxidative stress, and microglial activation. Inspired by a reported clinical trial, we converted a riluzole (1)-rasagiline (2) combination into single-molecule multi-target-directed ligands. By a ligand-based approach, the highly structurally integrated hybrids 3-8 were designed and synthesized. Through a target- and phenotypic-based screening pipeline, we identified hit compound 6. It showed monoamine oxidase A (MAO-A) inhibitory activity (IC50 = 6.9 mu M) rationalized by in silico studies as well as in vitro brain permeability. By using neuronal and non-neuronal cell models, including ALS-patient-derived cells, we disclosed for 6 a neuroprotective/neuroinflammatory profile similar to that of the parent compounds and their combination. Furthermore, the unexpected MAO inhibitory activity of 1 (IC50 = 8.7 mu M) might add a piece to the puzzle of its anti-ALS molecular profile.

Abstract Non-alcoholic fatty liver disease (NAFLD) is a health concern affecting 24% of the population worldwide. Although the pathophysiologic mechanisms underlying disease are not fully clarified, mitochondrial dysfunction and oxidative stress are key players in disease progression. Consequently, efforts to develop more efficient pharmacologic strategies targeting mitochondria for NAFLD prevention/treatment are underway. The conjugation of caffeic acid anti-oxidant moiety with an alkyl linker and a triphenylphosphonium cation (TPP+), guided by structure-activity relationships, led to the development of a mitochondria-targeted anti-oxidant (AntiOxCIN(4)) with remarkable anti-oxidant properties. Recently, we described that AntiOxCIN4 improved mitochondrial function, upregulated anti-oxidant defense systems, and cellular quality control mechanisms (mitophagy/autophagy) via activation of the Nrf2/Keap1 pathway, preventing fatty acid-induced cell damage. Despite the data obtained, AntiOxCIN4 effects on cellular and mitochondrial energy metabolism in vivo were not studied. In the present work, we proposed that AntiOxCIN4 (2.5 mg/day/animal) may prevent non-alcoholic fatty liver (NAFL) phenotype development in a C57BL/6J mice fed with 30% high-fat, 30% high-sucrose diet for 16 weeks. HepG2 cells treated with AntiOxCIN4 (100 mu M, 48 h) before the exposure to supraphysiologic free fatty acids (FFAs) (250 mu M, 24 h) were used for complementary studies. AntiOxCIN(4) decreased body (by 43%), liver weight (by 39%), and plasma hepatocyte damage markers in WD-fed mice. Hepatic-related parameters associated with a reduction of fat liver accumulation (by 600%) and the remodeling of fatty acyl chain composition compared with the WD-fed group were improved. Data from human HepG2 cells confirmed that a reduction of lipid droplets size and number can be a result from AntiOxCIN4-induced stimulation of fatty acid oxidation and mitochondrial OXPHOS remodeling. In WD-fed mice, AntiOxCIN(4) also induced a hepatic metabolism remodeling by upregulating mitochondrial OXPHOS, anti-oxidant defense system and phospholipid membrane composition, which is mediated by the PGC-1 alpha-SIRT3 axis. AntiOxCIN4 prevented lipid accumulation-driven autophagic flux impairment, by increasing lysosomal proteolytic capacity. AntiOxCIN(4) improved NAFL phenotype of WD-fed mice, via three main mechanisms: a) increase mitochondrial function (fatty acid oxidation); b) stimulation anti-oxidant defense system (enzymatic and non-enzymatic) and; c) prevent the impairment in autophagy. Together, the findings support the potential use of AntiOxCIN4 in the prevention/treatment of NAFLD.