Oxidative stress accelerates skin aging by causing damage to DNA, lipids and proteins in skin cells. Exacerbated by environmental factors such as UV rays, pollution and smoking, it leads to loss of elasticity, the appearance of wrinkles, cutaneous dryness, pigmentation spots and a general weakening of the skin's natural defenses. These changes, accumulated over time, are responsible for premature or accelerated aging. Against this backdrop, PAOTScan is an innovative, non-invasive technology for assessing the oxidative state of the skin in real time. The device is based on a patch equipped with microelectrodes and an electrochemical gel. It provides two essential scores: the PAOTScore, which measures the skin's Total Antioxidant Power to neutralize free radicals, and the POTScore (Total Oxidant Power), which quantifies the level of oxidants. These data provide a detailed analysis of the skin's redox balance, enabling early detection of imbalances responsible for premature aging. The PAOTScan not only measures the speed of skin ageing, but also enables prevention and treatment strategies to be adapted. It is therefore an invaluable tool in dermatology and dermato-cosmetics, making it easier to monitor the effectiveness of anti-aging interventions and helping to preserve the skin's health and youthfulness.

Abstract Graphical Abstract Abstract Age-related diseases linked to obesity are often associated with significant oxidative stress. In this context, the antioxidant properties of a polyphenol-rich plant extract (PRPE) were evaluated using complementary biochemical assays and in vivo in the skeletal gastrocnemius muscle of mice treated with PRPE and fed with different diets, i.e. standard (Std) diet or high-fat/high-sucrose (HFHS) diet. We report that PRPE is a potent antioxidant mixture, as shown by its reactive oxygen species (ROS)-scavenging properties using different assays: biological-based KRL (Kit Radicaux Libres, i.e., free radicals kit) and chemical-based assays: DPPH, FRAP, and TEAC. We observed an antioxidant effect in the gastrocnemius muscle from mice fed a high-fat/high-sucrose (HFHS) diet and treated with PRPE: increased antioxidant activities revealed with the KRL assay (expressed in Trolox equivalent), and stimulated expression of genes involved in oxidative stress defense under ROS exposure by RT-qPCR: nuclear respiratory factor 1 (Nrf1), sirtuin 1 (Sirt1), superoxide dismutase 1 (Sod1), and uncoupling protein 2 (Ucp2). These in vivo data, which were lacking until now, are in agreement with earlier results of the in vitro approach reporting significant protective activities of PRPE on the C2C12 skeletal muscle cell line. They confirm the efficacy of the PRPE in the diet of treated animals, especially in skeletal muscle.

Resveratrol (trans-resveratrol, RSV) is a naturally occurring polyphenol that has numerous biological properties, including neuroprotective, anti-inflammatory, and antioxidant effects. However, its effects are concentration-dependent, with both beneficial and detrimental outcomes in different cell types. This study investigates the dose-dependent prooxidant and proapoptotic mechanisms of RSV in murine neuro-2a neuroblastoma cells. We assessed the dose-dependent effects of RSV on cell viability, cytotoxicity, oxidative stress, and apoptosis. At low concentrations (≤6.25 μM), RSV was noncytotoxic, while higher concentrations (12.5 to 30 μM) markedly reduced cell viability and increased lactate dehydrogenase release, indicating cytotoxicity. This cytotoxic threshold was accompanied by a pronounced prooxidant shift, characterized by a dose-dependent increase in reactive oxygen species and nitric oxide, alongside a significant suppression of key antioxidant enzymes (superoxide dismutase, catalase, and peroxidase). Furthermore, high-dose RSV markedly up-regulated the expression of the proapoptotic gene caspase-3 and increased caspase-3 protein levels, as determined by caspase quantification assay. Our findings reveal a complex dose-dependent response, suggesting a threshold at which RSV loses its neuroprotective properties and becomes neurotoxic. A key novel finding was the rapid biotransformation of RSV, as revealed by high-performance liquid chromatography analysis. Resveratrol-3-sulfate was identified as the primary metabolite, detectable as early as 30 min posttreatment, suggesting that active cellular metabolism is associated with RSV bioactivity. This early metabolic conversion has not been previously reported in neuronal cells and may provide a mechanistic link to its concentration-dependent effects. This study highlights that understanding this precise concentration-dependent duality is essential for developing targeted RSV-based therapies for neurodegenerative diseases, where avoiding prooxidant effects is critical, and for neuroblastoma, where exploiting these effects could be therapeutically advantageous.

Breast cancer remains one of the leading causes of cancer-related mortality among women worldwide. Although cisplatin is widely used in chemotherapy, its clinical efficacy is often limited by adverse effects and resistance. Thus, natural bioactive compounds are gaining attention as complementary therapeutic agents. This study aimed to evaluate the anti-tumor effects of Annona muricata leaf extract on murine breast cancer 4T1 cells, used alone or in combination with cisplatin. Cisplatin induced intrinsic apoptosis through mitochondrial membrane disruption, up-regulation of the Bax gene and inhibition of the PI3K/AKT/mTOR signaling pathway. Cisplatin also promoted hypoxia by HIF1α gene expression, inflammation by TNFα and IL-6 gene expression, and induced cell cycle arrest at the sub-G1 phase by down-regulation of cyclin D1 and cyclin E1 genes. Annona muricata leaf extract triggered autophagy-mediated 4T1 cell death through mainly mTOR down-regulation and increased expression of Beclin1 and LC3 genes. It also induced cell cycle arrest at sub-G1 and S phases in a concentration- and time-dependent manner. When, combined with cisplatin, Annona muricata extract shifts the cell death pathway from intrinsic apoptosis toward autophagy by reduced caspase-3 gene expression and activity and enhanced LC3-I to LC3-II conversion. Moreover, Annona muricata extract attenuated cisplatin-induced inflammation by inhibiting TNFα and IL-6 gene expression and reinforced cell cycle arrest through suppression of the cyclin D1 gene. In conclusion, our results suggest that Annona muricata leaf extract exerts significant anti-tumor activity in breast cancer cells and may enhance cisplatin efficacy by shifting the signaling pathway from intrinsic apoptosis toward autophagy, and attenuating inflammation-related effects, supporting its potential use as a complementary therapeutic strategy.

Free radical-mediated cis-trans isomerization of polyunsaturated fatty acids (FA) is well established in food chemistry, yet its occurrence as an endogenous biochemical process in oxidatively stressed human tissues remains poorly characterized. Sarcopenia, a geriatric syndrome defined by progressive loss of skeletal muscle mass and function, is associated with chronic oxidative stress. We hypothesized that this oxidative milieu drives in vivo cis-trans isomerization of erythrocyte membrane FA, generating a trans isomers distinguishable from dietary exposure. A cross-sectional study was conducted in 160 subjects aged ≥65 years, classified as sarcopenic (n=97) or non-sarcopenic (n=63) by SARC-F questionnaire and handgrip strength. Erythrocyte FA profiles were determined by gas chromatography; plasma oxysterols were quantified by GC-MS. Specific trans isomers were markedly elevated in sarcopenic patients, especially C18:1 trans-11 (3.09-fold; p<0.001) and the linoleic acid isomer C18:2 trans-9, cis-12 (2.66-fold; p<0.001). Their cis counterparts were not significantly elevated. By contrast, two trans species that retain the cis-9 configuration, the ruminant dietary marker C18:2 cis-9, trans-11 (CLA) and the geometric isomer C18:2 cis-9, trans-12, were both paradoxically reduced (p=0.007 and p<0.001, respectively). Total trans FA correlated with non-enzymatic oxysterols 7-ketocholesterol (ρ=0.47, p=0.001),7α-hydroxycholesterol (ρ=0.44, p=0.003), and 7β-hydroxycholesterol (ρ=0.50, p<0.001), but not with enzymatically formed 24S-hydroxycholesterol. On multivariate analysis, total trans fatty acids remained independently associated with sarcopenia (OR 1.22; p=0.022). These findings provide the first biochemical evidence that chronic oxidative stress in sarcopenic elderly patients drives endogenous cis-trans isomerization of membrane FA, challenging the notion that elevated trans FA represent a purely dietary phenomenon.

7-Ketocholesterol (7KC) is mainly formed by cholesterol autoxidation and is a pro-oxidant and pro-inflammatory bioactive lipid that also induces different types of cell death, including oxiapoptophagy. It is frequently associated with major age-related diseases, such as cardiovascular diseases, age-related macular degeneration, and Alzheimer's disease. 7KC can therefore be considered a biomarker for these diseases, offering the possibility of developing theranostic strategies combining diagnosis and treatment. Currently, all the elements are in place to develop tools for the design of theranostic therapies targeting 7KC in diseased organs: antibodies, nanoparticles used as nanoplatforms, molecules that neutralize 7KC such as enzymes which degrade it, as well as natural or synthetic compounds that inhibit the cytotoxic signaling pathways associated with oxidative stress, inflammation and cell death activated by 7KC. Identifying and neutralizing 7KC biological activities using a theranostic approach could also be of interest for growing medical fields such as space medicine widely concerned by oxidative stress, aging and age-related diseases, driven by microgravity. This review supports that most of key tools are now available to develop theranostic treatments targeting 7KC in age-related pathologies, especially in cardiovascular diseases associated with atheroma, but also in age-related macular degeneration and Alzheimer's disease. Discovery of effective treatments for these diseases is a major challenge and will answer an important need for both patients and caregivers.

Oxysterols, which are cholesterol oxidation products, can be generated by either enzymatic reactions and/or reactive oxygen species (ROS). Oxysterols considered to play key roles in health and diseases, have several physiological and biological activities. They exhibit strong immune-modulatory, pro-inflammatory and pro-oxidant properties supporting that some of them are involved in the pathogenesis of numerous chronic diseases associated with inflammation mainly cardiovascular and neurological diseases. Some oxysterols, especially those oxidized on the lateral chain, can bind to nuclear receptors such as the liver X receptors (LXR) involved in the control of transcriptional programs that regulate cell metabolism. Since Behçet's disease (BD) is an acute systemic vasculitis leading to severe vascular damage, recent studies deem that BD could be considered a chronic immune inflammatory disease. Although BD constitutes a separate disease entity, it is still underdiagnosed, and no treatments are available. Whereas the pathophysiology of BD is not well known, the vasculitis is common to its different etiologies. Therefore, as several oxysterols are known to contribute to vascular damage, these molecules were analyzed in the plasma of BD patients. Noteworthy, altered oxysterol profiles were observed in BD patients from Tunisia. These patients were characterized by abnormal levels of 7-ketocholesterol (7KC), 25-hydroxycholesterol (25-OHC), 27-hydroxycholesterol (27-OHC), and cholestane-3β,5α,6β-triol (CT). Thus, 7KC and 25-OHC were decreased whereas 27-OHC and CT were increased. Cholesterol undergoes a rapid non enzymatic oxidation to form cholesterol-5α,6α-epoxide and cholesterol-5β,6β-epoxide, and these molecules are then converted by cholesterol 5,6 epoxide hydrolase (ChEH) and/or ROS to CT. In addition, cholestanol level was increased. Therefore, there are evidence of altered oxysterol profiles and cholestanol level in BD patients. It is proposed that oxysterols and cholestanol could be used as biomarkers to characterize BD disease i) to distinguish different forms of this disease and of its outcome, and ii) to identify efficient treatments. Based on the abnormal levels of oxysterols and cholestanol observed in the plasma of BD Tunisian patients, current data support that a rupture of oxysterol homeostasis and perturbations of cholesterol metabolism, suggested by increased cholestanol level, could both contribute to the pathophysiology of Behçet's disease.

BACKGROUND:Climate change has consequences for farming, food diversity and availability, and diet habits. There is now evidence that the Mediterranean climate is rapidly spreading to the Northern European latitudes. OBJECTIVE:This narrative review aims to identify relevant studies related to climate change that could favor the progression of the Mediterranean climate in the northern latitudes of Europe, mainly in France, and to predict what the consequences of these changes on the human diet could be, especially using the concept of the Mediterranean diet, with subsequent impacts on health, farming, and eating habits. METHODS:This narrative review was realized by consulting the PubMed, Scopus, Science Direct, and Google Scholar databases. RESULTS:The key points developed in this review are as follows: investigating the Mediterranean diet as a healthy diet, with evidence supporting health benefits and perspectives; similarities with other places in the world at the same Mediterranean latitudes; climate change and the resulting consequences on plant growth, farming, and food habits; and perspectives on the need for societal adaptations of populations towards agriculture, food, and cooking changes. As climate change facilitates the development of new farming practices with more or fewer environmental impacts, the growth of Mediterranean plants in the highest latitudes of Europe, such as olive trees, pomegranates, and almonds, has already begun for economic reasons. FUTURE PERSPECTIVES:In the near future, besides economic interests, climate change will favor the consumption of several products associated with the Mediterranean diet in the Northern European latitudes. In this context, producers and consumers play major roles.

Based on the consequences of global warming within 50 years from now, we can suppose to see a progression of the Mediterranean climate, in highest latitudes especially in the North-East of France, including Burgundy. The main challenge is to transform this change into an opportunity: adapt plant species (vegetables, trees, herbs, spices), and vineyards to new climates with methods having no or little environmental impacts and no negative consequences on human and animal health. The development of innovative methods of cultures with new socio-economical concepts seems crucial. The following objectives to consider are the advantage of keeping a local production associated with a reduction the carbon footprint (circular economy). The important sociological question is how can we stimulate people to embrace this new health-food approach, and encourage them to adopt it. Some proposals have been recently presented on a round table in Dijon, France on the topic « Which agriculture and food of the mediterranean diet in the next 50 years, in the septentrional area of France. The key points developped in the review are the followings : - climate change and resulting consequences on food habits and plant growth;- impact on plant growth and characteristics ; - the modifications of food habits and consequences on health ; - healthy diet : the cretan or mediterranean diet, benefit proofs and perspectives ; - similarities of world places at the same mediterranean latitudes; - perspectives given by experts from a brain storming; - towards a need of societal adaptations of populations towards agriculture, food and cooking changes.

Arginase plays a crucial role in the urea cycle; it also has immunosuppressive and pro-tumor effects. The present study aimed to assess the effects of arginase inhibition by thymoquinone (2-Isopropyl-5-methyl-1,4-benzoquinone), an active compound of Nigella sativa, on cell death in the MDA-MB-231 triple-negative breast tumor cell line. Cell viability assays, Western blot analysis, and flow cytometry analysis were used to characterize oxidative stress and cell death. Our results showed that inhibition of arginase activity with thymoquinone significantly increased intracellular nitric oxide levels and resulted in overproduction of cellular and mitochondrial reactive oxygen species. Reductions in cell viability, cycle arrest, and increased cell death were also observed. Loss of transmembrane mitochondrial potential, activation of caspase-3, -7, and -9, cleavage of PARP, condensation and/or fragmentation of the nuclei, suggest that this cell death involved apoptosis. Furthermore, a cytoplasm vacuole formation and an increase in the ratio of [LC3-II/LC3-I] suggests a concomitant activation of autophagy with apoptosis. Altogether, the present study highlighted that arginase inhibition with thymoquinone induces a hybrid type of cell death defined as oxiapoptophagy. Thus, arginase inhibition with thymoquinone in the MDA-MB-231 cell line could be, in part, involved in the anticancer effect of thymoquinone.

Oxysterols can be derived from the diet, physiologically produced via specific enzymes, or are generated by autoxidation. These molecules have physiological properties and can also adversely affect vital organs. Indeed, some of them have pro-oxidant and pro-inflammatory activities and can lead to major pathologies. The present review focuses on oxysterols (7-ketocholesterol, 7β-hydroxycholesterol, 25-hydroxycholesterol, 27-hydroxycholesterol, 5,6α-epoxycholesterol, 5,6β-epoxycholesterol, and cholestane-3β, 5α, 6β-triol) involved either in cholesterol metabolism, age-related diseases (such as cardiovascular, neurodegenerative, and eye diseases, e.g., sarcopenia), and inflammatory diseases (especially Behcet’s disease and bowel and lung diseases (e.g., sarcoidosis, COVID-19)). Metabolic pathways associated with oxysterol-induced inflammation are discussed considering the cytokinic TLR4 pathway, non-cytokinic pathways, and the contribution of Ca2+ and K+ channels. Therapeutic approaches targeting oxysterol-induced inflammation either by natural or synthetic molecules are also presented.

Age-related diseases are often associated with a disruption of RedOx balance that can lead to lipid peroxidation with the formation of oxysterols, especially those oxidized on carbon-7: 7-ketocholesterol (also known as 7-oxo-cholesterol) and 7β-hydroxycholesterol. Like cholesterol, these oxysterols have 27 carbons, they are composed of a sterane nucleus and have a hydroxyl function in position 3. The oxysterols 7-ketocholesterol and 7β-hydroxycholesterol are mainly formed by cholesterol autoxidation and are biomarkers of oxidative stress. These two oxysterols are frequently found at increased levels in the biological fluids (plasma, cerebrospinal fluid), tissues and/or organs (arterial wall, retina, brain) of patients with age-related diseases, especially cardiovascular diseases, neurodegenerative diseases (mainly Alzheimer's disease), ocular diseases (cataract, age-related macular degeneration), and sarcopenia. Depending on the cell type considered, 7-ketocholesterol and 7β-hydroxycholesterol induce either caspase- dependent or -independent types of cell death associated with mitochondrial and peroxisomal dysfunctions, autophagy and oxidative stress. The caspase dependent type of cell death associated with oxidative stress and autophagy is defined as oxiapoptophagy. These two oxysterols are also inducers of inflammation. These biological features associated with the toxicity of 7-ketocholesterol, and 7β-hydroxycholesterol are often observed in patients with age-related diseases, suggesting an involvement of these oxysterols in the pathophysiology of these disorders. The cytotoxic effects of 7-ketocholesterol and 7β-hydroxycholesterol are counteracted on different cell models by representative nutrients of the Mediterranean diet: ω3 and ω9 fatty acids, polyphenols, and tocopherols. There are also evidences, mainly in cardiovascular diseases, of the benefits of α-tocopherol and phenolic compounds. These in vitro and in vivo observations on 7-ketocholesterol and 7β-hydroxycholesterol, which are frequently increased in age-related diseases, reinforce the interest of nutritherapeutic treatments to prevent and/or cure age-related diseases currently without effective therapies.

Ethnopharmacological relevance Modern research has increasingly focused on the traditional use of plants for radioprotection. Plant extracts, rich in bioactive compounds, represent promising candidates for mitigating radiation-induced damage. This ethnopharmacological perspective highlights the value of ancestral knowledge in developing complementary therapeutic strategies. Purpose Radiotherapy remains a cornerstone of cancer treatment, yet it is often accompanied by adverse effects that impair patients' quality of life. The search for effective, safe, and natural radioprotective agents is therefore of high importance. Methods Following PRISMA guidelines, a systematic search was conducted using PubMed and Google Scholar for articles published between April 2019 and February 2025. Keywords included “radioprotective potential” AND (“plant extracts” OR “natural radioprotectors” OR “radioprotection”). Only studies reporting experimental or clinical evidence on the radioprotective effects of plant-derived compounds were selected. Results Numerous studies demonstrate that plant-based compounds may protect against ionizing radiation through mechanisms such as reactive oxygen species scavenging, DNA repair, anti-inflammatory activity, and regulation of apoptosis-related pathways. These effects are primarily attributed to secondary metabolites, including polyphenols, vitamins, terpenoids, alkaloids, and glucosinolates. Conclusion This review compiles recent advances on the use of plant-based natural products for radioprotection. These findings encourage further research into phytomedicine as a supportive approach to reduce radiation-induced side effects and improve cancer care.

Peroxisomes have gained increasing attention and are now considered vital players in normal physiological functions. To gain further insight into how peroxisomal defects influence cellular functions, we developed BV-2 microglial models featuring CRISPR/Cas9 gene-edited mutations in peroxisomal Acox1 or Abcd1 and Abcd2 genes. The Acox1−/− BV-2 cell line we generated lacks acyl-CoA oxidase 1, the key enzyme that initiates peroxisomal β-oxidation. In contrast, the double mutant Abcd1/d2−/− BV-2 cell line carries mutations in the genes encoding the membranous ABC transporters ABCD1 and ABCD2, which are responsible for transporting fatty acyl-thioesters inside peroxisome. Here, for the first time, we used analytical fractionation to compare these three genotypes. Through flow cytometry, we observed an increase in cell granularity in these mutant cells, which could be associated with alterations in peroxisome distribution and mitochondrial dynamics. Additionally, the analysis of organelle markers in microglial cells, employing differential centrifugation, exhibited an enrichment of peroxisomes particularly in both L and P fractions of these BV-2 cell line models. The use of an isopycnic Nycodenz density gradient showed that peroxisomes sedimented with a median density of 1.18 g/ml. Notably, our results revealed no significant differences in the distribution profiles of organelles when comparing microglial BV-2 Wt cells with deficient Acox1‒/‒ or Abcd1/d2−/‒ BV-2 cells, which lack peroxisomal fatty acid beta-oxidation. Our study is the first to report on the fractionation of brain-derived microglial cells, laying valuable groundwork for future proteomic and/or metabolomic analyses of peroxisome fractions.

Superparamagnetic iron oxide nanoparticles (SPIONs) are widely used in biomedical applications due to their unique magnetic and physicochemical properties. Surface stabilization and functionalization further expand their applicability in biological environments and help overcome the challenges of achieving targeted therapy. Here, nanodiamonds (NDs) decorated with SPIONs were developed for a dual therapy approach combining magnetic and optical properties: NDs offer excellent properties for optical imaging while SPIONs serve as effective contrast agents. In the present study, amino-PEGylated SPIONs were covalently linked to carboxylated NDs via carbodiimide conjugation, to enhance the colloidal stability of the nanoparticles (NPs) and improve their biocompatibility and stealth properties. The functionalization process was evaluated using various analytical techniques, including TGA, XPS, FTIR, DLS, and zeta potential measurements, which confirmed and validated successful functionalization in each consecutive step. Given that organelle dysfunction plays a critical role in neurodegeneration, and in an effort to specifically target peroxisomes, the serine-lysine-leucine (SKL) peptide was thus anchored on ND-PEG-SPIONs surface with the remaining free amines. To further assess the biological response of these nanohybrids, their colloidal stability was compared in different biological media. Strikingly, based on the in vitro data obtained from BV-2 cells, we demonstrate that the nanoparticles accumulate intracellularly without inducing cell death or mitochondrial dysfunction, a result that fulfills a crucial prerequisite for their future application in targeted therapeutic delivery of antioxidant molecules to peroxisomes. This work thus paves the way for the development of in pexotherapy, opening new avenues for the treatment of neurodegenerative diseases associated with peroxisomal dysfunction.