Evaluation of core-shell Fe3O4@Au nanoparticles as radioenhancer in A549 cell lung cancer model.

In radiotherapy, metallic nanoparticles are of high interest in the fight against cancer for their radiosensitizing effects. This study aimed to evaluate the ability of core-shell Fe3O4@Au nanoparticles to potentiate the irradiation effects on redox-, pro-inflammatory markers, and cell death of A549 human pulmonary cancer cells. The hybrid Fe3O4@Au nanoparticles were synthesized using green chemistry principles by the sonochemistry method. Their characterization by transmission electron microscopy demonstrated an average size of 8 nm and a homogeneous distribution of gold. The decreased hydrodynamic size of these hybrid nanoparticles compared to magnetite (Fe3O4) nanoparticles showed that gold coating significantly reduced the aggregation of Fe3O4 particles. The internalization and accumulation of the Fe3O4@Au nanoparticles within the cells were demonstrated by Prussian Blue staining. The reactive oxygen species (ROS) levels measured by the fluorescent probe DCFH-DA were up-regulated, as well as mRNA expression of SOD, catalase, GPx antioxidant enzymes, redox-dependent transcription factor Nrf2, and ROS-producing enzymes (Nox2 and Nox4), quantified by RT-qPCR. Furthermore, irradiation coupled with Fe3O4@Au nanoparticles increased the expression of canonical pro-inflammatory cytokines and chemokines (TNF-α, IL-1ß, IL-6, CXCL8, and CCL5) assessed by RT-qPCR and ELISA. Hybrid nanoparticles did not potentiate the increased DNA damage detected by immunofluorescence following the irradiation. Nevertheless, Fe3O4@Au caused cellular damage, leading to apoptosis through activation of caspase 3/7, secondary necrosis quantified by LDH release, and cell growth arrest evaluated by clonogenic-like assay. This study demonstrated the potential of Fe3O4@Au nanoparticles to potentiate the radiosensitivity of cancerous cells.

Retrospective study on the toxicity induced by stereotactic body radiotherapy: overview of the reunion experience on prostate cancer in elderly patients.

Introduction: Prostate cancer is the fourth most commonly diagnosed cancer among men worldwide. Various tools are used to manage disease such as conventional radiotherapy. However, it has been demonstrated that large prostate volumes were often associated with higher rates of genitourinary and gastrointestinal toxicities. Currently, the improvements in radiotherapy technology have led to the development of stereotactic body radiotherapy, which delivers higher and much more accurate radiation doses. In order to complete literature data about short-term outcome and short-term toxic effects of stereotactic body radiotherapy, we aimed to share our experience about gastrointestinal and genitourinary toxicities associated with stereotactic body radiotherapy in prostate cancer in patients over 70 years old. Methods: We retrospectively reviewed the medical records of elderly patients with prostate cancer treated between 2021 and 2022. The elderly patients were treated with a non-coplanar robotic stereotactic body radiotherapy platform using real-time tracking of implanted fiducials. The prostate, with or without part of the seminal vesicles, was treated with a total dose of 36.25 Gy delivered in five fractions, each fraction being administered every other day. Results: We analyzed a total of 80 elderly patients, comprising 38 low-, 37 intermediate- and 5 high-risk patients. The median follow-up duration was 12 months. We did not observe biochemical/clinical recurrence, distant metastasis, or death. Grade 2 acute genitourinary toxicity was observed in 9 patients (11.25%) and Grade 2 acute gastrointestinal toxicity in 4 patients (5.0%). We did not observe any grade 3 or more acute or late toxicities. Conclusion: Over the follow-up period, we noted a low frequency of gastrointestinal and genitourinary toxicities induced by stereotactic body radiotherapy in the context of prostate cancer in elderly patients. Therefore, stereotactic body radiotherapy seems to represent a promising treatment option for elderly patients, with acceptable acute toxicity.

The Dual Role of Mesenchymal Stem Cells in Cancer Pathophysiology: Pro-Tumorigenic Effects versus Therapeutic Potential.

Mesenchymal stem/stromal cells (MSCs) are multipotent cells involved in numerous physiological events, including organogenesis, the maintenance of tissue homeostasis, regeneration, or tissue repair. MSCs are increasingly recognized as playing a major, dual, and complex role in cancer pathophysiology through their ability to limit or promote tumor progression. Indeed, these cells are known to interact with the tumor microenvironment, modulate the behavior of tumor cells, influence their functions, and promote distant metastasis formation through the secretion of mediators, the regulation of cell-cell interactions, and the modulation of the immune response. This dynamic network can lead to the establishment of immunoprivileged tissue niches or the formation of new tumors through the proliferation/differentiation of MSCs into cancer-associated fibroblasts as well as cancer stem cells. However, MSCs exhibit also therapeutic effects including anti-tumor, anti-proliferative, anti-inflammatory, or anti-oxidative effects. The therapeutic interest in MSCs is currently growing, mainly due to their ability to selectively migrate and penetrate tumor sites, which would make them relevant as vectors for advanced therapies. Therefore, this review aims to provide an overview of the double-edged sword implications of MSCs in tumor processes. The therapeutic potential of MSCs will be reviewed in melanoma and lung cancers.

Medicinal Plant Polyphenols Attenuate Oxidative Stress and Improve Inflammatory and Vasoactive Markers in Cerebral Endothelial Cells during Hyperglycemic Condition.

Blood-brain barrier endothelial cells are the main targets of diabetes-related hyperglycemia that alters endothelial functions and brain homeostasis. Hyperglycemia-mediated oxidative stress may play a causal role. This study evaluated the protective effects of characterized polyphenol-rich medicinal plant extracts on redox, inflammatory and vasoactive markers on murine bEnd3 cerebral endothelial cells exposed to high glucose concentration. The results show that hyperglycemic condition promoted oxidative stress through increased reactive oxygen species (ROS) levels, deregulated antioxidant superoxide dismutase (SOD) activity, and altered expression of genes encoding Cu/ZnSOD, MnSOD, catalase, glutathione peroxidase (GPx), heme oxygenase-1 (HO-1), NADPH oxidase 4 (Nox4), and nuclear factor erythroid 2-related factor 2 (Nrf2) redox factors. Cell preconditioning with inhibitors of signaling pathways highlights a causal role of nuclear factor kappa B (NFκB), while a protective action of AMP-activated protein kinase (AMPK) on redox changes. The hyperglycemic condition induced a pro-inflammatory response by elevating NFκB gene expression and interleukin-6 (IL-6) secretion, and deregulated the production of endothelin-1 (ET-1), endothelial nitric oxide synthase (eNOS), and nitric oxide (NO) vasoactive markers. Importantly, polyphenolic extracts from Antirhea borbonica, Ayapana triplinervis, Dodonaea viscosa, and Terminalia bentzoe French medicinal plants, counteracted high glucose deleterious effects by exhibiting antioxidant and anti-inflammatory properties. In an innovative way, quercetin, caffeic, chlorogenic and gallic acids identified as predominant plant polyphenols, and six related circulating metabolites were found to exert similar benefits. Collectively, these findings demonstrate polyphenol protective action on cerebral endothelial cells during hyperglycemic condition.

Protective Effects of Antioxidant Polyphenols against Hyperglycemia-Mediated Alterations in Cerebral Endothelial Cells and a Mouse Stroke Model.

SCOPE: Hyperglycemia alters cerebral endothelial cell and blood-brain barrier functions, aggravating cerebrovascular complications such as stroke during diabetes. Redox and inflammatory changes play a causal role. This study evaluates polyphenol protective effects in cerebral endothelial cells and a mouse stroke model during hyperglycemia. METHODS AND RESULTS: Murine bEnd.3 cerebral endothelial cells and a mouse stroke model are exposed to a characterized, polyphenol-rich extract of Antirhea borbonica or its predominant constituent caffeic acid, during hyperglycemia. Polyphenol effects on redox, inflammatory and vasoactive markers, infarct volume, and hemorrhagic transformation are determined. In vitro, polyphenols improve reactive oxygen species levels, Cu/Zn superoxide dismutase activity, and both NAPDH oxidase 4 and nuclear factor erythroid 2-related factor 2 (Nrf2) gene expression deregulated by high glucose. Polyphenols reduce Nrf2 nuclear translocation and counteract nuclear factor-ĸappa B activation, interleukin-6 secretion, and the altered production of vasoactive markers mediated by high glucose. In vivo, polyphenols reduce cerebral infarct volume and hemorrhagic transformation aggravated by hyperglycemia. Polyphenols attenuate redox changes, increase vascular endothelial-Cadherin production, and decrease neuro-inflammation in the infarcted hemisphere. CONCLUSION: Polyphenols protect against hyperglycemia-mediated alterations in cerebral endothelial cells and a mouse stroke model. It is relevant to assess polyphenol benefits to improve cerebrovascular damages during diabetes.

SGLT2 Inhibitor-Induced Sympathoinhibition: A Novel Mechanism for Cardiorenal Protection.

Recent clinical trial data suggest a cardiorenal protective effect of sodium glucose cotransporter 2 (SGLT2) inhibition. We demonstrate that chemical denervation in neurogenic hypertensive Schlager (BPH/2J) mice reduced blood pressure, improved glucose homeostasis, and reduced renal SGLT2 protein expression. Inhibition of SGLT2 prevented weight gain, reduced blood pressure, significantly reduced elevations of tyrosine hydroxylase and norepinephrine, and protects against endothelial dysfunction. These findings provide evidence for significant crosstalk between activation of the sympathetic nervous system and SGLT2 regulation and possible ancillary effects on endothelial function, which may contribute to the observed cardiorenal protective effects of SGLT2 inhibition.

Hyperglycemia modulates redox, inflammatory and vasoactive markers through specific signaling pathways in cerebral endothelial cells: Insights on insulin protective action.

Type 2 diabetes is associated with major vascular dysfunctions, leading to clinical complications such as stroke. It is also known that hyperglycemia dysregulates blood-brain barrier homeostasis by altering cerebral endothelial cell function. Oxidative stress may play a critical role. The aim of this study was to evaluate the effect of hyperglycemia and insulin on the production of redox, inflammatory and vasoactive markers by cerebral endothelial cells. Murine bEnd.3 cerebral endothelial cells were exposed to hyperglycemia in the presence or not of insulin. Results show that hyperglycemia altered the expression of genes encoding the ROS-producing enzyme Nox4, antioxidant enzymes Cu/ZnSOD, catalase and HO-1 as well as Cu/ZnSOD, MnSOD and catalase enzymatic activities, leading to a time-dependent modulation of ROS levels. Cell preconditioning with inhibitors targeting PI3K, JNK, ERK, p38 MAPK or NFĸB signaling molecules partly blocked hyperglycemia-induced oxidative stress. Conversely, AMPK inhibitor exacerbated ROS production, suggesting a protective role of AMPK on the antioxidant defense system. Hyperglycemia also modulated both gene expression and nuclear translocation of the redox-sensitive transcription factor Nrf2. Moreover, hyperglycemia caused a pro-inflammatory response by activating NFĸB-AP-1 pathway and IL-6 secretion. Hyperglycemia reduced eNOS gene expression and NO levels, while increasing ET-1 gene expression. Importantly, insulin counteracted all the deleterious effects of hyperglycemia. Collectively, these results demonstrate that hyperglycemia dysregulated redox, inflammatory and vasoactive markers in cerebral endothelial cells. Insulin exerted a protective action against hyperglycemia effects. Thus, it will be of high interest to evaluate the benefits of antioxidant and anti-inflammatory strategies against hyperglycemia-mediated vascular complications in type 2 diabetes.