Ferroptosis-enhanced chemotherapy for triple-negative breast cancer with magnetic composite nanoparticles.

Triple-negative breast cancer (TNBC) causes great suffering to patients because of its heterogeneity, poor prognosis, and chemotherapy resistance. Ferroptosis is characterized by iron-dependent oxidative damage by accumulating intracellular lipid peroxides to lethal levels, and plays a vital role in the treatment of TNBC based on its intrinsic characteristics. To identify the relationship between chemotherapy resistance and ferroptosis in TNBC, we analyzed the single cell RNA-sequencing public dataset of GSE205551. It was found that the expression of Gpx4 in DOX-resistant TNBC cells was significantly higher than that in DOX-sensitive TNBC cells. Based on this finding, we hypothesize that inducing ferroptosis by inhibiting the expression of Gpx4 can reduce the resistance of TNBC to DOX and enhance the therapeutic effect of chemotherapy on TNBC. Herein, dihydroartemisinin (DHA)-loaded polyglutamic acid-stabilized Fe3O4 magnetic nanoparticles (Fe3O4-PGA-DHA) was combined with DOX-loaded polyaspartic acid-stabilized Fe3O4 magnetic nanoparticles (Fe3O4-PASP-DOX) for ferroptosis-enhanced chemotherapy of TNBC. Compared with Fe3O4-PASP-DOX, Fe3O4-PGA-DHA + Fe3O4-PASP-DOX demonstrated significantly stronger cytotoxicity against different TNBC cell lines and achieved significantly more intracellular accumulation of reactive oxygen species and lipid peroxides. Furthermore, transcriptomic analyses demonstrated that Fe3O4-PASP-DOX-induced apoptosis could be enhanced by Fe3O4-PGA-DHA-induced ferroptosis and Fe3O4-PGA-DHA + Fe3O4-PASP-DOX might trigger ferroptosis in MDA-MB-231 cells by inhibiting the PI3K/AKT/mTOR/GPX4 pathway. Fe3O4-PGA-DHA + Fe3O4-PASP-DOX showed superior anti-tumor efficacy on MDA-MB-231 tumor-bearing mice, providing great potential for improving the therapeutic effect of TNBC.

Activatable unsaturated liposomes increase lipid peroxide of cell membrane and inhibit tumor growth.

The cancer chemodynamic therapy based on the Fenton reaction has been attracting more and more attention. However, the performance of the Fenton reaction is restricted by the unsuitable physiological pH value and inadequate H2O2 content in the tumor microenvironment (TME). In this study, we proposed a novel method of inducing lipid peroxide (LPO) of the cancer cell membrane, whose performance is not limited by the pH value and H2O2 in the TME. The activatable LPO-inducing liposomes were constructed by encapsulating Fe3+-containing compound ferric ammonium citrate (FC) in the unsaturated soybean phospholipids (SPC). It was found that the FC could be reduced by the overexpressed glutathione (GSH) in the TME and produce iron redox couple. The Fe3+/Fe2+ mediated the peroxidation of the unsaturated SPC and induced the LPO in the cancer cells. Finally, LPO accumulation led to cancer cell death and tumor growth inhibition. Furthermore, the activatable liposomes did not damage healthy tissues because of the low GSH content in normal tissues and the GSH-triggered activation of the nanocarrier. Together, our findings revealed that FC-SPC-lipo displayed excellent anti-tumor performance and its therapeutic effects are less influenced by the TME, compared with the traditional ferroptosis.

Self-Deliverable Peptide-Mediated and Reactive-Oxygen-Species-Amplified Therapeutic Nanoplatform for Highly Effective Bacterial Inhibition.

An "antibiotic-free strategy" provides a viable option to address bacterial infections, especially for the "superbug" challenge. However, the undesirable antibacterial activity of antibiotic-free agents hinders their practical applications. In this study, we developed a combination antibacterial strategy of coupling peptide-drug therapy with chemodynamic therapy (CDT) to achieve the effective bacterial inhibition. An amphiphilic oligopeptide (LAOOH-OPA) containing a therapeutic unit of D(KLAK)2 peptide and a hydrophobic linoleic acid hydroperoxide (LAHP) was designed. The positively charged D(KLAK)2 peptide with an α-helical conformation enabled rapid binding with microbial cells via electrostatic interaction and subsequent membrane insertion to deactivate the bacterial membrane. When triggered by Fe2+, moreover, LAHP could generate singlet oxygen (1O2) to elicit lipid bilayer leakage for enhanced bacteria inhibition. In vitro assays demonstrated that the combination strategy possessed excellent antimicrobial activity not only merely toward susceptible strains (Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli) but also toward methicillin-resistant Staphylococcus aureus (MRSA). On the mouse skin abscess model induced by S. aureus, self-assembled LAOOH-OPA exhibited a more significant bacteria reduction (1.4 log10 reduction) in the bioburden compared to that of the standard vancomycin (0.9 log10 reduction) without apparent systemic side effects. This combination antibacterial strategy shows great potential for effective bacterial inhibition.

Trojan Horse-Like Nano-AIE Aggregates Based on Homologous Targeting Strategy and Their Photodynamic Therapy in Anticancer Application.

Photodynamic therapy (PDT) has become a promising candidate for cancer theranostics; however, traditional photosensitizers (PSs) usually exhibit weak fluorescence and poor reactive oxygen species (ROS) generation efficiency when aggregated. Recently, aggregation-induced emission (AIE) luminogens have shown great potential in the development of novel PSs owing to their excellent aggregation-induced ROS generation (AIG-ROS) activity. However, there are still concerns that must be addressed. In this study, two near-infrared (NIR) emitters (PI and PTI) are synthesized with AIG-ROS characteristic. PTI exhibit a valuable redder emission with more effective intersystem crossing (ISC) process than PI. The two AIE-active PSs show excellent lipid droplet (LD)-specific targeting ability. The detailed therapeutic mechanism of PDT in LDs specificity is also investigated. The mechanism of oxidation of polyunsaturated fatty acids (PUFAs) in LDs to form toxic lipid peroxides (LPOs) and thereby causing cellular ferroptosis is confirmed first. Homologous targeting is also used to achieve tumor targeting via coating PSs with active cancer cell membranes. Biomimetic aggregates exhibit good targeting ability, and an improved PDT antitumor effect via AIG-ROS activity. These findings offer a clear route to develop advanced PSs with good targeting specificity. A template has also been provided for studying the therapeutic mechanism of AIE-active PSs.

Peroxiredoxin III Protects Tumor Suppressor PTEN from Oxidation by 15-Hydroperoxy-eicosatetraenoic Acid.

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a lipid and protein phosphatase that coordinates various cellular processes. Its activity is regulated by the reversible oxidation of an active-site cysteine residue by H2O2 and thioredoxin. However, the potential role of lipid peroxides in the redox regulation of PTEN remains obscure. To evaluate this, 15-hydroperoxy-eicosatetraenoic acid (15s-HpETE), a lipid peroxide, was employed to investigate its effect on PTEN using molecular and cellular-based assays. Exposure to 15s-HpETE resulted in the oxidation of recombinant PTEN. Reversible oxidation of PTEN was also observed in mouse embryonic fibroblast (MEF) cells treated with a 15s-HpETE and Lipofectamine mixture. The oxidative dimerization of thioredoxin was found simultaneously. In addition, the absence of peroxiredoxin III aggravated 15s-HpETE-induced PTEN oxidation in MEF cells. Our study provides novel insight into the mechanism linking lipid peroxidation to the etiology of tumorigenesis.

Mitochondrial membrane anchored photosensitive nano-device for lipid hydroperoxides burst and inducing ferroptosis to surmount therapy-resistant cancer.

Rationale: Ferroptosis is a regulated process of cell death caused by iron-dependent accumulation of lipid hydroperoxides (LPO). It is sensitive to epithelial-to-mesenchymal transition (EMT) cells, a well-known therapy-resistant state of cancer. Previous studies on nanomaterials did not investigate the immense value of ferroptosis therapy (FT) in epithelial cell carcinoma during EMT. Herein, we describe an EMT-specific nanodevice for a comprehensive FT strategy involving LPO burst. Methods: Mitochondrial membrane anchored oxidation/reduction response and Fenton-Reaction-Accelerable magnetic nanophotosensitizer complex self-assemblies loading sorafenib (CSO-SS-Cy7-Hex/SPION/Srfn) were constructed in this study for LPO produced to overcome the therapy-resistant state of cancer. Both in vitro and in vivo experiments were performed using breast cancer cells to investigate the anti-tumor efficacy of the complex self-assemblies. Results: The nano-device enriched the tumor sites by magnetic targeting of enhanced permeability and retention effects (EPR), which were disassembled by the redox response under high levels of ROS and GSH in FT cells. Superparamagnetic iron oxide nanoparticles (SPION) released Fe2+ and Fe3+ in the acidic environment of lysosomes, and the NIR photosensitizer Cy7-Hex anchored to the mitochondrial membrane, combined sorafenib (Srfn) leading to LPO burst, which was accumulated ~18-fold of treatment group in breast cancer cells. In vivo pharmacodynamic test results showed that this nanodevice with small particle size and high cytotoxicity increased Srfn circulation and shortened the period of epithelial cancer treatment. Conclusion: Ferroptosis therapy had a successful effect on EMT cells. These findings have great potential in the treatment of therapy-resistant epithelial cell carcinomas.

Sequential Intercellular Delivery Nanosystem for Enhancing ROS-Induced Antitumor Therapy.

Despite recent advances in enhancing photodynamic therapy efficacy, high-efficiency reactive oxygen species (ROS)-based therapy approach, especially in malignancy tumor treatment, remains challenging. Relieving the hypoxia of tumor tissue has been considered to be an attractive strategy for enhancing ROS-based treatment effect. Nevertheless, it is frequently neglected that the hypoxic regions are usually located deep in the tumors and therefore are usually inaccessible. To address these limitations, herein we constructed a sequential intercellular delivery system (MFLs/LAOOH@DOX) that consists of a membrane fusion liposomes (MFLs) doped with linoleic acid hydroperoxide (LAOOH) in the lipid bilayer and antitumor doxorubicin (DOX) encapsulated inside. In this report, LAOOH, one of the primary products of lipid peroxidation in vivo, was selected as ROS-generated agent herein, which depends on Fe2+ rather than oxygen and other external stimuli to produce ROS. Upon the enhanced permeation and retention effect, MFLs/LAOOH@DOX first fused with tumor cell membranes in the perivascular region in synchrony with selective delivery of LAOOH into the plasma membrane and the on-demand intracellular release of DOX. By hitchhiking with extracellular vesicles, LAOOH, as a cell membrane natural ingredient, spread gradually to neighboring cells and throughout the entire tumor eventually. Combined with subsequent administration of nano Fe3O4, ROS was specifically generated on the tumor cell membrane by LAOOH throughout the tumor tissues. This study offers a new method to enhance ROS-based antitumor treatment efficiency.

A new approach in the first-line treatment of bacterial and mycotic vulvovaginitis with topical lipohydroperoxides and glycyrrhetic acid: a comparative study.

UNLABELLED: PURPOSE OF INVESTIGATIONS: The aim of this randomized controlled trial was to evaluate efficacy and tolerability of a new association of lipohydroperoxides and glycyrrhetic acid on topical treatment of bacterial and mycotic vulvovaginitis. METHODS: One hundred consecutive patients with bacterial or mycotic vulvovaginitis were randomly assigned to a study group treated with vaginal lipohydroperoxides and a derivative of glycyrrhetic acid for three days (n = 50), and a control group using vaginal antibacterial metronidazole (500 mg) or antimycotic econazole (150 mg) for six days (n = 50). RESULTS: A clinical and microbiological response was achieved in 80.4% and 88.9% in investigational and control group, respectively (p > 0.05). Compared to traditional antimicrobial drugs, the effect appears to be faster and safer, even if not significantly. The 6-month recurrence rate was 7.7% and 5.6% in the investigational and control group, respectively. CONCLUSION: Topical medication based on lipohydroperoxides and glycyrrhetic acid showed a clinical and microbiological efficacy in the first-line treatment of bacterial and mycotic vulvovaginitis, comparable to conventional drugs.

Fabrication and characterization of solid lipid microparticles of ketoprofen

Solid lipid microparticles (SLMs) loaded with ketoprofen were prepared by single emulsion-solvent evaporation method, in which glyceryl monostearate and Tween 80 were employed. The particle size was found to be 99.80±2.1μm. Microparticles observed by scanning electron microscope (SEM) showed spherical shape. The entrapment efficiency (EE %) and drug loading capacity (DL %) were found to be 72.60±1.6 % and 17.98±0.7% respectively. Results of stability evaluation showed relatively long term stability after storage at 4˚C for 3 months. The in-vivo study revealed slightly better per cent inhibition of pain i.e. 74% in comparison with 68% produced by plain drug(AU)

Las micropartículas lipídicas sólidas (MLS) cargadas con ketoprofeno se han preparado a través del método de evaporación del disolvente en emulsión simple, en el que se ha utilizado monoestearato de glicerilo y Tween 80. El tamaño de la partícula ha resultado ser de 99,80±2,1 μm. Las micropartículas observadas a través del microscopio electrónico de barrido (MEB) han mostrado una forma esférica. La eficacia de compresión (EC %) y la capacidad de concentración (CC %) del fármaco han resultado ser de 72,60±1,6% y 17,98±0,7% respectivamente. Los resultados de la evaluación de estabilidad han mostrado una estabilidad relativa a largo plazo después de una conservación a 4˚C durante 3 meses. El estudio in vivo ha revelado un ligero mejor porcentaje de inhibición del dolor, es decir, un 74% en comparación con un 68% producido por un fármaco corriente(AU)

Duración mínima del tratamiento balneario con aguas bicarbonatadas sulfatadas para conseguir un efecto antioxidante en personas mayores de 65 años / Minimum duration of spa treatment with bicarbonated-sulfated waters to obtain an antioxidant effect in persons aged more than 65 years

Introducción: desde que se utilizan los tratamientos balnearios, siempre ha habido la duda sobre el tiempo mínimo necesario para que dicho tratamiento fuera eficaz y efectivo. Forma parte de la tradición balnearia realizar la llamada "la novena", que se corresponde con la duración mínima de 9 días continuados de tratamiento y estancia balnearia para conseguir los efectos beneficiosos de la cura balnearia, hechos que han sido observados durante años. Objetivo: estudiar y evaluar el tiempo mínimo de tratamiento cenoterápico con aguas bicarbonatadas sulfatadas necesario para obtener una disminución estadísticamente significativa de la eliminación de sustancias reactivas al ácido tiobarbitúrico (TBARS) en una población balnearia mayor de 65 años. Pacientes y método: estudio clínico prospectivo realizado en el balneario de aguas bicarbonatadas sulfatadas de Jaraba-Sicilia (Zaragoza) en 3 estaciones climatológicas diferentes del mismo año, con 120 voluntarios del Programa de Termalismo Social del IMSERSO, 60 varones y 60 mujeres (edad media 70,9 ñ 0,5 años); no había diferencias estadísticamente significativas entre la edad de ambos grupos, homogéneos en su conjunto y de muestras pareadas dependientes e igual tamaño. Se obtuvieron muestras de orina para determinar la concentración de TBARS mediante espectrofotometría a la llegada al balneario, a los 9 y a los 14 días de tratamiento; se les realizó una historia clínica completa y se valoraron diferentes variables médicas tras aplicar crenoterapia por vía tópica (baños de 37,5-39 0 C durante 15 min) y/o hidropínica. Las muestras urinarias se analizaron siguiendo una modificación de la técnica descrita en 1978 por Mihara et al. Resultados: la producción urinaria de peroxidación lipídica (TBARS) en orina, principalmente malondialdehído, fue, a la llegada, de 0,368 ñ 0,0095 nM/ml, a los 9 días de tratamiento de 0,352 ñ 0,0088 nM/ml y al finalizar el mismo, tras 14 días de crenoterapia, de 0,337 ñ 0,0083 nM/ml; el beneficio poscrenoterápico obtenido en su estado oxidativo (efecto crenoterápico terapéutico) fue de -0,016 ñ 0,0019 (4,35 por ciento) a los 9 días, el cual se duplicó a los 14 días, con cifras de -0,031 ñ 0,0017 (8,4 por ciento). Esta disminución de los valores de oxidación obtenidos presentó diferencias estadísticamente significativas (p < 0,001) en toda la población estudiada. Conclusión: a partir del noveno día de tratamiento con aguas bicarbonatadas sulfatadas hay evidencias de que el efecto crenoterápico antioxidante comienza a ser eficaz y estadísticamente significativo en la población estudiada, lo que coincide con la mejoría física obtenida. Este efecto crenoterápico se potencia al doble si se prolonga el tratamiento hasta 14 días (AU)

Concentraciones de malondialdehido en un grupo de diabéticos tipo 1 con retinopatía diabética / Malondialdehyde concentrations in a group of type 1 diabetics with diabetic retinopathy

Antecedentes y objetivos: Se realizó un estudio transversal en 70 diabéticos tipo l(35 sin retinopatía diabética (RD) y 35 con RD) con el objetivo de determinar la relación existente entre las concentraciones de malondialdehido (MDA) con la presencia y gravedad de la RD. Material y métodos: A todos los pacientes se les determinó en plasma: glucosa, creatinina, hemoglobina glicosilada (Hb A1), y MDA. También se determinó la excreción urinaria de albúmina (EUA). Resultados: Los niveles de EUA fueron significativamente mayores en los afectados de RD al compararlos con los de los pacientes sin esta complicación (99,1 ñ 129,8 mg/L vs 34,3 ñ 69,8 mg/L. Las concentraciones de MDA fueron significativamente mayores (p<0,01) en los pacientes portadores de RD al compararlos con los que no la tenían (863,4ñ 348,0 nmol/L vs 183,5 ñ 435,0 nmol/L) y significativamente mayores en aquellos con RD proliferativa al compararlos con los valores de los afectados de RD no proliferativa (1196,2 ñ 398,1 nmol/L vs 914,4 ñ 448,2 nmol/L). Conclusiones: comprobamos en nuestro estudio que en los pacientes con DM tipo 1 existe un estrés oxidativo, expresado por concentraciones elevadas de MDA, significativamente mayor en los portadores de RD, el cual se incrementa con la severidad de esta complicación. Los niveles de MDA constituyen un buen marcador del estrés oxidativo en los pacientes portadores de RD. (AU)