Nanomedicine : nanotechnology, biology, and medicine最新文献

Chronic inflammatory diseases are increasing in developed societies, thus new anti-inflammatory approaches are needed in the clinic. Synthetic peptides complexes can be designed to mimic the activity of anti-inflammatory mediators, in order to alleviate inflammation. Here, we evaluated the anti-inflammatory efficacy of tethered peptides mimicking the interleukin-1 receptor antagonist (IL-1Ra) and the heat-shock protein 70 (HSP70). We tested their biocompatibility and anti-inflammatory activity in vitro in primary human monocytes and differentiated macrophages activated with two different stimuli: the TLR agonists (LPS + IFN-γ) or Pam3CSK4. Our results demonstrate that IL-1Ra and HSP70 synthetic peptides present a satisfactory biocompatible profile and significantly inhibit the secretion of several pro-inflammatory cytokines (IL-6, IL-8, IL-1β and TNFα). We further confirmed their anti-inflammatory activity when peptides were coated on a biocompatible material commonly employed in surgical implants. Overall, our findings support the potential use of IL-1Ra and HSP70 synthetic peptides for the treatment of inflammatory conditions.

Myocardial infarction (MI) is a cardiovascular disease and troubles patients all over the world. Exosomes produced after long-term exercise training were discovered to mediate intercellular communication and alleviate MI-induced heart injury. However, the detailed roles of long-term exercise-derived exosomal long noncoding RNAs (LncRNAs) in MI remain uncovered. In this study, we collected and identified long-term exercise-derived exosomes, and established MI or hypoxia/reoxygenation (H/R) model after LncRNA colorectal neoplasia differentially expressed (CRNDE) depletion. This work proved that LncRNA CRNDE was highly expressed in long-term exercise-derived exosomes (p = 0.0078). CRNDE knockdown increased cardiomyocytes apoptosis and oxidative stress (p = 0.0036), and suppressed MI progress (p = 0.0005). CRNDE served as the sponge of miR-489-3p to affect Nrf2 expression (p = 0.0001). MiR-489-3p inhibition effectively reversed the effects of CRNDE depletion on hypoxia cardiomyocytes (p = 0.0002). These findings offered a promising therapeutic option for the treatment of MI.

Rheumatoid arthritis is a chronic inflammatory autoimmune disease caused by alteration of the immune system. Current therapies have several limitations and the use of nanomedicines represents a promising strategy to overcome them. By employing a mouse model of adjuvant induced arthritis, we aimed to evaluate the biodistribution and therapeutic effects of glucocorticoid dexamethasone conjugated to a nanocarrier based on biocompatible N-(2-hydroxypropyl) methacrylamide copolymers. We observed an increased accumulation of dexamethasone polymer nanomedicines in the arthritic mouse paw using non-invasive fluorescent in vivo imaging and confirmed it by the analysis of tissue homogenates. The dexamethasone conjugate exhibited a dose-dependent healing effect on arthritis and an improved therapeutic outcome compared to free dexamethasone. Particularly, significant reduction of accumulation of RA mediator RANKL was observed. Overall, our data suggest that the conjugation of dexamethasone to a polymer nanocarrier by means of stimuli-sensitive spacer is suitable strategy for improving rheumatoid arthritis therapy.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with poor survival rates. Here, we evaluated iron-doped hydroxyapatite (FeHA) as a potential nanomedicine-based approach to combat PDAC. FeHA, in combination with a sublethal dose of the glutathione peroxidase 4 (GPX4) inhibitor RSL3, was found to trigger ferroptosis in KRAS mutant PANC-1 cells, but not in BxPC3 cells, while sparing normal human cells (fibroblasts and peripheral blood mononuclear cells). These findings were recapitulated in 3D spheroids generated using PDAC cells harboring wild-type versus mutant KRAS. Moreover, ferroptosis induction by FeHA plus RSL3 was reversed by the knockdown of STEAP3, a metalloreductase responsible for converting Fe³⁺ to Fe²⁺. Taken together, our data show that FeHA is capable of triggering cancer cell death in a KRAS-selective, STEAP3-dependent manner in PDAC cells.

The emergency of antibiotic-resistant bacteria in severe infections is increasing, especially in nosocomial environments. The ESKAPE group is of special importance in the groups of multi-resistant bacteria due to its high capacity to generate resistance to antibiotics and bactericides. Therefore, metal-based nanomaterials are an attractive alternative to combat them because they have been demonstrated to damage biomolecules in the bacterial cells. However, there is a concern about bacteria developing resistance to NPs and their harmful effects due to environmental accumulation. Therefore, this systematic review aims to report the clinically relevant bacteria that have developed resistance to the NPs. According to the results of this systematic review, various mechanisms to counteract the antimicrobial activity of various NP types have been proposed. These mechanisms can be grouped into the following categories: production of extracellular compounds, metal efflux pumps, ROS response, genetic changes, DNA repair, adaptative morphogenesis, and changes in the plasma membrane.

Primary myelofibrosis (PM) is one of the myeloproliferative neoplasm, where stem cell-derived clonal neoplasms was noticed. Diagnosis of this disease is based on: physical examination, peripheral blood findings, bone marrow morphology, cytogenetics, and molecular markers. However, the molecular marker of PM, which is a mutation in the JAK2V617F gene, was observed also in other myeloproliferative neoplasms such as polycythemia vera and essential thrombocythemia. Therefore, there is a need to find methods that provide a marker unique to PM and allow for higher accuracy of PM diagnosis and consequently the treatment of the disease. Continuing, in this study, we used Raman spectroscopy, Principal Components Analysis (PCA), and Partial Least Squares (PLS) analysis as helpful diagnostic tools for PM. Consequently, we used serum collected from PM patients, which were classified using clinical parameters of PM such as the dynamic international prognostic scoring system (DIPSS) for primary myelofibrosis plus score, the JAK2V617F mutation, spleen size, bone marrow reticulin fibrosis degree and use of hydroxyurea drug features. Raman spectra showed higher amounts of C-H, C-C and C-C/C-N and amide II and lower amounts of amide I and vibrations of CH₃ groups in PM patients than in healthy ones. Furthermore, shifts of amides II and I vibrations in PM patients were noticed. Machine learning methods were used to analyze Raman regions: (i) 800 cm⁻¹ and 1800 cm⁻¹, (ii) 1600 cm⁻¹–1700 cm⁻¹, and (iii) 2700 cm⁻¹–3000 cm⁻¹ showed 100 % accuracy, sensitivity, and specificity. Differences in the spectral dynamic showed that differences in the amide II and amide I regions were the most significant in distinguishing between PM and healthy subjects. Importantly, until now, the efficacy of Raman spectroscopy has not been established in clinical diagnostics of PM disease using the correlation between Raman spectra and PM clinical prognostic scoring. Continuing, our results showed the correlation between Raman signals and bone marrow fibrosis, as well as JAKV617F. Consequently, the results revealed that Raman spectroscopy has a high potential for use in medical laboratory diagnostics to quantify multiple biomarkers simultaneously, especially in the selected Raman regions.

Arterial injury makes the tissue in a state of high oxidative stress. At the same time, abnormal lipid metabolism can further lead to bleeding and thrombosis. Therefore, the anti-inflammatory and anti-oxidant polyphenol, EGCG was organically complexed with Fe³⁺ to form a metal-phenolic framework carrier. And the antihyperlipidemic drug, atorvastatin (ATV) was loaded into the carrier to enhance the bioavailability, and simultaneously alleviate the oxidative stress of the inflammatory site and abnormal lipid metabolism. The results confirmed that the obtained material EGCG-Fe-ATV had good biocompatibility and biosafety effect. In addition, EGCG-Fe-ATV showed outstanding anti-inflammatory, anti-oxidant and lipid-lowering properties. These therapeutic outcomes of EGCG-Fe-ATV were achieved by reducing systemic and local oxidative stress and inflammation, alleviating inflammatory cell infiltration in plaques, and modulating lipid synthesis and transferase to alter cholesterol transport. In conclusion, the combination of metal-phenolic capsules with ATV provides a new strategy for reshaping the oxidative microenvironment of atherosclerosis.

Spinal cord injury is a dramatic disease leading to severe motor, sensitive and autonomic impairments. After injury the axonal regeneration is partly inhibited by the glial scar, acting as a physical and chemical barrier. The scarring process involves microglia, astrocytes and extracellular matrix components, such as collagen, constructing the fibrotic component of the scar. To investigate the role of collagen, we used a multimodal label-free imaging approach combining multiphoton and atomic force microscopy. The second harmonic generation signal exhibited by fibrillar collagen enabled to specifically monitor it as a biomarker of the lesion. An increase in collagen density and the formation of more tortuous fibers over time after injury are observed. Nano-mechanical investigations revealed a noticeable hardening of the injured area, correlated with collagen fibers' formation. These observations indicate the concomitance of important structural and mechanical modifications during the fibrotic scar evolution.

Acid sphingomyelinase deficiency (ASMD) is a severe lipid storage disorder caused by the diminished activity of the acid sphingomyelinase enzyme. ASMD is characterized by the accumulation of sphingomyelin in late endosomes and lysosomes leading to progressive neurological dysfunction and hepatosplenomegaly. Our objective was to investigate the utility of synthetic apolipoprotein A-I (ApoA-I) mimetics designed to act as lipid scavengers for the treatment of ASMD. We determined the lead peptide, 22A, could reduce sphingomyelin accumulation in ASMD patient skin fibroblasts in a dose dependent manner. Intraperitoneal administration of 22A formulated as a synthetic high-density lipoprotein (sHDL) nanodisc mobilized sphingomyelin from peripheral tissues into circulation and improved liver function in a mouse model of ASMD. Together, our data demonstrates that apolipoprotein mimetics could serve as a novel therapeutic strategy for modulating the pathology observed in ASMD.

Carbosilane metallodendrimers, based on the arene Ru(II) complex (CRD13) and integrated to imino-pyridine surface groups have been investigated as an anticancer agent in a mouse model with triple-negative breast cancer. The dendrimer entered into the cells efficiently, and exhibited selective toxicity for 4T1 cells. In vivo investigations proved that a local injection of CRD13 caused a reduction of tumour mass and was non-toxic. ICP analyses indicated that Ru(II) accumulated in all tested tissues with a greater content detected in the tumour.