The immunotherapy with immune checkpoints inhibitors (ICI) has changed the life expectancy in metastatic melanoma (MM) patients. Nevertheless, several patients do not respond hence, the ...identification and validation of novel biomarkers of response to ICI is of crucial importance. Circulating extracellular vesicles (EVs) such as PD-L1
EV mediate resistance to anti-PD1, instead the role of PD1
EV is not fully understood.
We isolated the circulating EVs from the plasma of an observational cohort study of 71 metastatic melanoma patients and correlated the amount of PD-L1
EVs and PD1
EVs with the response to ICI. The analysis was performed according to the origin of EVs from the tumor and the immune cells. Subsequently, we analysed the data in a validation cohort of 22 MM patients to assess the reliability of identified EV-based biomarkers. Additionally we assessed the involvement of PD1
EVs in the seizure of nivolumab and in the perturbation of immune cells-mediated killing of melanoma spheroids.
The level of PD-L1
EVs released from melanoma and CD8
T cells and that of PD1
EVs irrespective of the cellular origin were higher in non-responders. The Kaplan-Meier curves indicated that higher levels of PD1+ EVs were significantly correlated with poorer progression-free survival (PFS) and overall survival (OS). Significant correlations were found for PD-L1
EVs only when released from melanoma and T cells. The multivariate analysis showed that high level of PD1
EVs, from T cells and B cells, and high level of PD-L1
EVs from melanoma cells, are independent biomarkers of response. The reliability of PD-L1
EVs from melanoma and PD1
EVs from T cells in predicting PFS was confirmed in the validation cohort through the univariate Cox-hazard regression analysis. Moreover we discovered that the circulating EVs captured nivolumab and reduced the T cells trafficking and tumor spheroids killing.
Our study identified circulating PD1
EVs as driver of resistance to anti-PD1, and highlighted that the analysis of single EV population by liquid biopsy is a promising tool to stratify MM patients for immunotherapy.
Bioencapsulation involves the envelopment of bioactive compounds or cells to host and protect them from chemical/physical degradation and biological attack from hazardous species or undesired immune ...responses ...
ZnO@Ag patchy nanostructures were demonstrated to be efficient and stable photocatalysts for the photodegradation of organic contaminants in aqueous solutions. The photoinduced charge transfer from ...the conduction band of ZnO toward the Fermi level of the noble metal was favored and exploited to enhance the photocatalytic efficiency of ZnO, with a mechanism based on hole stabilization. Naked ZnO and ZnO@Ag patchy nanostructures were demonstrated to degrade methylene blue, a model compound, in aqueous solution under 370–800 nm light irradiation (100 mW cm–2); in particular, the introduction of silver nanoparticles allowed one to increment twice the constant rate of the reaction when fitted as pseudo-first-order kinetics. Furthermore, the degradation of 2,4-dichlorophenol under direct sunlight irradiation was studied. The photo-oxidation catalyzed by patchy nanostructures was noticeably increased. In fact, the observed half time (t 1/2) was reduced by almost 4 times in comparison with the value observed for bare ZnO.
Inorganic nanoparticles have great potential for application in many fields, including nanomedicine. Within this class of materials, inorganic nanoheterostructures (NHS) look particularly promising ...as they can be formulated as the combination of different domains; this can lead to nanosystems with different functional properties, which, therefore, can perform different functions at the same time. This review reports on the latest development in the synthesis of advanced NHS for biomedicine and on the tests of their functional properties in in vivo studies. The literature discussed here focuses on the diagnostic and therapeutic applications with special emphasis on cancer. Considering the diagnostics, a description of the NHS for cancer imaging and multimodal imaging is reported; more specifically, NHS for magnetic resonance, computed tomography and luminescence imaging are considered. As for the therapeutics, NHS employed in magnetic hyperthermia or photothermal therapies are reported. Examples of NHS for cancer theranostics are also presented, emphasizing their dual usability in vivo, as imaging and therapeutic tools. Overall, NHS show a great potential for biomedicine application; further studies, however, are necessary regarding the safety associated to their use.
Reactive oxygen and nitrogen species (RONS) are produced endogenously in our body, or introduced through external factors, such as pollution, cigarette smoke, and excessive sunlight exposure. In ...normal conditions, there is a physiological balance between pro-oxidant species and antioxidant molecules that are able to counteract the detrimental effect of the former. Nevertheless, when this homeostasis is disrupted, the resulting oxidative stress can lead to several pathological conditions, from inflammation to cancer and neurodegenerative diseases. In this review, we report on the recent developments of different polymeric formulations that are able to reduce the oxidative stress, from natural extracts, to films and hydrogels, and finally to nanoparticles (NPs).
Subtle adjustment of the activation status of CNS resident microglia and peripheral macrophages, to promote their neuroprotective and neuroregenerative functions, may facilitate research towards ...curing neurodegenerative disorders. In the present study, we investigated whether targeted intracerebral delivery of the anti-inflammatory cytokine interleukin (IL)13, by means of transplanting IL13-expressing mesenchymal stem cells (IL13-MSCs), can promote a phenotypic switch in both microglia and macrophages during the pro-inflammatory phase in a mouse model of ischemic stroke.
We used the CX
CR1
CCR2
transgenic mouse model to separately recognize brain-resident microglia from infiltrated macrophages. Quantitative immunohistochemical analyses were applied to characterize polarization phenotypes of both cell types.
Distinct behaviors of both cell populations were noted dependent on the anatomical site of the lesion. Immunohistochemistry revealed that mice grafted with IL13-MSCs, in contrast to non-grafted and MSC-grafted control mice, were able to drive recruited microglia and macrophages into an alternative activation state, as visualized by a significant increase of Arg-1 and a noticeable decrease of MHC-II expression at day 14 after ischemic stroke. Interestingly, both Arg-1 and MHC-II were expressed more abundantly in macrophages than in microglia, further confirming the distinct behavior of both cell populations.
The current data highlight the importance of controlled and localized delivery of the anti-inflammatory cytokine IL13 for modulation of both microglia and macrophage responses after ischemic stroke, thereby providing pre-clinical rationale for the application of L13-MSCs in future investigations of neurodegenerative disorders.
The increasing drug resistance of infectious microorganisms is considered a primary concern of global health care. The screening and identification of natural compounds with antibacterial properties ...have gained immense popularity in recent times. It has previously been shown that several bioactive compounds derived from marine algae exhibit antibacterial activity. Similarly, polyphenolic compounds are generally known to possess promising antibacterial capacity, among other capacities. Phlorotannins (PTs), an important group of algae-derived polyphenolic compounds, have been considered potent antibacterial agents both as single drug entities and in combination with commercially available antibacterial drugs. In this context, this article reviews the antibacterial properties of polyphenols in brown algae, with particular reference to PTs. Cell death through various molecular modes of action and the specific inhibition of biofilm formation by PTs were the key discussion of this review. The synergy between drugs was also discussed in light of the potential use of PTs as adjuvants in the pharmacological antibacterial treatment.
Monodisperse cubic spinel iron oxide magnetic nanoparticles with variable sizes were prepared following a multi-injection seeded-growth approach. As expected from such a well-known synthetic route, ...all samples were characterized by narrow size distributions, and showed excellent stability in both organic and aqueous media without the presence of aggregates, thus becoming ideal candidates for the study of their hyperthermia performance. Specific Loss Power measurements indicated low heating powers for all samples without a maximum for any specific size, contrary to what theory predicts. The magnetic study showed the formation of size-dependent nonsaturated magnetic regions, which enlarged with the particle size, evidencing a clear discrepancy between the crystal size and the effective magnetic volume. Strain map analysis of high resolution transmission electron micrographs indicated the presence of highly strained crystal areas even if nanoparticles were monocrystalline. The origin of the crystal strain was found to be strictly correlated with the seeded-growth synthetic procedure used for the preparation of the nanoparticles, which turned out to alter their magnetic structure by creating antiphase boundaries. Considering the calculated effective magnetic volumes and their magnetic dispersions in each sample, a reasonable agreement between hyperthermia experiments and theory was obtained.
Abstract A systematic and thorough quantitative analysis of the in vivo effects of inorganic nanoparticles is extremely important for the design of functional nanomaterials for diagnostic and ...therapeutic applications, better understanding of their non-specificity toward tissues and cell types, and for assessments of their toxicity. This study was undertaken to examine the impact of CdTe quantum dots (QDs) on an invertebrate freshwater model organism, Hydra vulgaris , for assessment of long term toxicity effects. The continuous exposure of living polyps to sub-lethal doses of QDs caused time and dose dependent morphological damages more severe than Cd2+ ions at the same concentrations, impaired both reproductive and regenerative capability, activated biochemical and molecular responses. Of remarkable interest, low QD doses, apparently not effective, caused early changes in the expression of general stress responsive and apoptotic genes. The occurrence of subtle genetic variations, in the absence of morphological damages, indicates the importance of genotoxicity studies for nanoparticle risk assessment. The versatility in morphological, cellular, biochemical and molecular responses renders Hydra a perfect model system for high-throughput screening of toxicological and ecotoxicological impact of nanomaterials on human and environmental health.
Over the last few years, much attention has been paid to phytocannabinoids derived from Cannabis for their therapeutic potential. Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) are the most ...abundant compounds of the Cannabis sativa L. plant. Recently, novel phytocannabinoids, such as cannabidibutol (CBDB) and cannabidiphorol (CBDP), have been discovered. These new molecules exhibit the same terpenophenolic core of CBD and differ only for the length of the alkyl side chain. Roles of CBD homologs in physiological and pathological processes are emerging but the exact molecular mechanisms remain to be fully elucidated. Here, we investigated the biological effects of the newly discovered CBDB or CBDP, compared to the well-known natural and synthetic CBD (nat CBD and syn CBD) in human breast carcinoma cells that express CB receptors. In detail, our data demonstrated that the treatment of cells with the novel phytocannabinoids affects cell viability, increases the production of reactive oxygen species (ROS) and activates cellular pathways related to ROS signaling, as already demonstrated for natural CBD. Moreover, we observed that the biological activity is significantly increased upon combining CBD homologs with drugs that inhibit the activity of enzymes involved in the metabolism of endocannabinoids, such as the monoacylglycerol lipase (MAGL) inhibitor, or with drugs that induces the activation of cellular stress pathways, such as the phorbol ester 12-myristate 13-acetate (PMA).
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