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We investigate the extreme X-ray variability of a z = 1.608 active galactic nucleus in the 7 Ms Chandra Deep Field-South (XID 403), which showed two significant X-ray brightening events. In the first event, XID 403 brightened by a factor of >2.5 in ≲6.1 rest-frame days in the observed-frame 0.5–5 keV band. The event lasted for ≈5.0–7.3 days, and then XID 403 dimmed by a factor of >6.0 in ≲6.1 days. After ≈1.1–2.5 yr in the rest frame (including long observational gaps), it brightened again, with the 0.5–5 keV flux increasing by a factor of >12.6. The second event lasted over 251 days, and the source remained bright until the end of the 7 Ms exposure. The spectrum is a steep power law (photon index Γ = 2.8 ± 0.3) without obscuration during the second outburst, and the rest-frame 2–10 keV luminosity reaches ${1.5}_{-0.5}^{+0.8}\times {10}^{43}\,\mathrm{erg}\,{{\rm{s}}}^{-1}$ ; there is no significant spectral evolution within this epoch. The infrared-to-UV spectral energy distribution of XID 403 is dominated by the host galaxy. There is no significant optical/UV variability and R -band (rest-frame ≈2500 Å) brightening contemporaneous with the X-ray brightening. The extreme X-ray variability is likely due to two X-ray unveiling events, where the line of sight to the corona is no longer shielded by high-density gas clumps in a small-scale dust-free absorber. XID 403 is probably a high-redshift analog of local narrow-line Seyfert 1 galaxies, and the X-ray absorber is a powerful accretion disk wind. On the other hand, we cannot exclude the possibility that XID 403 is an unusual candidate for tidal disruption events.

In deep X-ray surveys, active galactic nuclei (AGNs) with a broad range of luminosities have been identified. However, cosmologically distant low-luminosity AGN (LLAGN, erg s−1) identification still poses a challenge because of significant contamination from host galaxies. Based on the 7 Ms Chandra Deep Field-South (CDF-S) survey, the longest-timescale (∼17 years) deep X-ray survey to date, we utilize an X-ray variability selection technique to search for LLAGNs that remain unidentified among the CDF-S X-ray sources. We find 13 variable sources from 110 unclassified CDF-S X-ray sources. Except for one source that could be an ultraluminous X-ray source, the variability of the remaining 12 sources is most likely due to accreting supermassive black holes. These 12 AGN candidates have low intrinsic X-ray luminosities, with a median value of 7 × 1040 erg s−1. They are generally not heavily obscured, with an average effective power-law photon index of 1.8. The fraction of variable AGNs in the CDF-S is independent of X-ray luminosity and is only restricted by the total number of observed net counts, confirming previous findings that X-ray variability is a near-ubiquitous property of AGNs over a wide range of luminosities. There is an anticorrelation between X-ray luminosity and variability amplitude for high-luminosity AGNs, but as the luminosity drops to ≲1042 erg s−1, the variability amplitude no longer appears dependent on the luminosity. The entire observed luminosity–variability trend can be roughly reproduced by an empirical AGN variability model based on a broken power-law power spectral density function. [ABSTRACT FROM AUTHOR]

In the core of the Fornax cluster, on the west side of NGC 1399, we have detected a previously unknown region of intracluster light (ICL). It is made up by several faint ( mag arcsec−2) patches of diffuse light. The bulk of the ICL is located in between the three bright galaxies in the core, NGC 1387, NGC 1379, and NGC 1381, at arcmin (∼58–230 kpc) from the central galaxy NGC 1399. We show that the ICL is the counterpart in the diffuse light of the known over-density in the population of blue globular clusters (GCs). The total g-band luminosity of the ICL is L⊙, which is ∼5% of the total luminosity of NGC 1399. This is consistent with the fraction of the blue GCs in the same region of the cluster. The ICL has mag, which is similar to the colors in the halo of the bright galaxies in the cluster core. The new findings were compared with theoretical predictions for the ICL formation and they support a scenario in which the intracluster population detected in the core of the Fornax cluster is build up by the tidal stripping of material (stars and GCs) from galaxy outskirts in a close passage with the central brightest galaxy (cD). Moreover, the diffuse form of the ICL and its location close to the core of the cluster is expected in a dynamically evolved cluster like Fornax. [ABSTRACT FROM AUTHOR]

We systematically analyze the X-ray variability of active galactic nuclei (AGNs) in the 7 Ms Chandra Deep Field-South survey. On the longest timescale (≈17 years), we find only a weak (if any) dependence of X-ray variability amplitudes on energy bands or obscuration. We use four different power spectral density (PSD) models to fit the anticorrelation between normalized excess variance () and luminosity, and obtain a best-fit power-law index for the low-frequency part of the AGN PSD. We also divide the whole light curves into four epochs in order to inspect the dependence of on these timescales, finding an overall increasing trend. The analysis of these shorter light curves also infers a β of ∼1.3 that is consistent with the above-derived β, which is larger than the frequently assumed value of . We then investigate the evolution of . No definitive conclusion is reached because of limited source statistics, but if present, the observed trend goes in the direction of decreasing AGN variability at fixed luminosity toward high redshifts. We also search for transient events and find six notable candidate events with our considered criteria. Two of them may be a new type of fast transient events, one of which is reported here for the first time. We therefore estimate a rate of fast outbursts and a tidal disruption event (TDE) rate assuming the other four long outbursts to be TDEs. [ABSTRACT FROM AUTHOR]

We perform long-term (≈15 years, observed-frame) X-ray variability analyses of the 68 brightest radio-quiet active galactic nuclei (AGNs) in the 6 Ms Chandra Deep Field-South survey; the majority are in the redshift range of 0.6–3.1, providing access to penetrating rest-frame X-rays up to ≈10–30 keV. Of the 68 sources, 24 are optical spectral type I AGNs, and the rest (44) are type II AGNs. The timescales probed in this work are among the longest for X-ray variability studies of distant AGNs. Photometric analyses reveal widespread photon flux variability: 90% of AGNs are variable above a 95% confidence level, including many X-ray obscured AGNs and several optically classified type II quasars. We characterize the intrinsic X-ray luminosity () and absorption () variability via spectral fitting. Most (74%) sources show variability; the variability amplitudes are generally smaller for quasars. A Compton-thick candidate AGN shows variability of its high-energy X-ray flux, indicating the size of reflecting material to be ≲0.3 pc. variability is also detected in a broad absorption line quasar. The variability amplitude for our sample appears to rise as time separation increases. About 16% of sources show variability. One source transitions from an X-ray unobscured to obscured state, while its optical classification remains type I; this behavior indicates the X-ray eclipsing material is not large enough to obscure the whole broad-line region. [ABSTRACT FROM AUTHOR]

We have started a new, deep multi-imaging survey of the Fornax cluster, dubbed the Fornax Deep Survey (FDS), at the VLT Survey Telescope (VST). In this paper we present the deep photometry inside two square degrees around the bright galaxy NGC 1399 in the core of the cluster. We found that the core of the Fornax cluster is characterized by a very extended and diffuse envelope surrounding the luminous galaxy NGC 1399: we map the surface brightness out to 33 arcmin (∼192 kpc) from the galaxy center and down to μg ∼ 31 mag arcsec−2 in the g band. The deep photometry allows us to detect a faint stellar bridge in the intracluster region on the west side of NGC 1399 and toward NGC 1387. By analyzing the integrated colors of this feature, we argue that it could be due to the ongoing interaction between the two galaxies, where the outer envelope of NGC 1387 on its east side is stripped away. By fitting the light profile, we found that there exists a physical break radius in the total light distribution at R = 10 arcmin (∼58 kpc) that sets the transition region between the bright central galaxy and the outer exponential halo, and that the stellar halo contributes 60% of the total light of the galaxy (Section 3.5). We discuss the main implications of this work on the build-up of the stellar halo at the center of the Fornax cluster. By comparing with the numerical simulations of the stellar halo formation for the most massive bright cluster galaxies (i.e., ), we find that the observed stellar halo mass fraction is consistent with a halo formed through the multiple accretion of progenitors with stellar mass in the range 108–1011M⊙. This might suggest that the halo of NGC 1399 has also gone through a major merging event. The absence of a significant number of luminous stellar streams and tidal tails out to 192 kpc suggests that the epoch of this strong interaction goes back to an early formation epoch. Therefore, different from the Virgo cluster, the extended stellar halo around NGC 1399 is characterized by a more diffuse and well-mixed component, including the intracluster light. [ABSTRACT FROM AUTHOR]

The binding of the potential drug [V IV O(8-HQ) 2 ], where 8-HQ is 8-hydroxyquinolinato, with hen egg white lysozyme (HEWL) was evaluated through spectroscopic (electron paramagnetic resonance, EPR, and UV-visible), spectrometric (electrospray ionization-mass spectrometry, ESI-MS), crystallographic (X-ray diffraction, XRD), and computational (DFT and docking) studies. ESI-MS indicates the interaction of [V IV O(8-HQ)(H 2 O)] + and [V IV O(8-HQ) 2 (H 2 O)] species with HEWL. Room temperature EPR spectra suggest both covalent and non-covalent binding of the two different V-containing fragments. XRD analyses confirm these findings, showing that [V IV O(8-HQ)(H 2 O)] + interacts covalently with the solvent exposed Asp119, while cis-[V IV O(8-HQ) 2 (H 2 O)] non-covalently with Arg128 and Lys96 from a symmetry mate. The covalent binding of [V IV O(8-HQ)(H 2 O)] + to Asp119 is favored by a π-π contact with Trp62 and a H-bond with Asn103 of a symmetry-related molecule. Additionally, the covalent binding of V V O 2 + to Asp48 and non-covalent binding of other V-containing fragments to Arg5, Cys6, and Glu7 are revealed. Molecular docking indicates that, in the absence of the interactions occurring at the protein-protein interface close to Asp119, the covalent binding to Glu35 or Asp52 should be preferred. Such a protein-protein stabilization could be more common than what believed up today, at least in the solid state, and should be considered in the characterization of metal-protein adducts., (© 2024 Wiley-VCH GmbH.)

Metastasis is the main cause of anti-cancer therapy failure, leading to unfavorable prognosis for patients. The true challenge to increase cancer patient life expectancy by making cancer a chronic disease with periodic but manageable relapses relies on the development of efficient therapeutic strategies specifically directed against key targets in the metastatic process. Traditional chemotherapy with classical alkylating agents, microtubule inhibitors, and antimetabolites has demonstrated its limited efficacy against metastatic cells due to their capacity to select chemo-resistant cell populations that undergo epithelial-to-mesenchymal transition (EMT), thus promoting the colonization of distant sites that, in turn, sustain the initial metastatic process. This scenario has prompted efforts aimed at discovering a wide variety of small molecules and biologics as potential anti-metastatic drugs directed against more specific targets known to be involved in the various stages of metastasis. In this short review, we give an overview of the most recent advances related to important families of antimetastatic small molecules: intracellular tyrosine kinase inhibitors, cyclin-dependent kinase inhibitors, KRAS inhibitors, and integrin antagonists. Although the majority of these small molecules are not yet approved and not available in the drug market, any information related to their stage of development could represent a precious and valuable tool to identify new targets in the endless fight against metastasis.

Vanadium complexes (VCs) are promising agents for the treatment, among others, of diabetes and cancer. The development of vanadium-based drugs is mainly limited by a scarce knowledge of the active species in the target organs, which is often determined by the interaction of VCs with biological macromolecules like proteins. Here, we have studied the binding of [V IV O(empp) 2 ] (where Hempp is 1-methyl-2-ethyl-3-hydroxy-4(1 H )-pyridinone), an antidiabetic and anticancer VC, with the model protein hen egg white lysozyme (HEWL) by electrospray ionization-mass spectrometry (ESI-MS), electron paramagnetic resonance (EPR), and X-ray crystallography. ESI-MS and EPR techniques reveal that, in aqueous solution, both the species [V IV O(empp) 2 ] and [V IV O(empp)(H 2 O)] + , derived from the first one upon the loss of a empp(-) ligand, interact with HEWL. Crystallographic data, collected under different experimental conditions, show covalent binding of [V IV O(empp)(H 2 O)] + to the side chain of Asp48, and noncovalent binding of cis -[V IV O(empp) 2 (H 2 O)], [V IV O(empp)(H 2 O)] + , [V IV O(empp)(H 2 O) 2 ] + , and of an unusual trinuclear oxidovanadium(V) complex, [V V 3 O 6 (empp) 3 (H 2 O)], with accessible sites on the protein surface. The possibility of covalent and noncovalent binding with different strength and of interaction with various sites favor the formation of adducts with the multiple binding of vanadium moieties, allowing the transport in blood and cellular fluids of more than one metal-containing species with a possible amplification of the biological effects.

Salicylaldehyde (SA) derivatives are emerging as useful fragments to obtain reversible-covalent inhibitors interacting with the lysine residues of the target protein. Here the SA installation at the C terminus of an integrin-binding cyclopeptide, leading to enhanced ligand affinity for the receptor as well as stronger biological activity in cultured glioblastoma cells is reported., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Developing drug delivery systems to target cytotoxic drugs directly into tumor cells is still a compelling need with regard to reducing side effects and improving the efficacy of cancer chemotherapy. In this work, silk fibroin nanoparticles (SFNs) have been designed to load a previously described cytotoxic compound (NDI-1) that disrupts the cell cycle by specifically interacting with non-canonical secondary structures of DNA. SFNs were then functionalized on their surface with cyclic pentapeptides incorporating the Arg-Gly-Asp sequence ( c RGDs) to provide active targeting toward glioma cell lines that abundantly express ανβ3 and ανβ5 integrin receptors. Cytotoxicity and selective targeting were assessed by in vitro tests on human glioma cell lines U373 (highly-expressing integrin subunits) and D384 cell lines (low-expressing integrin subunits in comparison to U373). SFNs were of nanometric size (d 50 less than 100 nm), round shaped with a smooth surface, and with a negative surface charge; overall, these characteristics made them very likely to be taken up by cells. The active NDI-1 was loaded into SFNs with high encapsulation efficiency and was not released before the internalization and degradation by cells. Functionalization with c RGDs provided selectivity in cell uptake and thus cytotoxicity, with a significantly higher cytotoxic effect of NDI-1 delivered by cRGD-SFNs on U373 cells than on D384 cells. This manuscript provides an in vitro proof-of-concept of c RGD-silk fibroin nanoparticles' active site-specific targeting of tumors, paving the way for further in vivo efficacy tests.

Chlorogenic acids are hydroxycinnamic derivatives widespread in food or food by-products, known for their antioxidant effects and ability to interfere with the formation of advanced glycation end products (AGEs). AGEs are potential glycotoxins involved in age-related disorders, such as diabetes, cardiovascular diseases, and neurological disorders. The ability of chlorogenic acids to inhibit AGE formation under physiological conditions needs further investigation other than the in vitro assays. Therefore, in this study, the capacity of 5-caffeoylquinic acid (5-CQA) to effectively trap methylglyoxal (MGO), an AGE precursor compound also present in daily consumed food, was investigated by evaluating 5-CQA and MGO metabolic fate when subjected to digestion. Two different in vitro digestion approaches (static based on the Infogest protocol and dynamic based on a novel millifluidic gastrointestinal model) were set up and the samples collected at different steps of the static and dynamic processes were analyzed by a validated RP-HPLC-DAD method. The obtained results indicated that the gastrointestinal process strongly affected the 5-CQA capacity to trap MGO and its resulting antiglycation activity. Therefore, preliminary investigation using advanced in vitro tests, particularly dynamic approaches, should always be performed to predict the effect of the digestion process on the potential bioactives present in food, food by-products, or plant extracts.

The interaction with proteins of metal-based drugs plays a crucial role in their transport, mechanism, and activity. For an active ML n complex, where L is the organic carrier, various binding modes (covalent and non-covalent, single or multiple) may occur and several metal moieties (M, ML, ML 2 , etc.) may interact with proteins. In this study, we have evaluated the interaction of [V IV O(malt) 2 ] (bis(maltolato)oxidovanadium(IV) or BMOV, where malt = maltolato, i.e., the common name for 3-hydroxy-2-methyl-4 H -pyran-4-onato) with the model protein hen egg white lysozyme (HEWL) by electrospray ionization mass spectrometry, electron paramagnetic resonance, and X-ray crystallography. The multiple binding of different V-containing isomers and enantiomers to different sites of HEWL is observed. The data indicate both non-covalent binding of cis -[VO(malt) 2 (H 2 O)] and [VO(malt)(H 2 O) 3 ] + and covalent binding of [VO(H 2 O) 3-4 ] 2+ and cis -[VO(malt) 2 ] and other V-containing fragments to the side chains of Glu35, Asp48, Asn65, Asp87, and Asp119 and to the C-terminal carboxylate. Our results suggest that the multiple and variable interactions of potential V IV OL 2 drugs with proteins can help to better understand their solution chemistry and contribute to define the molecular basis of the mechanism of action of these intriguing molecules.

Photodynamic therapy (PDT) has recently attracted interest as an innovative and adjuvant treatment for different cancers including malignant gliomas. Among these, Glioblastoma (GBM) is the most prevalent neoplasm in the central nervous system. Despite conventional therapeutic approaches that include surgical removal, radiation, and chemotherapy, GBM is characterized by an extremely poor prognosis and a high rate of recurrence. PDT is a physical process that induces tumor cell death through the genesis and accumulation of reactive oxygen species (ROS) produced by light energy interaction with a photosensitizing agent. In this contribution, we explored the potentiality of the plant alkaloid berberine (BBR) as a photosensitizing and cytotoxic agent coupled with a PDT scheme using a blue light source in human established astrocytoma cell lines. Our data mainly indicated for the combined BBR-PDT scheme a potent activation of the apoptosis pathway, through a massive ROS production, a great extent of mitochondria depolarization, and the sub-sequent activation of caspases. Altogether, these results demonstrated that BBR is an efficient photosensitizer agent and that its association with PDT may be a potential anticancer strategy for high malignant gliomas.

Extracellular vesicles (EVs), comprising large microvesicles (MVs) and exosomes (EXs), play a key role in intercellular communication, both in physiological and in a wide variety of pathological conditions. However, the education of EV target cells has so far mainly been investigated as a function of EX cargo, while few studies have focused on the characterization of EV surface membrane molecules and the mechanisms that mediate the addressability of specific EVs to different cell types and tissues. Identifying these mechanisms will help fulfill the diagnostic, prognostic, and therapeutic promises fueled by our growing knowledge of EVs. In this review, we first discuss published studies on the presumed EV "delivery code" and on the combinations of the hypothesized EV surface membrane "sender" and "recipient" molecules that may mediate EV targeting in intercellular communication. Then we briefly review the main experimental approaches and techniques, and the bioinformatic tools that can be used to identify and characterize the structure and functional role of EV surface membrane molecules. In the final part, we present innovative techniques and directions for future research that would improve and deepen our understandings of EV-cell targeting.

Glioblastoma multiforme (GBM) is the most lethal primary brain tumor in adults, with an average survival time of about one year from initial diagnosis. In the attempt to overcome the complexity and drawbacks associated with in vivo GBM models, together with the need of developing systems dedicated to screen new potential drugs, considerable efforts have been devoted to the implementation of reliable and affordable in vitro GBM models. Recent findings on GBM molecular features, revealing a high heterogeneity between GBM cells and also between other non-tumor cells belonging to the tumoral niche, have stressed the limitations of the classical 2D cell culture systems. Recently, several novel and innovative 3D cell cultures models for GBM have been proposed and implemented. In this review, we first describe the different populations and their functional role of GBM and niche non-tumor cells that could be used in 3D models. An overview of the current available 3D in vitro systems for modeling GBM, together with their major weaknesses and strengths, is presented. Lastly, we discuss the impact of groundbreaking technologies, such as bioprinting and multi-omics single cell analysis, on the future implementation of 3D in vitro GBM models.

Arg-Gly-Asp (RGD)-based cyclopentapeptides (cRGDs) have a high affinity towards integrin αvβ3 and αvβ5, which are overexpressed by many tumor cells. Here, curcumin-loaded silk fibroin nanoparticles (SFNs) have been functionalized on the surface with cRGD to provide active targeting towards tumor cells; a "click reaction" between the RGD-based cyclopentapeptide carrying an azide group and triple-bond-functionalized nanoparticles has been exploited. Both naked and functionalized SFNs were less than 200 nm in diameter and showed a round-shaped morphology but, after functionalization, SFNs increased in size and protein molecular weight. The functionalization of SFNs' surfaces with cRGD provided active internalization by cells overexpressing integrin receptors. At the lowest concentration tested (0.01 mg/mL), functionalized SFNs showed more effective uptake with respect to the naked by tumor cells that overexpress integrin receptors (but not for non-overexpressing ones). In contrast, at higher concentrations, the non-specific cell membrane protein-particle interactions are promoted and coupled to specific and target mediated uptake. Visual observations by fluorescence microscopy suggested that SFNs bind to integrin receptors on the cell surface and are then internalized by endocytosis. Overall, SFN functionalization provided in vitro active targeting for site-specific delivery of anticancer drugs, boosting activity and sparing healthy organs.

Extracellular vesicles (EVs) are considered as promising nanoparticle theranostic tools in many pathological contexts. The increasing clinical employment of therapeutic nanoparticles is contributing to the development of a new research area related to the design of artificial EVs. To this aim, different approaches have been described to develop mimetic biologically functional nanovescicles. In this paper, we suggest a simplified procedure to generate plasma membrane-derived nanovesicles with the possibility to efficiently encapsulate different drugs during their spontaneously assembly. After physical and molecular characterization by Tunable Resistive Pulse Sensing (TRPS) technology, transmission electron microscopy, and flow cytometry, as a proof of principle, we have loaded into mimetic EVs the isoquinoline alkaloid Berberine chloride and the chemotherapy compounds Temozolomide or Givinostat. We demonstrated the fully functionality of these nanoparticles in drug encapsulation and cell delivery, showing, in particular, a similar cytotoxic effect of direct cell culture administration of the anticancer drugs. In conclusion, we have documented the possibility to easily generate scalable nanovesicles with specific therapeutic cargo modifications useful in different drug delivery contexts., Competing Interests: The authors declare no conflict of interest.

Cancer cells demonstrate elevated expression levels of the inhibitor of apoptosis proteins (IAPs), contributing to tumor cell survival, disease progression, chemo-resistance, and poor prognosis. Smac/DIABLO is a mitochondrial protein that promotes apoptosis by neutralizing members of the IAP family. Herein, we describe the preparation and in vitro validation of a synthetic mimic of Smac/DIABLO, based on fluorescent polyethylene glycol (PEG)-coated silica-core nanoparticles (NPs) carrying a Smac/DIABLO-derived pro-apoptotic peptide and a tumor-homing integrin peptide ligand. At low μM concentration, the NPs showed significant toxicity towards A549, U373, and HeLa cancer cells and modest toxicity towards other integrin-expressing cells, correlated with integrin-mediated cell uptake and consequent highly increased levels of apoptotic activity, without perturbing cells not expressing the α5 integrin subunit.

Metastatic spread is mainly sustained by cancer stem cells (CSC), a subpopulation of cancer cells that displays stemness features. CSC are thought to be derived from cancer cells that undergo epithelial to mesenchymal transition (EMT), thus acquiring resistance to anoikis and anti-cancer drugs. After detachment from the primary tumor mass, CSC reach the blood and lymphatic flow, and disseminate to the target tissue. This process is by nature dynamic and in vitro models are quite far from the in vivo situation. In this study, we have tried to reproduce the adhesion process of CSC to a target tissue by using a 3D dynamic cell culture system. We isolated two populations of 3D tumor spheroids displaying CSC-like features from breast carcinoma (MCF-7) and lung carcinoma (A549) cell lines. Human fibroblasts were layered on a polystyrene scaffold placed in a dynamically perfused millifluidic system and then the adhesion of tumor cell derived from spheroids to fibroblasts was investigated under continuous perfusion. After 24 h of perfusion, we found that spheroid cells tightly adhered to fibroblasts layered on the scaffold, as assessed by a scanning electron microscope (SEM). To further investigate mechanisms involved in spheroid cell adhesion to fibroblasts, we tested the effect of three RGD integrin antagonists with different molecular structures on cell adhesion; when injected into the circuit, only cilengitide was able to inhibit cell adhesion to fibroblasts. Although our model needs further refinements and improvements, we do believe this study could represent a promising approach in improving current models to study metastatic infiltration in vitro and a new tool to screen new potential anti-metastatic molecules.

A C 2 -symmetric bicyclic peptide bearing two RGD motifs was developed as a dimeric ligand, and it displayed enhanced inhibition of ECM protein binding to purified integrin receptors as compared to monomeric RGD analogues. Moreover, the dimeric bicyclic ligand induced cell detachment and inhibited FAK phosphorylation in U-373 MG glioblastoma cells.