Platinum(II) and Copper(II) complexes of asymmetric halogen-substituted [NN'O] ligands: Synthesis, characterization, structural investigations and antiproliferative activity.

In order to better understand the effect of structure, halogen substitution, metal ions and ligand flexibility on antiproliferative activity, eight Cu(II) complexes and eight Pt(II) complexes were obtained of 2,4-X1,X2-6-((pyridine-2-ylmethylamino)methyl)phenol and 2,4-X1,X2-6-((pyridine-2-ylmethylamino)ethyl)phenol (where X is Cl, Br, or I) ligands. The compounds were characterized with various techniques, such as FT-IR, NMR, elemental analysis and single-crystal X-ray diffraction (SCXRD). The X-ray structures showed that ligand acts as a bidentate and tridentate donor in Cu(II) and Pt(II) complexes, respectively. This difference in structures is due to the use or non-use of base in the preparation of complexes. Also, complexation of Cl2-H2L1 with CuCl2·2H2O gives two different types of structures: polymer (Cl2-H2L1-Cupolymer) and dimer (Cl2-H2L1-Cudimer), according to the crystal color. In addition, 1H NMR spectrum for platinum complexes display two set of signals that can be attributed to the presence of two isomers in solution. All complexes induced moderate to high reduction in A2780 and HCT116 cancer cell viability. However, only complexes bearing iodo- substituted in ligands exhibited significantly low cytotoxicity in normal fibroblasts when compared with cancer cell lines. The antiproliferative effect exhibited by I2-H2L2-Cu complex in A2780 cell line was due to induction of cell death mechanisms, namely by apoptosis and autophagy. I2-H2L2-Cu complex does not cause DNA cleavage but a slight delay in cell cycle was observed for the first 24 h of exposition. High cytotoxicity was related with the induction of intracellular ROS. This increase in intracellular ROS was not accompanied by destabilization of the mitochondrial membrane which is an indication that ROS are being triggered externally by I2-H2L2-Cu complex and in agreement with an extrinsic apoptosis activation. I2-H2L2-Cu complex has a pro-angiogenic effect, increasing the vascularization of the CAM in chicken embryos. This is also a very important characteristic in cancer treatment since the increased vascularization in tumors might facilitate the delivery of therapeutic drugs. Taken together, these results support the potential therapeutic of the I2-H2L2-Cu complex.

Vanadium(IV) Complexes with Methyl-Substituted 8-Hydroxyquinolines: Catalytic Potential in the Oxidation of Hydrocarbons and Alcohols with Peroxides and Biological Activity.

Methyl-substituted 8-hydroxyquinolines (Hquin) were successfully used to synthetize five-coordinated oxovanadium(IV) complexes: [VO(2,6-(Me)2-quin)2] (1), [VO(2,5-(Me)2-quin)2] (2) and [VO(2-Me-quin)2] (3). Complexes 1-3 demonstrated high catalytic activity in the oxidation of hydrocarbons with H2O2 in acetonitrile at 50 °C, in the presence of 2-pyrazinecarboxylic acid (PCA) as a cocatalyst. The maximum yield of cyclohexane oxidation products attained was 48%, which is high in the case of the oxidation of saturated hydrocarbons. The reaction leads to the formation of a mixture of cyclohexyl hydroperoxide, cyclohexanol and cyclohexanone. When triphenylphosphine is added, cyclohexyl hydroperoxide is completely converted to cyclohexanol. Consideration of the regio- and bond-selectivity in the oxidation of n-heptane and methylcyclohexane, respectively, indicates that the oxidation proceeds with the participation of free hydroxyl radicals. The complexes show moderate activity in the oxidation of alcohols. Complexes 1 and 2 reduce the viability of colorectal (HCT116) and ovarian (A2780) carcinoma cell lines and of normal dermal fibroblasts without showing a specific selectivity for cancer cell lines. Complex 3 on the other hand, shows a higher cytotoxicity in a colorectal carcinoma cell line (HCT116), a lower cytotoxicity towards normal dermal fibroblasts and no effect in an ovarian carcinoma cell line (order of magnitude HCT116 > fibroblasts > A2780).

Copper(ii) complexes with tridentate halogen-substituted Schiff base ligands: synthesis, crystal structures and investigating the effect of halogenation, leaving groups and ligand flexibility on antiproliferative activities.

To investigate the effect of different halogen substituents and leaving groups and the flexibility of ligands on the anticancer activity of copper complexes, sixteen copper(ii) complexes with eight different tridentate Schiff-base ligands containing pyridine and 3,5-halogen-substituted phenol moieties were synthesized and characterized by spectroscopic methods. Four of these complexes were also characterized by X-ray crystallography. The cytotoxicity of the complexes was determined in three different tumor cell lines (i.e. the A2780 ovarian, HCT116 colorectal and MCF7 breast cancer cell line) and in a normal primary fibroblast cell line. Complexes were demonstrated to induce a higher loss of cell viability in the ovarian carcinoma cell line (A2780) with respect to the other two tumor cell lines, and therefore the biological mechanisms underlying this loss of viability were further investigated. Complexes with ligand L1 (containing a 2-pycolylamine-type motif) were more cytotoxic than complexes with L2 (containing a 2-(2-pyridyl)ethylamine-type motif). The loss of cell viability in A2780 tumor cells was observed in the order Cu(Cl2-L1)NO3 > Cu(Cl2-L1)Cl > Cu(Br2-L1)Cl > Cu(BrCl-L1)Cl. All complexes were able to induce reactive oxygen species (ROS) that could be related to the loss of cell viability. Complexes Cu(BrCl-L1)Cl and Cu(Cl2-L1)NO3 were able to promote A2780 cell apoptosis and autophagy and for complex Cu(BrCl-L1)Cl the increase in apoptosis was due to the intrinsic pathway. Cu(Cl2-L1)Cl and Cu(Br2-L1)Cl complexes lead to cellular detachment allowing to correlate with the results of loss of cell viability. Despite the ability of the Cu(BrCl-L1)Cl complex to induce programmed cell death in A2780 cells, its therapeutic window turned out to be low making the Cu(Cl2-L1)NO3 complex the most promising candidate for additional biological applications.

In Vitro and In Vivo Effect of Palladacycles: Targeting A2780 Ovarian Carcinoma Cells and Modulation of Angiogenesis.

Palladacycles are versatile organometallic compounds that show potential for therapeutic use. Here are described the synthesis and characterization of mono- and dinuclear palladacycles bearing diphosphines. Their biological effect was investigated in A2780, an ovarian-derived cancer line, and in normal dermal fibroblasts. The compounds displayed selective cytotoxicity toward the A2780 cell line. Compound 3 decreased the cell viability through cell cycle retention in G0/G1, triggered apoptosis through the intrinsic pathway, and induced autophagy in A2780 cells. Compound 9 also induced cell cycle retention, apoptosis, and cellular detachment. Notably, compound 9 induced the production of intracellular reactive oxygen species (ROS). Our work demonstrated that compound 3 enters A2780 cells via active transport, which requires energy, while compound 9 enters A2780 cells mostly passively. The potential effect of palladacycles in angiogenesis was investigated for the first time in an in vivo chorioallantoic membrane model, showing that while compound 3 displayed an antiangiogenic effect crucial to fighting cancer progression, compound 9 promoted angiogenesis. These results show that palladacycles may be used in different clinical applications where pro- or antiangiogenic effects may be desirable.

Combined cancer therapeutics-Tackling the complexity of the tumor microenvironment.

Cancer treatment has yet to find a "silver bullet" capable of selectively and effectively kill tumor cells without damaging healthy cells. Nanomedicine is a promising field that can combine several moieties in one system to produce a multifaceted nanoplatform. The tumor microenvironment (TME) is considered responsible for the ineffectiveness of cancer therapeutics and the difficulty in the translation from the bench to bed side of novel nanomedicines. A promising approach is the use of combinatorial therapies targeting the TME with the use of stimuli-responsive nanomaterials which would increase tumor targeting. Contemporary combined strategies for TME-targeting nanoformulations are based on the application of external stimuli therapies, such as photothermy, hyperthermia or ultrasounds, in combination with stimuli-responsive nanoparticles containing a core, usually composed by metal oxides or graphene, and a biocompatible stimuli-responsive coating layer that could also contain tumor targeting moieties and a chemotherapeutic agent to enhance the therapeutic efficacy. The obstacles that nanotherapeutics must overcome in the TME to accomplish an effective therapeutic cargo delivery and the proposed strategies for improved nanotherapeutics will be reviewed. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Emerging Technologies.

Rosa x hybrida extracts with dual actions: Antiproliferative effects against tumour cells and inhibitor of Alzheimer disease.

Edible flowers are being used as a new ingredient in modern gastronomy. Recently, these products have also gained interest as an important source of phenolic compounds with potential for biomedical applications. The present work studied a methanolic extract of Rosa x hybrida in which 35 individual phenolic compounds were identified. The extract has been evaluated for its antiproliferative properties in ovarian carcinoma cells. Results showed that the antiproliferative effect was associated with the induction of autophagy and apoptosis with the concomitant ROS increase probably related to mitochondria dysfunction. These antiproliferative effects might be associated with some components of the extract such as quercetin. The extract did not induce damage in healthy cells and that it was able to improve the wound healing activity. The present study also evaluated the properties of the mentioned extract in vivo in C. elegans. Tests demonstrated a lack of toxicity in the worm model. Promising results have been obtained in transgenic strains of C. elegans that produce human beta amyloid peptide, suggesting the possible utility of the extract from the point of view of Alzheimer disease. Altogether, results suggest that Rosa x hybrida extracts could be a new tool for the development of functional foods.

Exploiting the antiproliferative potential of spiropyrazoline oxindoles in a human ovarian cancer cell line.

Cancer is still one of the deadliest diseases worldwide despite the efforts in its early detection and treatment strategies. However, most chemotherapeutic agents still present side effects in normal tissues and acquired resistance that limit their efficacy. Spiropyrazoline oxindoles might be good alternatives as they have shown antiproliferative activity in human breast and colon cancer cell lines, without eliciting cytotoxicity in healthy cells. However, their potential for ovarian cancer was never tested. In this work, the antiproliferative activity of five spiropyrazoline oxindoles was assessed in ovarian cancer cells A2780 and the biological targets and mechanism of action of the most promising compound evaluated. Compound 1a showed the highest antiproliferative effect, as well as the highest selectivity for A2780 cells compared to healthy fibroblasts. This antiproliferative effect results from the induction of cell death by mitochondria-mediated apoptosis and autophagy. In vitro DNA interaction studies demonstrated that 1a interacts with DNA by groove-binding, without triggering genotoxicity. In addition, 1a showed a strong affinity to bovine serum albumin that might be important for further inclusion in drug delivery platforms. Proteomic studies reinforced 1a role in promoting A2780 endoplasmatic reticulum (ER) stress by destabilizing the correct protein folding which triggers cell death via apoptosis and autophagy.

In vitro antiproliferative effect of vanadium complexes bearing 8-hydroxyquinoline-based ligands - the substituent effect.

This is the first comprehensive study demonstrating the antiproliferative effect of vanadium complexes bearing 8-hydroxyquinoline (quinH) ligands, including the parent and -CH3 (Me), -NO2, -Cl and -I substituted ligands, on HCT116 and A2780 cancer cell lines. To determine the structure-cytotoxicity relationships seven six-coordinate oxovanadium(v) complexes [VO(OMe)(5,7-(Me)2-quin)2] (1), [VO(OMe)(5,7-Cl2-quin)2] (2), [VO(OMe)(5,7-Cl,I-quin)2] (3), [VO(OMe)(5,7-I2-quin)2] (4), [VO(OMe)(5-NO2-quin)2] (5), [VO(OMe)(5-Cl-quin)2] (6), and [VO(OMe)(quin)2] (7) were investigated. The cytotoxicity of 8-hydroxyquinoline oxovanadium(v) complexes is higher in the A2780 cell line (lower IC50) than that observed for the widely used chemotherapeutic agent, cisplatin, while displaying low cytotoxicity for normal human primary fibroblasts. Substituents introduced into the 8-hydroxyquinoline backbone reduced the antiproliferative effect of the vanadium complexes, and the complexes with the ligand substituted only in the 5 position (5 and 6) were more cytotoxic than those with substituents in the 5,7 positions of the quin backbone (1-4). Depending on the substituent type, the cytotoxicity of 1-4 followed the trend: -Cl > -CH3 > -I. Incubation of A2780 cancer cells with IC50 concentrations of complexes 5, 6 and 7 promoted cellular detachment, possibly through membrane destabilization, and triggered apoptosis and necrosis. ROS production might be responsible for the cell death mechanism observed particularly in the A2780 cells exposed to complexes 5 and 6.

Antiproliferative Activities of Diimine-Based Mixed Ligand Copper(II) Complexes.

A series of Cu(diimine)(X-sal)(NO3) complexes, where the diimine is either 2,2'-bipyridine (bpy) or 1,10-phenanthroline (phen) and X-sal is a monoanionic halogenated salicylaldehyde (X = Cl, Br, I, or H), have been synthesized and characterized by elemental analysis and X-ray crystallography. Penta-coordinate geometries copper(II) were observed for all cases. The influence of the diimine coligands and different halogen atoms on the antiproliferative activities toward human cancer cell lines have been investigated. All Cu(II) complexes were able to induce a loss of A2780 ovarian carcinoma cell viability, with phen derivatives more active than bpy derivatives. In contrast, no in vitro antiproliferative effects were observed against the HCT116 colorectal cancer cell line. These cytotoxicity differences were not due to a different intracellular concentration of the complexes determined by inductively coupled plasma atomic emission spectroscopy. A small effect of different halogen substituents on the phenolic ring was observed, with X = Cl being the most highly active toward A2780 cells among the phen derivatives, while X = Br presented the lowest IC50 in A2780 cells for bpy analogs. Importantly, no reduction in normal primary fibroblasts cell viability was observed in the presence of bpy derivatives (IC50 > 40 µM). Mechanistically, complex 1 seems to induce a stronger apoptotic response with a higher increase in mitochondrial membrane depolarization and an increased level of intracellular reactive oxygen species (ROS) compared to complex 3. Together, these data and the low IC50 compared to cisplatin in A2780 ovarian carcinoma cell line demonstrate the potential of these bpy derivatives for further in vivo studies.

Improving the Anti-inflammatory Response via Gold Nanoparticle Vectorization of CO-Releasing Molecules.

CO-releasing molecules (CORMs) have been widely studied for their anti-inflammatory, antiapoptotic, and antiproliferative effects. CORM-3 is a water-soluble Ru-based metal carbonyl complex, which metallates serum proteins and readily releases CO in biological media. In this work, we evaluated the anti-inflammatory and wound-healing effects of gold nanoparticles-CORM-3 conjugates, AuNPs@PEG@BSA·Ru(CO)x, exploring its use as an efficient CO carrier. Our results suggest that the nanoformulation was capable of inducing a more pronounced cell effect, at the anti-inflammatory level and a faster tissue repair, probably derived from a rapid cell uptake of the nanoformulation that results in the increase of CO inside the cell.

Zn(II) and Co(II) derivatives anchored with scorpionate precursor: Antiproliferative evaluation in human cancer cell lines.

A 'scorpionate' type precursor [bdtbpza = bis(3,5-di-t-butylpyrazol-1-yl)acetate] has been employed to synthesize two mononuclear ZnII and CoII derivatives, namely [Zn(bdtbpza)2 (H2O)2]·2.5CH3OH·2[(CH3)3C-C3H2N2-C(CH3)3] (1) and [Co(bdtbpza)2(CH3OH)4] (2) in good yield. Single crystal X-ray diffraction analysis reveals that in 1, the ZnII atom is tetrahedrally surrounded by a pair of Oacetate atoms of two bis(pyrazol-1-yl)acetate units and two water molecules; while in 2, the CoII atom shows an octahedral environment coordinating a pair of Oacetate atoms of two bis(pyrazol-1-yl)acetate units along with four methanol molecules. The EPR spectra of 2 recorded at 77 and 298 K confirmed the tetragonal symmetry of the high spin Co(II). The DFT (Density functional theory) computation is in good agreement with the geometry proposed for compounds 1 and 2. Both the compounds display a high antiproliferative activity against HCT116 (colorectal carcinoma) and A2780 (ovarian carcinoma) cell lines compared to human normal dermal fibroblasts. In the case of A2780 cells, compounds 1 and 2 exhibit IC50 values that are similar to those described for cisplatin, a widely used chemotherapeutic drug. Exposure of A2780 cells to the IC50 concentration of each compound led to an increase of the number of apoptotic and autophagic cells. In the case of compound 1, the accumulation of intracellular ROS (Reactive oxygen species) is responsible for triggering A2780 cell death.

Antiproliferative activity of heterometallic sodium and potassium-dioxidovanadium(V) polymers.

The syntheses of the heterometallic sodium and potassium-dioxidovanadium 2D polymers, [NaVO2(1κNOO';2κO"-L)(H2O)]n(1) and [KVO2(1κNOO';2κO';3κO"-L)(EtOH)]n(2) (where the κ notation indicates the coordinating atoms of the polydentate ligand L) derived from (3,5-di-tert-butyl-2-hydroxybenzylidene)-2-hydroxybenzohydrazide (H2L) are reported. The polymers were characterized by IR, NMR, elemental analysis and single crystal X-ray diffraction analysis. The antiproliferative potential of 1 and 2 was examined towards four human cancer cell lines (ovarian carcinoma, A2780, colorectal carcinoma, HCT116, prostate carcinoma, PC3 and breast adenocarcinoma, MCF-7cell lines) and normal human fibroblasts. Complex 1 and 2 showed the highest cytotoxic activity against A2780 cell line (IC50 8.2 and 11.3 µM, respectively) with 1 > 2 and an IC50 in the same range as cisplatin (IC50 3.4 µM; obtained in the same experimental conditions) but, interestingly, with no cytotoxicity to healthy human fibroblasts for concentrations up to 75 µM. This high cytotoxicity of 1 in ovarian cancer cells and its low cytotoxicity in healthy cells demonstrates its potential for further biological studies. Our results suggest that both complexes induce ovarian carcinoma cell death via apoptosis and autophagy, but autophagy is the main biological cause of the reduction of viability observed and that ROS (reactive oxygen species) may play an important role in triggering cell death.

Copper(ii) complexes with 2,2':6',2''-terpyridine, 2,6-di(thiazol-2-yl)pyridine and 2,6-di(pyrazin-2-yl)pyridine substituted with quinolines. Synthesis, structure, antiproliferative activity, and catalytic activity in the oxidation of alkanes and alcohols with peroxides.

A series of 2,2':6',2''-terpyridine (terpy), 2,6-di(thiazol-2-yl)pyridine (dtpy) and 2,6-di(pyrazin-2-yl)pyridine (dppy) derivatives with n-quinolyl substituents (n = 2 and 4) was used to synthesize five-coordinate complexes [CuCl2(n-quinolyl-terpy)] (1-2), [CuCl2(n-quinolyl-dtpy)] (3-4) and [CuCl2(n-quinolyl-dppy)] (5-6), respectively. The main emphasis of the research was to investigate the impact of the triimine skeleton (terpy, dtpy and dppy) and n-quinolyl pendant substituent on the antiproliferative and catalytic properties of 1-6. The obtained Cu(ii) compounds were studied as antiproliferative agents against human colorectal (HCT116) and ovarian (A2780) carcinoma, and they were used as catalysts for the oxidation of alkanes and alcohols with peroxides under mild conditions. The kinetic characteristics of the oxidizing species generated by the catalytic system Cu(ii) complex-H2O2 in CH3CN were obtained from the dependence of the alkane oxidation rate on its initial concentration. A model of competitive interaction of hydroxyl radicals with CH3CN and RH in the catalyst cavity has been proposed which is based on the simultaneous study of kinetics and selectivity in alkane oxidations.

Platinum(ii) complexes showing high cytotoxicity toward A2780 ovarian carcinoma cells.

2,6-Bis(thiazol-2-yl)pyridines functionalized with 9-anthryl (L1), 9-phenanthryl (L2), and 1-pyrenyl (L3) groups were used for the preparation of [Pt(Ln)Cl]CF3SO3 (1-3). The constitution of the Pt(ii) complexes was determined by 1H and 13C NMR spectroscopy, HR-MS spectrometry, elemental analysis and X-ray analysis (for (1)). The electrochemical and photophysical properties of [Pt(Ln)Cl]CF3SO3 were compared with the behaviour of the Pt(ii) complexes with aryl-substituted 2,2':6',2''-terpyridine ligands. What is noteworthy is that the coordination ability of dtpy toward the Pt(ii) centre was investigated for the first time. All complexes were tested in vitro by MTS assay on four tumor cell lines, A2780 (ovarian carcinoma), HTC116 (colon rectal carcinoma), MCF7 (breast adenocarcinoma), and PC3 (prostate carcinoma) and on normal primary fibroblasts. Compounds (1-3) showed a dose dependent antiproliferative effect in the A2780 cell line with (3) > (2) > (1) and this loss of A2780 cell viability was due to a combination of an apoptotic cell death mechanism via mitochondria and autophagic cell death. Exposure to IC50 concentration of (2) induced an increase in the number of apoptotic nuclei and a depolarization of the mitochondrial membrane which is consistent with the induction of apoptosis while exposure to IC50 concentration of (3) showed an increase in the apoptotic nuclei with a slight hyperpolarization of the mitochondrial membrane that might indicate an initial step of apoptosis induction. The complexes (2) and (3) induce an increase in the production of intracellular ROS which is associated with the trigger of the apoptotic pathways. The ROS production was augmented by the presence of oxidants and correlated with an increase of oxygen radicals. The IC50 of (2) and (3) (4.4 µM and 2.9 µM, respectively) was similar to the IC50 of cisplatin (3.4 µM) in the A2780 cell line, which together with their low cytotoxicity in normal fibroblasts, demonstrates their potential for further studies.

Enhancement of water solubility of poorly water-soluble drugs by new biocompatible N-acetyl amino acid N-alkyl cholinium-based ionic liquids.

The major challenge of the pharmaceutical industry is to find potential solvents for poorly water-soluble drug molecules. Ionic liquids (ILs) have attracted this industry as (co-) solvents due to their unique physicochemical and biological properties. Herein, a straightforward approach for the enhancement of the water solubility of paracetamol and sodium diclofenac is presented, using new biocompatible N-acetyl amino acid N-alkyl cholinium-based ionic liquids as co-solvents (0.2-1 mol%). These new ionic liquids were able to increase the water solubility of these drugs up to four times that in pure water or in an inorganic salt solution. In the presence of these ILs, the drugs lipophilicity (log P was not significantly changed for paracetamol, but for sodium diclofenac it was possible to decrease significantly its lipophilicity. Concerning cytotoxicity in human dermal fibroblasts it was observed that ILs did not show a significant toxicity, and were able to improve cell viability compared with the respective precursors.

Ionic Liquids and Salts from Ibuprofen as Promising Innovative Formulations of an Old Drug.

Herein we report the synthesis of novel ionic liquids (ILs) and organic salts by combining ibuprofen as anion with ammonium, imidazolium, or pyridinium cations. The methodology consists of an acid-base reaction of neutral ibuprofen with cation hydroxides, which were previously prepared by anion exchange from the corresponding halide salts with Amberlyst A-26(OH). In comparison with the parent drug, these organic salts display higher solubility in water and biological fluids and a smaller degree of polymorphism, which in some cases was completely eliminated. With the exception of [C16 Pyr][Ibu] and [N1,1,2,2OH1 ][Ibu], the prepared salts did not affect the viability of normal human dermal fibroblasts or ovarian carcinoma (A2780) cells. Therefore, these ibuprofen-based ionic liquids may be very promising lead candidates for the development of effective formulations of this drug.

Streptococcus dysgalactiae subsp. dysgalactiae isolated from milk of the bovine udder as emerging pathogens: In vitro and in vivo infection of human cells and zebrafish as biological models.

Streptococcus dysgalactiae subsp. dysgalactiae (SDSD) is a major cause of bovine mastitis and has been regarded as an animal-restricted pathogen, although rare infections have been described in humans. Previous studies revealed the presence of virulence genes encoded by phages of the human pathogen Group A Streptococcus pyogenes (GAS) in SDSD isolated from the milk of bovine udder with mastitis. The isolates SDSD VSD5 and VSD13 could adhere and internalize human primary keratinocyte cells, suggesting a possible human infection potential of bovine isolates. In this work, the in vitro and in vivo potential of SDSD to internalize/adhere human cells of the respiratory track and zebrafish as biological models was evaluated. Our results showed that, in vitro, bovine SDSD strains could interact and internalize human respiratory cell lines and that this internalization was dependent on an active transport mechanism and that, in vivo, SDSD are able to cause invasive infections producing zebrafish morbidity and mortality. The infectious potential of these isolates showed to be isolate-specific and appeared to be independent of the presence or absence of GAS phage-encoded virulence genes. Although the infection ability of the bovine SDSD strains was not as strong as the human pathogenic S. pyogenes in the zebrafish model, results suggested that these SDSD isolates are able to interact with human cells and infect zebrafish, a vertebrate infectious model, emerging as pathogens with zoonotic capability.

Tumor Microenvironment Modulation via Gold Nanoparticles Targeting Malicious Exosomes: Implications for Cancer Diagnostics and Therapy.

Exosomes are nanovesicles formed in the endosomal pathway with an important role in paracrine and autocrine cell communication. Exosomes secreted by cancer cells, malicious exosomes, have important roles in tumor microenvironment maturation and cancer progression. The knowledge of the role of exosomes in tumorigenesis prompted a new era in cancer diagnostics and therapy, taking advantage of the use of circulating exosomes as tumor biomarkers due to their stability in body fluids and targeting malignant exosomes' release and/or uptake to inhibit or delay tumor development. In recent years, nanotechnology has paved the way for the development of a plethora of new diagnostic and therapeutic platforms, fostering theranostics. The unique physical and chemical properties of gold nanoparticles (AuNPs) make them suitable vehicles to pursuit this goal. AuNPs' properties such as ease of synthesis with the desired shape and size, high surface:volume ratio, and the possibility of engineering their surface as desired, potentiate AuNPs' role in nanotheranostics, allowing the use of the same formulation for exosome detection and restraining the effect of malicious exosomes in cancer progression.

Infection of human keratinocytes by Streptococcus dysgalactiae subspecies dysgalactiae isolated from milk of the bovine udder.

Streptococcus dysgalactiae subsp. dysgalactiae (SDSD) are considered exclusive animal pathogens; however, a putative zoonotic upper limb cellulitis, a prosthetic joint infection and an infective endocarditis were described in humans. To unravel if bovine SDSD isolates are able to infect human cells, the adherence and internalization to human primary keratinocytes of two bovine SDSD strains isolated from milk collected from udder were analyzed. Bacterial adhesion assays and confocal microscopy indicate a high adherence and internalization of SDSD isolates to human cells, suggesting for the first time the ability of bovine isolates to infect human cells.

MicroRNAs Based Therapy of Hypertrophic Cardiomyopathy: The Road Traveled So Far.

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease characterized by variable expressivity, age penetrance, and a high heterogeneity. The transcriptional profile (miRNAs, mRNAs), epigenetic modifications, and posttranslational modifications seem to be highly relevant for the onset of the disease. miRNAs, small noncoding RNAs with 22 nucleotides, have been implicated in the regulation of cardiomyocyte function, being differentially expressed in several heart diseases, including HCM. Moreover, a different miRNA expression profile in the various stages of HCM development is also observed. This review summarizes the current knowledge of the profile of miRNAs characteristic of asymptomatic to overt HCM patients, discussing alongside their potential use for diagnosis and therapy. Indeed, the stability and specificity of miRNAs make them suitable targets for use as biomarkers for diagnosis and prognosis and as therapeutical targets.