Gelatin Carbon Dots Interaction with Nitrosyl Ruthenium Complex: Fluorescence Quenching and Chemiluminescence Mechanisms.

Carbon dots (CDs) exhibit luminescence, biocompatibility, and higher water solubility. This material has been developed for biological applications, specifically in bioimaging. In this work, the gelatin carbon dots (CDg) was obtained from commercial gelatin using a hydrothermal method in domestic microwave, and the suppression fluorescent mechanism were enhanced by the addition of the [RuII(bdq)(NO)(tpy)]3+ (Rubdq-NO+) complex ion. After purification through a dialysis bag, the resulting CDs (CDg) exhibit fluorescent emission at 400 nm and maintained fluorescence stability in an aqueous solution (pH = 7) for 30 days under 5 ◦C. Fluorescence quenching studies revealed an electrostatic interaction between the negative charge from CDg (δ = - 20 mV) and the positively charged nitrosyl (NO+) ligand of the ruthenium complex (Rubdq-NO+), resulting in quenching of the CDg fluorescence due to the inner filter effects (IFE). The chemiluminescence reaction of CDg and Rubdq-NO-CDg in presence of norepinephrine (NOR) were evaluated. NOR in PBS are liable to undergo spontaneous oxidation to quinone form (NOR-quinone). CDg are believed interact with NOR-quinone and an electron transfer occur obtained CDg+ accompanied to green emission fluorescence (520 nm). While for Rubdq-NO-CDg in presence of NOR, the green emission occurs accompanied by NO0 release using DAF-2 probe.

Synergic Action of Systemic Risedronate and Local Rutherpy in Peri-implantar Repair of Ovariectomized Rats: Biomechanical and Molecular Analysis.

Postmenopausal osteoporosis and poor dietary habits can lead to overweightness and obesity. Bisphosphonates are the first-line treatment for osteoporosis. However, some studies show that they may increase the risk of osteonecrosis of the jaw. Considering the antimicrobial, angiogenic and vasodilatory potential of nitric oxide, this study aims to evaluate the local activity of this substance during the placement of surface-treated implants. Seventy-two Wistar rats were divided into three groups: SHAM (SHAM surgery), OVX + HD (ovariectomy + cafeteria diet), and OVX + HD + RIS (ovariectomy + cafeteria diet + sodium risedronate treatment), which were further subdivided according to the surface treatment of the future implant: CONV (conventional), TE10, or TE100 (TERPY at 10 or 100 µM concentration); n = 8 per subgroup. The animals underwent surgery for implant installation in the proximal tibia metaphysis and were euthanized after 28 days. Data obtained from removal torque and RT-PCR (OPG, RANKL, ALP, IBSP and VEGF expression) were subjected to statistical analysis at 5% significance level. For biomechanical analysis, TE10 produced better results in the OVX + HD group (7.4 N/cm, SD = 0.6819). Molecular analysis showed: (1) significant increase in OPG gene expression in OVX groups with TE10; (2) decreased RANKL expression in OVX + HD + RIS compared to OVX + HD; (3) significantly increased expressions of IBSP and VEGF for OVX + HD + RIS TE10. At its lowest concentration, TERPY has the potential to improve peri-implant conditions.

RuBPY decreases intracellular calcium by decreasing influx and increasing storage.

cis-[Ru(bpy)2(py)NO2](PF6) (RuBPY) is a ruthenium complex nitric oxide (NO) donor that presents a nitrite in its moiety and has been shown to induce vasodilation in various arteries, as well as arterial pressure reduction with no changes in heart rate. Because vascular tone is highly dependent on the cytosolic calcium concentration ([Ca2+ ]c), the current study aimed to investigate the effects of RuBPY on the intracellular mobilization of calcium stores of rat aortic vascular smooth muscle cells. Vascular reactivity experiments were performed in isolated aortic rings that were contracted with a high concentration of KCl or phenylephrine (Phe). Moreover, primary cultured vascular smooth muscle cells were used to measure [Ca2+ ]c by confocal microscopy. The NO donor RuBPY decreased the [Ca2+ ]c and reduced KCl and Phe-induced contractile responses. The selective inhibitor of sarco-endoplasmic Ca-ATPase (SERCA) with thapsigargin impaired the effect of RuBPY on Phe-induced contractile response. RuBPY also reduced caffeine-induced contraction, and the contraction dependent on the capacitive Ca2+ influx. Therefore, our results suggest that NO released from RuBPY decreased [Ca2+ ]c by calcium influx blockade and activation of guanylyl-cyclase-cGMP-GK pathway. These results indicate that RuBPY increases Ca2+ storage in the sarcoplasmic reticulum by SERCA activation and also by capacitive Ca2+ influx inhibition, which is dependent on the intracellular release of nitric oxide from this compound.

An Epigallocatechin-3-gallate Formulation Developed for Endodontic Use: A Physicochemical and Biological Evaluation.

INTRODUCTION: Although epigallocatechin-3-gallate (EGCG) from green tea has been successfully used in the prevention and treatment of several infectious and immunoinflammatory diseases because of its proven anti-inflammatory, antioxidant, antimicrobial, and antiresorptive role, its use as an intracanal dressing has not been proposed. The aim of this study was to develop a formulation based on EGCG for endodontic use by assessing its physicochemical and biological properties. METHODS: Initially, physicochemical characterization of EGCG was performed by ultraviolet-visible and fluorescence spectroscopy to evaluate if the properties were maintained in acidic pH and time (1-6, 24, and 27 hours). After that, biological studies evaluated the developed formulation of EGCG at different concentrations (1.25, 5, 10, and 20 mg/mL). The tissue compatibility with subcutaneous tissue of mice was evaluated by plasma leakage after 24 hours and the examination of macroscopic and microscopic features at 7, 21, and 63 days after the insertion of polyethylene tubes containing the formulations. The repair of experimentally induced periapical lesions in dog's teeth by radiographic and histopathologic analysis was also evaluated. The scores were statistically analyzed by the chi-square and Fisher exact test. Analysis of variance followed by the Tukey posttest were used for the quantitative analysis. The significance level was 5%. RESULTS: The physicochemical characterization performed under ultraviolet-visible spectrophotometry showed that the EGCG properties remained unaltered in acid pH and function of time, keeping its wavelength to 274 nm. Macroscopic parameters evaluated at 7, 21, and 63 days showed that all concentrations presented no epithelial ulceration or presence of mild superficial tissue necrosis, edema, or vascularization with no significant difference in the control group. During all periods of microscopic examination, all groups presented the absence of abscess foci and edema and the presence of fibrous capsule and neovascularization. The presence of reparative tissue with a gentle presence of neutrophilic inflammatory cells was also observed for all groups, except for the calcium hydroxide paste group, which presented a more pronounced inflammation and tissue necrosis at days 7 and 21 (P < .001). At day 63, all groups presented an absence of inflammatory infiltrate and necrosis. The evaluation of dog teeth showed that treatment with the EGCG formulation provided a reduction of the periapical radiolucent area and allowed the repair of apical and periapical tissues (P > .05). CONCLUSIONS: The developed formulation based on EGCG from green tea presented physicochemical stability and tissue compatibility and provided the repair of periapical lesions when used as an intracanal dressing.

Improving Cytotoxicity against Breast Cancer Cells by Using Mixed-Ligand Ruthenium(II) Complexes of 2,2'-Bipyridine, Amino Acid, and Nitric Oxide Derivatives as Potential Anticancer Agents.

BACKGROUND: Several metal-based molecules that display cytotoxicity against multiple cell lines have been pursued in an attempt to fight against cancer and to overcome the typical side effects of drugs like cisplatin. In this scenario, ruthenium complexes have been extensively studied due to their activity in both in vitro and in vivo biological systems, including various cancer cell strains. OBJECTIVE: We aimed to develop a method to synthesize novel [Ru(NO)(bpy)2L2]2+ complexes containing amino acid ligands by using an alternative Click Chemistry approach, namely the copper azide-alkyne cycloaddition reaction (CuAAC reaction), to construct nitrosyl/nitrite complexes bearing a modified lysine residue. METHODS: We synthesized a new ligand by Click Chemistry approach and new compounds bearing the unprecedented ligand. Cytotoxicity was assessed by the classical MTT colorimetric assay. MCF-7 and MDAMB- 231 cells were used as breast cancer cell models. MCF-10 was used as a model of healthy cells. RESULTS: Amino acid ligands related to N3-Lys(Fmoc) and the new pyLys were successfully synthesized by the diazotransfer reaction and the CuAAC reaction, respectively. The latter reaction involves coupling between N3-Lys(Fmoc) and 3ethynylpyridine. Both N3-Lys(Fmoc) and the new pyLys were introduced into the ruthenium bipyridine complex I, or cis-[RuII(NO)(NO2)(bpy)2]2+, to generate the common nitro-based complex III, which was further converted to the final complex IV. Results of the MTT assay proved the cytotoxic effect of cis- [RuII(NO)(pyLysO-)(bpy)2](PF6)2 against the mammalian breast cancer cells MCF-7 and MDA-MB231. CONCLUSION: The viability assays revealed that complex IV, bearing a NO group and a modified lysine residue, was able to release NO and cross tumor cell membranes. In this work, Complex IV was observed to be the most active ruthenium bipyridine complex against the mammalian breast cancer cells MCF-7 and MDA-MB231: it was approximately twice as active as cisplatin, whilst complexes I-III proved to be less cytotoxic than complex IV. Additional tests using healthy MCF 10A cells showed that complexes II-IV were three- to sixfold less toxic than cisplatin, which suggested that complex IV was selective against cancer cells.

Vascular tone and angiogenesis modulation by catecholamine coordinated to ruthenium.

Catecholamines participate in angiogenesis, an important tumor development process. However, the way catecholamines interact with their receptors has not been completely elucidated, and doubts still remain as to whether these interactions occur between catechol and/or amine sites and particular amino acid residues on the catecholamine receptors. To evaluate how catechol and amine groups contribute to angiogenesis, we immobilized the catechol site through ruthenium ion (Ru) coordination, to obtain species with the general formula [Ru(NH3)4(catecholamine-R)]Cl. We then assessed the angiogenic activity of the complexes in a chorioallantoic membrane model (CAM) and examined vascular reactivity and calcium mobilization in rat aortas and vascular cells. [Ru(NH3)4(catecholamine-R)]Cl acted as partial agonists and/or antagonists of their respective receptors and induced calcium mobilization. [Ru(NH3)4(isoproterenol)]+ [Ru(NH3)4(noradrenaline)]+, and [Ru(NH3)4(adrenaline)]+ behaved as antiangiogenic complexes, whereas [Ru(NH3)4(dopamine)]+ proved to be a proangiogenic complex. In conclusion, catecholamines and [Ru(NH3)4(catecholamine-R)]Cl can modulate angiogenesis, and catechol group availability can modify the way these complexes impact the vascular tone, suggesting that catecholamines and their receptors interact differently after catecholamine coordination to ruthenium.

Photobiomodulation combined with photodynamic therapy using ruthenium phthalocyanine complexes in A375 melanoma cells: Effects of nitric oxide generation and ATP production.

Light irradiation has been used in clinical therapy for several decades. In this context, photobiomodulation (PBM) modulates signaling pathways via ROS, ATP, Ca2+, while photodynamic therapy (PDT) generates reactive oxygen species by excitation of a photosensitizer. NO generation could be an important tool when combined with both kinds of light therapy. By using a metal-based compound, we found that PBM combined with PDT could be a beneficial cancer treatment option. We used two types of ruthenium compounds, ([Ru(Pc)], Pc = phthalocyanine) and trans-[Ru(NO)(NO2)(Pc)]. The UV-vis spectra of both complexes displayed a band in the 660 nm region. In the case of 0.5 µM trans-[Ru(NO)(NO2)(Pc)], light irradiation at the Q-band reduced the percentage of viable human melanoma (A375) cells to around 50% as compared to [Ru(Pc)]. We hypothesized that these results were due to a synergistic effect between singlet oxygen and nitric oxide. Similar experiments performed with PDT (660 nm) combined with PBM (850 nm) induced more photocytotoxicity using both [Ru(Pc)] and trans-[Ru(NO)(NO2)(Pc)]. This was interpreted as PBM increasing cell metabolism (ATP production) and the consequent higher uptake of the ruthenium phthalocyanine compounds and more efficient apoptosis. The use of metal-based photosensitizers combined with light therapy may represent an advance in the field of photodynamic therapy.

Ultradeformable liposome loaded with zinc phthalocyanine and [Ru(NH.NHq)(tpy)NO]3+ for photodynamic therapy by topical application.

Ultradeformable liposomes (UDLs) as a drug delivery system (DDS), prepared from the unsaturated phospholipid, dioleylphosphocholine (DOPC), and containing the non-ionic surfactant Tween 20 as edge activator, have been explored as topical vehicles for zinc phthalocyanine (ZnPc) and the nitrosyl ruthenium complex [Ru(NH.NHq)(tpy)NO]3+ (RuNO) as a photosensitizers for co-generation of 1O2 and NO as reactive species, respectively. However, in order to ensure that ZnPc was present in the UDLs in its monomeric form - essential for maximal ZnPc photophysical properties - it was necessary to replace 40wt% of the DOPC with the saturated phospholipid, dimyristoylphosphocholine (DMPC). The resultant ZnPc and complex [Ru(NH.NHq)(tpy)NO]3+ containing UDLs were stable for at least a month when stored at 4°C, six times more elastic/deformable than conventional liposome (c-Ls), i.e. liposome prepared using the same weight ratio of lipids but in the absence of Tween 20, and to significantly enhance the in vitro permeation of ZnPc across fresh pig ear skin. The UDLs DDS incorporating ZnPc and [Ru(NH.NHq)(tpy)NO]3+ were toxic (by the MTT assay) towards B16-F10 melanoma cells when irradiated with visible light at 670nm, the maximum absorption of ZnPc, and at a dose of 3.18J/cm2, but not when applied in the absence of light as expected. Based on these results it is proposed that the novel topical UDLs formulation developed is a suitable delivery vehicle for photodynamic therapy.

Antifungal mechanism of [RuIII(NH3)4catechol]+ complex on fluconazole-resistant Candida tropicalis.

Candidiasis, a major opportunistic mycosis caused by Candida sp., may comprise life-threatening systemic infections. The incidence of non-albicans species is rising, particularly in South America and they are frequently drug resistant, causing unresponsive cases. Thus, novel antimycotic agents are required. Here we tested the antifungal activity of [RuIII(NH3)4catechol]+ complex (RuCat), approaching possible action mechanisms on fluconazole-resistant Candida tropicalis. RuCat significantly (P < 0.05) inhibited the growth and viability of C. tropicalis dose-dependently (IC50 20.3 µM). Cytotoxicity of RuCat upon murine splenocytes was lower (Selectivity Index = 16). Scanning electron microscopy analysis showed pseudohyphae formation, yeast aggregation and surface damage. RuCat-treated samples investigated by transmission electron microscopy showed melanin granule trafficking to cell surfaces and extracellular milieu. Surface-adherent membrane fragments and extracellular debris were also observed. RuCat treatment produced intense H2DCFDA labeling, indicating reactive oxygen species (ROS) production which caused increased lipoperoxidation. ROS are involved in the fungicidal effect as N-acetyl-L-cysteine completely restored cell viability. Calcofluor White chitin staining suggests that 70 or 140 µM RuCat treatment for 2 h affected cell-wall structure. PI labeling indicated necrotic cell death. The present data indicate that RuCat triggers ROS production, lipoperoxidation and cell surface damage, culminating in selective necrotic death of drug-resistant C. tropicalis.

Diethylamino hydroxybenzoyl hexyl benzoate (DHHB) as additive to the UV filter avobenzone in cosmetic sunscreen formulations - Evaluation of the photochemical behavior and photostabilizing effect.

The aim of the present study was to investigate the photochemical behavior of DHHB and its photostabilizing effect on avobenzone (AVO) in different sunscreen formulations. The formulations were subjected to photostability studies by HPLC and spectrophotometry. In vitro phototoxicity was assessed using 3T3 fibroblast cultures. The mechanism of interaction between DHHB and AVO was investigated by steady state and time-resolved fluorescence spectroscopy. All formulations provided ultra-protection against UVA radiation. HPLC results demonstrated that DHHB did not present a photostabilizing effect on AVO. Fluorescence spectroscopy showed that AVO and DHHB interact by a static quenching mechanism and DHHB did not affect the AVO excited state lifetime. In addition, the energy transfer by Förster mechanism (FRET), which is the most often mechanism responsible for singlet-singlet quenching, is unlikely in this work. These results suggest why DHHB did not work as a photostabilizer on AVO singlet excited state. Phototoxicity results demonstrated that combinations containing DHHB (C2) did not show a phototoxic potential. Finally, although DHHB was considered to be photostable for all formulations studied (F2 and F3) it did not increase the photostability of AVO (F3). Thus, we suggested that formulations containing DHHB (F2) should be considered more advantageous than formulations containing AVO and AVO/DHHB (F1 and F3 respectively).

Hypotensive effect and vascular relaxation in different arteries induced by the nitric oxide donor RuBPY.

NO donors are compounds that release NO that can be used when the endogenous NO bioavailability is impaired. The compound cis-[Ru(bpy)2(py)(NO2)](PF6) (RuBPY) is a nitrite-ruthenium, since it has a NO2 in its molecule. The aim of the present study was to evaluate the effect of RuBPY on arterial pressure, as well as on the vascular relaxation of different vascular arteries in renal hypertensive (2K-1C) and normotensive (2K) rats. We have evaluated the arterial pressure and heart rate changes as well as the RuBPY and SNP-induced relaxation (thoracic aorta, mesenteric resistance, coronary and basilar arteries). The administration of RuBPY in awake rats evoked a smaller but long lasting hypotensive effect when compared to SNP, with no increase in heart rate. The relaxation induced by RuBPY was similar between 2K-1C and 2K rats in thoracic aorta, mesenteric resistance and coronary arteries. However, the relaxation induced by RuBPY was smaller in basilar arteries from 2K-1C than in 2K. Taken together, our results show that RuBPY presents several advantages over SNP, since it does not induce hypotensive effect in normotensive animals, the hypotensive effect is slower, with no reflex tachycardia, and it is long lasting. In addition, RuBPY induces coronary artery relaxation (useful for angina) and presented only a small effect on basilar artery (may not induce headache).

Structural, Spectroscopic, and Photochemical Investigation of an Octahedral NO-Releasing {RuNO}(7) Species.

[Ru(Me3[9]aneN3)(bpy)(NO)](BF4)2 ([1](BF4)2) was explored by single-crystal X-ray diffractometry, leading to the first crystal structure of an octahedral {RuNO}(7) complex. The metal resides on the center of a distorted octahedron, with dN-O and ∠Ru-N-O at 1.177(3) Å and 141.6(2)°, respectively. [1](BF4)2 can be stored indefinitely under argon. Solutions of [1](2+) show no signs of decomposition when protected from air and light. The electron paramagnetic resonance X-band spectrum at 85 K in vitrified acetonitrile (MeCN) shows signals consistent with an S = (1)/2 spin state, better described as Ru(II)NO(•) (g = [2.030, 1.993, 1.880] and A = [11.0, 30.4, 3.9]/10(-4) cm(-1)). In water, the {RuNO}(7) species reacts with O2 in a 1:4 stoichiometry. The reaction is first-order in both reactants with k = (1.9 ± 0.2) M(-1) s(-1) at 25 °C (ΔH(⧧) = 11.5 ± 0.3 kJ mol(-1); ΔS(⧧) = -189 ± 1 J K(-1) mol(-1)). Solutions of [1](2+) evolve NO when irradiated a 365 nm with ϕNO = 0.024 and 0.090 mol einstein(-1) in H2O and MeCN, respectively.

Relaxing effect of a new ruthenium complex nitric oxide donor on airway smooth muscle of an experimental model of asthma in rats.

NO is a potent bronchodilator and NO-donor compounds have demonstrated clinical significance for obstructive airway diseases. This study evaluated the relaxation mechanisms of two NO donors, a ruthenium compound (TERPY), and sodium nitroprusside (SNP), in rat tracheas with ovalbumin-induced asthma (OVA group) and in another control group. The effect of TERPY and SNP was evaluated in tracheal rings in an isolated organ chamber. The contribution of K(+) channels, sGC/cGMP pathway, phosphodiesterases, and extra and intracellular Ca(2+) sources were analyzed. The TERPY and SNP-induced tracheal smooth muscle relaxation in both groups. However, the maximum effect induced by TERPY was higher than that of SNP in both control (110.2 ± 3.2% vs 68.3 ± 3.1%, P < 0.001) and OVA groups (106.1 ± 1.5% vs 49.9 ± 2.7%, P < 0.001). In the control group, TERPY relaxation was induced by the activation of K(+) channels and reduction of the calcium influx, while in the OVA group, these same effects were also brought about by TERPY, but with participation of the sGC/cGMP pathway. In both groups, SNP-induced relaxation occurred through the activation of K(+) channels, sGC/cGMP pathway and reduction of calcium influx. However, the activation of sGC pathway and reticular Ca(2+) -ATPase seemed to be reduced in the OVA group. Furthermore, TERPY is capable of reversing the contraction of carbachol in asthmatic bronchioles. Finally, TERPY and SNP relaxation mechanisms were modified by asthma. SNP presented less relaxation than TERPY, which induced full relaxation with greater participation of K(+) and Ca(2+) fluxes through the membrane, thereby making TERPY a promising drug for reversing the narrowing of airways.

In vitro Treatment with cis-[Ru(H-dcbpy-)2(Cl)(NO)] Improves the Endothelial Function in Aortic Rings with Endothelial Dysfunction.

PURPOSE: The ruthenium complex cis-[Ru(H-dcbpy-)2(Cl)(NO)] (DCBPY) is a nitric oxide (NO) donor and studies suggested that the ruthenium compounds can inactivate O2-. The aim of this study is to test if DCBPY can revert and/or prevent the endothelial dysfunction. METHODS: Normotensive (2K) and hypertensive (2K-1C) wistar rats were used. To vascular reactivity study, thoracic aortas were isolated, rings with intact endothelium were incubated with: DCBPY: 0.1; 1 and 10µM, DCBPY plus hydroxocobalin (NO scavenger) or tempol during 30 minutes, and concentration effect curves to acetylcholine were performed. The potency values (pD2) and maximum effect (ME) were analyzed. The O2- was generated using hypoxantine xantine oxidase and the reduction of cytochrome c, NO consumption by O2- and the effect in avoid NO consumption was measured. RESULTS: In 2K-1C DCBPY at 0.1; 1 or 10µM improved the relaxation endothelium dependent induced by acetylcholine in aortic rings compared to control 2K-1C, and also improved ME. In rings from 2K incubation with DCBPY (0.1; 1.0 and 10 µM) did not change pD2 or ME. Incubation with 0.1 µM of DCBPY plus hydroxocobalamin did not modify the potency and ME in 2K-1C compared to DCBPY (0.1 µM). DCBPY and SOD inhibits the reduction of cytochrome c and inhibited the NO consumption by O2-, showing that O2- has been removed from the solution. CONCLUSION: Our results suggest that DCBPY at a lower concentration (0.1 µM) is not an NO generator, but can inactivate superoxide and improves the endothelial function.

Photoreactivity of a quantum dot-ruthenium nitrosyl conjugate.

We describe the use of cadmium telluride quantum dots (CdTe QDs) as antennas for the photosensitization of nitric oxide release from a ruthenium nitrosyl complex with visible light excitation. The CdTe QDs were capped with mercaptopropionic acid to make them water-soluble, and the ruthenium nitrosyl complex was cis-[Ru(NO)(4-ampy)(bpy)2](3+) (Ru-NO; bpy is 2,2'-bipyridine, and 4-ampy is 4-aminopyridine). Solutions of these two components demonstrated concentration-dependent quenching of the QD photoluminescence (PL) as well as photoinduced release of NO from Ru-NO when irradiated by 530 nm light. A NO release enhancement of ∼8 times resulting from this association was observed under longer wavelength excitation in visible light range. The dynamics of the quenching determined by both PL and transient absorption measurements were probed by ultrafast flash photolysis. A charge transfer mechanism is proposed to explain the quenching of the QD excited states as well as the photosensitized release of NO from Ru-NO.

Ruthenium complexes as NO donors for vascular relaxation induction.

Nitric oxide (NO) donors are substances that can release NO. Vascular relaxation induction is among the several functions of NO, and the administration of NO donors is a pharmacological alternative to treat hypertension. This review will focus on the physicochemical description of ruthenium-derived NO donor complexes that release NO via reduction and light stimulation. In particular, we will discuss the complexes synthesized by our research group over the last ten years, and we will focus on the vasodilation and arterial pressure control elicited by these complexes. Soluble guanylyl cyclase (sGC) and potassium channels are the main targets of the NO species released from the inorganic compounds. We will consider the importance of the chemical structure of the ruthenium complexes and their vascular effects.

Production of reactive oxygen and nitrogen species by light irradiation of a nitrosyl phthalocyanine ruthenium complex as a strategy for cancer treatment.

Production of reactive oxygen species has been used in clinical therapy for cancer treatment in a technique known as Photodynamic Therapy (PDT). The success of this therapy depends on oxygen concentration since hypoxia limits the formation of reactive oxygen species with consequent clinical failure of PDT. Herein, a possible synergistic effect between singlet oxygen and nitric oxide (NO) is examined since this scenario may display increased tumoricidal activity. To this end, the trinuclear species [Ru(pc)(pz)2{Ru(bpy)2(NO)}2](PF6)6 (pc = phthalocyanine; pz = pyrazine; bpy = bipyridine) was synthesized to be a combined NO and singlet oxygen photogenerator. Photobiological assays using at 4 × 10(-6) M in the B16F10 cell line result in the decrease of cell viability to 21.78 ± 0.29% of normal under light irradiation at 660 nm. However, in the dark and at the same concentration of compound , viability was 91.82 ± 0.37% of normal. The potential application of a system like in clinical therapy against cancer may be as an upgrade to normal photodynamic therapy.

Systemically alendronate was incorporated into dental tissues but did not cause morphological or mechanical changes in rats teeth.

This study evaluated the effect of the systemic use of sodium alendronate in rats in vivo. Forty-five Wistar rats aged 36 to 42 days and weighing 200 to 230 g were randomly assigned to a control group (n = 20), which received distilled water, and an experimental group (n = 25), which received 2 weekly doses of 1 mg/kg of chemically pure sodium alendronate. The animals were killed after 60 days of treatment. The tibias were removed for analysis of bone mineral density by dual-energy X-ray absorptiometry (DXA). Then, the maxillary incisors were extracted for analysis of the mineralized dental tissues using fluorescence spectroscopy (FS), scanning electron microscopy (SEM), bright field microscopy (BFM), and cross-sectional microhardness (CSMH) testing. DXA and CSMH data were subjected to statistical analysis by Kruskal-Wallis test (5% significance level). The experimental group presented higher bone mineral density than the control group by DXA. FS analysis revealed presence of alendronate in the mineralized dental tissues of the specimens of the experimental group. Significant morphological differences were not found by SEM and BFM. Enamel and dentin (100 and 300 µm from the dentinoenamel junction) CSMH data did not show significant difference between the control and experimental groups. Based on the obtained results, we conclude that while alendronate increased the bone mineral density and was incorporated into the mineralized dental tissues it did not cause significant alterations in the morphology and microhardness of rat incisor enamel and dentin.

A series of mononuclear Co(III) complexes using tridentate N,O-donor ligands: chemical properties and cytotoxicity activity.

Continuing our interest in tridentate ligands to develop new prototypes of cobalt-based metallodrugs for combating cancer, modifications in the backbone of HL1, [(2-hydroxybenzyl)(2-(pyridil-2-yl)ethyl]amine) were proposed in order to modulate the redox potential of new Co(III) complexes. Three ligands with electron withdrawing groups were synthesized: HL2: [(2-hydroxy-5-nitrobenzyl)(2-(pyridil-2-yl)ethyl]amine); HL3: [(2-hydroxybenzyl)(2-(pyridil-2-yl)ethyl]imine) and HL4: [(2-hydroxy-5-nitrobenzyl)(2-(pyridil-2-yl)ethyl]imine). They were used to obtain the respective mononuclear complexes 2, 3 and 4, which are discussed compared to the previous reported complex 1 (obtained from HL1). The new complexes were characterized and studied by several techniques including X-ray crystallography, elemental and conductimetric analysis, IR, UV-vis and (1)H NMR spectroscopies, and electrochemistry. The substitutions of the group in the para position of the phenol (HL1 and HL2) and the imine instead of the amine (HL3 and HL4), promote anodic shifts in the complexes reduction potentials. The influence of these substitutions in the biological activities of the Co(III) complexes against the murine melanoma cell line (B16F10) was also evaluated. Little effect was observed on cellular viability decrease for all free ligands, however the coordination to Co(III) enhances their activities in the following range: 1>4≈2>3. The data suggest that no straight correlation can be addressed between the reduction potential of the Co(III) center and the cell viability.

NO donors-relaxation is impaired in aorta from hypertensive rats due to a reduced involvement of K(+) channels and sarcoplasmic reticulum Ca(2+)-ATPase.

AIMS: To examine the vasodilatation induce by the NO donors, [Ru(terpy)(bdq)NO](3+) (TERPY) and sodium nitroprusside (SNP), and to compare their effects in aortic rings from hypertensive 2K-1C and normotensive 2K rats. MAIN METHODS: Vascular reactivity was performed in aortic rings pre-contracted with phenylephrine (Phe 100nM). We have analyzed the maximal relaxation (Emax) and potency (pD(2)) of NO donors. KEY FINDINGS: Potency of SNP was greater than TERPY in both arterial groups. The vasodilatation induced by TERPY was greater in 2K than in 2K-1C, and it was inhibited by sGC inhibitor ODQ in 2K and in 2K-1C aortic rings. ODQ did not alter the efficacy to SNP, but it reduced its potency in 2K and 2K-1C. The blockade of K(+) channels reduced the potency of TERPY only in aortic rings of 2K. On the other hand, the potency of SNP was reduced in both 2K and 2K-1C. The combination of ODQ and TEA reduced the relaxation induced by TERPY and SNP in 2K and reduced the efficacy to SNP in 2K-1C aortic rings but it had no additional effect on the TERPY relaxation in 2K-1C aortas. The production of cGMP induced by TERPY was greater than that produced by SNP, which was similarly increased in 2K and 2K-1C. Sarcoplasmic reticulum Ca-ATPase inhibition only impaired the relaxation induced by SNP in 2K aortic rings. SIGNIFICANCE: Taken together, our results provide evidences that in this model of hypertension, impaired K(+) channels activation by TERPY and SERCA activation by SNP may contribute to decreased vasodilatation.