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Given the widely recognized bioactivity of 2-arylbenzothiazoles against tumor cells, we have designed a new family of luminescent heteroleptic pentafluorophenyl-bis(2-phenylbenzothiazolyl) PtIV derivatives, fac-[Pt(pbt)2(C6F5)L]n+ (n = 1, 0) [L = 4-Mepy 1, 4-pyridylbenzothiazole (pybt) 2, 4,4'-bipyridine (4,4'-bpy) 3, 1,2-bis-(4-pyridyl)ethylene (bpe) 4 (E/Z ratio: 90/10), 1,4-bis-(pyridyl)butadiyne (bpyb) 5, trifluoroacetate (-OCOCF3) 6] and a dinuclear complex [{Pt(pbt)2(C6F5)}2(µ-bpyb)](PF6)27, in which the trans ligand to the metalated C-(pbt) was varied to modify the optical properties and lipophilicity. Their photophysical properties were systematically studied through experimental and theoretical investigations, which were strongly dependent on the identity of the N-bonded ligand. Thus, complexes 1, 3 and 6 display, in different media, emission from the triplet excited states of primarily intraligand 3ILCT nature localized on the pbt ligand, while the emissions of 2, 5 and 7 were ascribed to a mixture of close 3IL'(N donor)/3ILCT(pbt) excited states, as supported by lifetime measurements and theoretical calculations. Irradiation of the initial E/Z mixture of 4 (15 min) led to a steady state composed of roughly 1 : 1.15 (E : Z) and this complex was not emissive at room temperature due to an enhanced intramolecular E to Z isomerization process of the 1,2-bis-(4-pyridyl)ethylene ligand. Complexes 1-3 and 6 showed excellent quantum yields for the generation of singlet oxygen in aerated MeCN solution with the values of Ï(1O2) ranging from 0.66 to 0.86 using phenalenone as a reference. Cationic complexes 1-3 exhibited remarkable efficacy in the nanomolar range against A549 (lung carcinoma) and HeLa (cervix carcinoma) cell lines with notable selectivity relative to the non-tumorigenic BEAS-2B (bronchial epithelium) cells. In the A549 cell line, the neutral complex 6 showed low cytotoxicity (IC50: 29.40 µM) and high photocytotoxicity (IC50: 5.75) when cells were irradiated with blue light for 15 min. These complexes do not show evidence of DNA interaction.
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Antineoplásicos , Carcinoma , Femenino , Humanos , Ligandos , Luminiscencia , Antineoplásicos/farmacología , Etilenos , Células HeLaRESUMEN
Recent studies highlight the importance of baseline functional immunity for immune checkpoint blockade therapies. High-dimensional systemic immune profiling is performed in a cohort of non-small-cell lung cancer patients undergoing PD-L1/PD-1 blockade immunotherapy. Responders show high baseline myeloid phenotypic diversity in peripheral blood. To quantify it, we define a diversity index as a potential biomarker of response. This parameter correlates with elevated activated monocytic cells and decreased granulocytic phenotypes. High-throughput profiling of soluble factors in plasma identifies fractalkine (FKN), a chemokine involved in immune chemotaxis and adhesion, as a biomarker of response to immunotherapy that also correlates with myeloid cell diversity in human patients and murine models. Secreted FKN inhibits lung adenocarcinoma growth in vivo through a prominent contribution of systemic effector NK cells and increased tumor immune infiltration. FKN sensitizes murine lung cancer models refractory to anti-PD-1 treatment to immune checkpoint blockade immunotherapy. Importantly, recombinant FKN and tumor-expressed FKN are efficacious in delaying tumor growth in vivo locally and systemically, indicating a potential therapeutic use of FKN in combination with immunotherapy.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Animales , Humanos , Ratones , Antígeno B7-H1/genética , Biomarcadores , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Quimiocina CX3CL1/genética , Quimiocina CX3CL1/uso terapéutico , Neoplasias Pulmonares/genéticaRESUMEN
By using N,N-dibutyl-2,2'-bipyridine-4,4'-dicarboxamide as a diimine (dbbpy) and distinctive cyclometalated groups, this work reports a new family of cationic phosphorescent Ir(III) cyclometalated [Ir(C^N)2(N^N)]X compounds [C^N = difluorophenylpyridine (dfppy) a, 2,6-difluoro-3-(pyridin-2-yl)benzaldehyde (CHO-dfppy) b, and 2,6-difluoro-3-pyridin-2-yl-benzoic acid (COOH-dfppy) c; X = Cl-2a,b,c-Cl; X = PF6-2b,c-PF6]. For comparative purposes, the related complex [Ir(dfppy)2(H2dcbpy)]+ (3a-PF6) incorporating 3,3'-dicarboxy-2,2'-bipyridine as an auxiliary ligand (N^N = H2dcbpy) is also presented. All complexes have been fully characterized and their photophysical properties were investigated in detail. The theoretically calculated results obtained by density functional theory (DFT) and time-dependent density functional theory (TD-DFT) studies indicate that luminescence is derived from mixed 3ML'CT (Ir â N^N)/3LL'CT (C^N â N^N) excited states with the predominant metal-to-diimine charge transfer character. Their antineoplastic activity against tumour cell lines A549 (lung carcinoma) and HeLa (cervix carcinoma), as well as the nontumor BEAS-2B (bronchial epithelium) cell line was assessed and fluorescence microscopy studies were performed for their cellular localization. Among them, 2a-Cl exhibited the most potent anticancer activity, being higher than cisplatin. However, 2b-Cl and 2c-Cl,-PF6 were the least toxic, while 2b-PF6 and 3a-PF6 exhibited only moderate activity. Confocal microscopy studies for 2a-Cl suggest that complexes localize preferentially in the lysosomes and to a lesser extent in the cytoplasm, but ultimately causing damage to the mitochondria. Finally, the potential photodynamic behaviour of scarcely toxic complexes 2b-Cl, 2b-PF6, 2c-Cl and 3a-PF6 was also studied.
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Antineoplásicos , Iridio , Humanos , 2,2'-Dipiridil , Luminiscencia , Antineoplásicos/farmacología , CisplatinoRESUMEN
Objective: We aimed to investigate the short and long-term metabolic consequences of IGF1R systemic gene deficiency in mice. Methods: UBC-CreERT2, Igf1rfl/fl mutant mice were used to suppress IGF1R signaling in adult tissues by inducing postnatal generalized Igf1r deletion with tamoxifen. Animals were analyzed at two different ages: i) 13-weeks old young mice, and ii) 12-months old middle-aged mice. In addition, the effects of 10 weeks-long high-fat diet (HFD) were investigated in middle-aged mice. Results: Young IGF1R-deficient mice were insulin-resistant, with high IGF1, growth hormone (GH) and IGFBP3, as well as low IGFBP2 circulating levels. Males also presented increased triglycerides in liver. In contrast, middle-aged mice did not clearly show all of these alterations, suggesting possible compensatory effects. Middle-aged IGF1R-deficient male mice were able to counteract the negative effects induced by aging and HFD in adiposity, inflammation and glucose metabolism. A metabolic sexual dimorphism dependent on IGF1R was observed, especially in middle-aged mice. Conclusions: These results demonstrate that IGF1R is involved in metabolic homeostasis, with effects modulated by diet-induced obesity and aging in a sex dependent manner. Thus, IGF1R deficiency in mice is proposed as a useful tool to understand metabolic alterations observed in patients with IGF1R gene deletions.
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Dieta Alta en Grasa , Resistencia a la Insulina , Femenino , Ratones , Masculino , Animales , Dieta Alta en Grasa/efectos adversos , Obesidad/metabolismo , Adiposidad , Insulina/metabolismoRESUMEN
Given the long-term ineffectiveness of current therapies and late-stage diagnoses, lung cancer is a leading cause of malignant diseases. Tumor progression is influenced by cancer cell interactions with the tumor microenvironment (TME). Insulin-like growth factor 1 receptor (IGF1R) was reported to affect the TME; however, the role of IGF1R in lung TME has not been investigated. First, we assessed IGF1R genomic alterations and expression in NSCLC patient tissue samples, as well as IGF1R serum levels. Next, we performed tumor heterotopic transplantation and pulmonary metastases in IGF1R-deficient mice using melanoma and Lewis lung carcinoma (LLC) cells. Herein we report increased amplification and mRNA expression, as well as increased protein expression (IGF1R/p-IGF1R) and IGF1R levels in tumor samples and serum from NSCLC patients, respectively. Moreover, IGF1R deficiency in mice reduced tumor growth, proliferation, inflammation and vascularization, and increased apoptosis after tumor heterotopic transplantation. Following induction of lung metastasis, IGF1R-deficient lungs also demonstrated a reduced tumor burden, and decreased expression of tumor progression markers, p-IGF1R and p-ERK1/2. Additionally, IGF1R-deficient lungs showed increased apoptosis and diminished proliferation, vascularization, EMT and fibrosis, along with attenuated inflammation and immunosuppression. Accordingly, IGF1R deficiency decreased expression of p-IGF1R in blood vessels, fibroblasts, tumor-associated macrophages and FOXP3+ tumor-infiltrating lymphocytes. Our results demonstrate that IGF1R promotes metastatic tumor initiation and progression in lung TME. Furthermore, our research indicates that IGF1R could be a potential biomarker for early prediction of drug response and clinical evolution in NSCLC patients.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Receptor IGF Tipo 1 , Animales , Biomarcadores de Tumor , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Proliferación Celular , Humanos , Inflamación , Neoplasias Pulmonares/patología , Ratones , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Microambiente TumoralRESUMEN
In the original article [...].
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BACKGROUND: Asthma is a chronic lung disease characterized by reversible airflow obstruction, airway hyperresponsiveness (AHR), mucus overproduction and inflammation. Although Insulin-like growth factor 1 receptor (IGF1R) was found to be involved in asthma, its pharmacological inhibition has not previously been investigated in this pathology. We aimed to determine if therapeutic targeting of IGF1R ameliorates allergic airway inflammation in a murine model of asthma. METHODS: C57BL/6J mice were challenged by house dust mite (HDM) extract or PBS for four weeks and therapeutically treated with the IGF1R tyrosine kinase inhibitor (TKI) NVP-ADW742 (NVP) once allergic phenotype was established. RESULTS: Lungs of HDM-challenged mice exhibited a significant increase in phospho-IGF1R levels, incremented AHR, airway remodeling, eosinophilia and allergic inflammation, as well as altered pulmonary surfactant expression, all of being these parameters counteracted by NVP treatment. HDM-challenged lungs also displayed augmented expression of the IGF1R signaling mediator p-ERK1/2, which was greatly reduced upon treatment with NVP. CONCLUSIONS: Our results demonstrate that IGF1R could be considered a potential pharmacological target in murine HDM-induced asthma and a candidate biomarker in allergic asthma.
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The optical and biological properties of 2-(4-dimethylaminophenyl)benzothiazole cycloplatinated complexes featuring bioactive ligands ([{Pt(Me2 N-pbt)(C6 F5 )}L] [L=Me2 N-pbtH 1, p-dpbH (4-(diphenylphosphino)benzoic acid) 2, o-dpbH (2-(diphenylphosphino)benzoic acid) 3), [Pt(Me2 N-pbt)(o-dpb)] 4, [{Pt(Me2 N-pbt)(C6 F5 )}2 (µ-PRn P)] [PR4 P=O(CH2 CH2 OC(O)C6 H4 PPh2 )2 5, PR12 P=O{(CH2 CH2 O)3 C(O)C6 H4 PPh2 }2 6] are presented. Complexes 1-6 display 1 ILCT and metal-perturbed 3 ILCT dual emissions. The ratio between both bands is excitation dependent, accomplishing warm-white emissions for 2, 5 and 6. The phosphorescent emission is lost in aerated solutions owing to photoinduced electron transfer to 3 O2 and the formation of 1 O2 , as confirmed in complexes 2 and 4. They also exhibit photoinduced phosphorescence enhancement in non-degassed DMSO due to local oxidation of DMSO by sensitized 1 O2 , which causes a local degassing. Me2 N-pbtH and the complexes specifically accumulate in the Golgi apparatus, although only 2, 3 and 6 were active against A549 and HeLa cancer cell lines, 6 being highly selective in respect to nontumoral cells. The potential photodynamic property of these complexes was demonstrated with complex 4.
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Benzotiazoles , Metales , Células HeLa , Humanos , Ligandos , Estructura MolecularRESUMEN
Four new cyclometalated Pt(ii) complexes bearing acyclic diaminocarbene (ADC) ligands, [Pt(C^N)Cl{C(NHXyl)(NHR)}] [C^N = 2,6-difluorophenylpyridine (dfppy), phenylquinoline (pq); R = Pr 3a, 4a, CH2Ph 3b, 4b], were prepared by the nucleophilic attack on the isocyanide [Pt(C^N)Cl(CNXyl)] (C^N = dfppy 1, pq 2) by the corresponding amine RNH2 (R = Pr, CH2Ph). Complexes 3 show in their 1H NMR spectra in CDCl3 a notable concentration dependence, with a clear variation of the δH (NHXyl) signal, suggesting an assembling process implying donor-acceptor NHXylCl bonding, also supported by 1D-PGSE (Pulse Field Gradient Spin Echo) and 2D-DOSY (Diffusion Ordered Spectroscopy) NMR experiments in solution and X-ray diffraction studies. The intermolecular interactions in compounds 3a and 3b were studied by using Hirshfeld surface analysis and Non-Covalent Interaction (NCI) methods on their X-ray structures. Their photophysical properties were investigated by absorption and emission spectroscopies and also by TD-DFT calculations performed on 3a and 4b. These complexes show green (3) or orange (4) phosphorescence, attributed to a mixed 3IL/3MLCT excited state. The carbene ligand does not affect the emission maxima but it produces an increase of the quantum yields in relation to the isocyanide in the precursors. In fluid solutions, the emission is not concentration-dependent, but the complexes may show aggregation induced emission as detailed for complexes 3a and 4a. In addition, cytotoxicity studies in the human cell lines A549 (lung carcinoma) and HeLa (cervix carcinoma) showed good activity for these complexes and 3a, 3b and 4a exhibit a strong effect on DNA electrophoretic mobility. To the best of our knowledge, compounds 3 and 4 represent the first examples of cycloplatinated complexes bearing acyclic diamino carbenes with antiproliferative properties.
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Alquinos/farmacología , Antineoplásicos/farmacología , Dioxolanos/farmacología , Sustancias Luminiscentes/farmacología , Compuestos Organoplatinos/farmacología , Alquinos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Teoría Funcional de la Densidad , Dioxolanos/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ligandos , Sustancias Luminiscentes/síntesis química , Sustancias Luminiscentes/química , Modelos Moleculares , Estructura Molecular , Compuestos Organoplatinos/síntesis química , Compuestos Organoplatinos/química , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Insulin-like growth factor 1 receptor (IGF1R)-mediated signaling pathways modulate important neurophysiological aspects in the central nervous system, including neurogenesis, synaptic plasticity and complex cognitive functions. In the present study, we intended to characterize the impact of IGF1R deficiency in the brain, focusing on PI3K/Akt and MAPK/ERK1/2 signaling pathways and mitochondria-related parameters. For this purpose, we used 13-week-old UBC-CreERT2; Igf1rfl/fl male mice in which Igf1r was conditionally deleted. IGF1R deficiency caused a decrease in brain weight as well as the activation of the IR/PI3K/Akt and inhibition of the MAPK/ERK1/2/CREB signaling pathways. Despite no alterations in the activity of caspases 3 and 9, a significant alteration in phosphorylated GSK3ß and an increase in phosphorylated Tau protein levels were observed. In addition, significant disturbances in mitochondrial dynamics and content and altered activity of the mitochondrial respiratory chain complexes were noticed. An increase in oxidative stress, characterized by decreased nuclear factor E2-related factor 2 (NRF2) protein levels and aconitase activity and increased H2O2 levels were also found in the brain of IGF1R-deficient mice. Overall, our observations confirm the complexity of IGF1R in mediating brain signaling responses and suggest that its deficiency negatively impacts brain cells homeostasis and survival by affecting mitochondria and redox homeostasis.
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Rationale: Cigarette smoke is considered the chief leading cause of chronic obstructive pulmonary disease (COPD). Its impact on the progressive deterioration of airways has been extensively studied, but its direct effects on the pulmonary vasculature are less known. Objectives: To prove that pulmonary arterial remodeling in patients with COPD is not just a consequence of alveolar hypoxia but also due to the direct effects of cigarette smoke on the pulmonary vascular bed. Methods: We have used different molecular and cell biology approaches, as well as traction force microscopy, wire myography, and patch-clamp techniques in human cells and freshly isolated pulmonary arteries. In addition, we relied on in vivo models and human samples to analyze the effects of cigarette smoke on pulmonary vascular tone alterations. Measurements and Main Results: Cigarette smoke extract exposure directly promoted a hypertrophic, senescent phenotype that in turn contributed, through the secretion of inflammatory molecules, to an increase in the proliferative potential of nonexposed cells. Interestingly, these effects were significantly reversed by antioxidants. Furthermore, cigarette smoke extract affected cell contractility and dysregulated the expression and activity of the voltage-gated K+ channel Kv7.4. This contributed to the impairment of vasoconstriction and vasodilation responses. Most importantly, the levels of this channel were diminished in the lungs of smoke-exposed mice, smokers, and patients with COPD. Conclusions: Cigarette smoke directly contributes to pulmonary arterial remodeling through increased cell senescence, as well as vascular tone alterations because of diminished levels and function in the Kv7.4 channel. Strategies targeting these pathways may lead to novel therapies for COPD.
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Canales de Potasio KCNQ/metabolismo , Arteria Pulmonar/fisiopatología , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Fumar/efectos adversos , Remodelación Vascular/fisiología , Animales , Modelos Animales de Enfermedad , Humanos , Ratones , Arteria Pulmonar/patología , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Humo/efectos adversos , Nicotiana , Vasoconstricción , VasodilataciónRESUMEN
Two series of neutral luminescent pentafluorophenyl cycloplatinated(II) complexes [Pt(C^N)(C6F5)L] [C^N = C-deprotonated 2-phenylpyridine (ppy; a), 2-(2,4-difluorophenylpyridine (dfppy; b)] incorporating dimethyl sulfoxide [L = DMSO for 1 (1a reported by us in ref (14) )] or biocompatible phosphine [L = PPh2C6H4COOH (dpbH; 2), PPh2C6H4CONHCH2COOMe (dpbGlyOMe; 3), P(C6H4SO3Na)3 (TPPTS; 4)] ligands have been prepared and characterized and their optical properties studied. Their cytotoxic activities against tumor A549 (lung carcinoma), HeLa (cervix carcinoma), and nontumor NL-20 (lung epithelium) cell lines, as well as the ability to interact with DNA (plasmid pBR322), were evaluated. Complexes 2 exhibit higher cytotoxicity (IC50 3.89-20.29 µM) than compounds 1 (9.03-20.50 µM), whereas the activities of complexes 3 and 4 are negligible. All cytotoxic complexes show low selective toxicities toward cancer cells. Interestingly, except 1a, these complexes do not show evidence of DNA intercalation. Along the same lines, fluorescence costaining with Hoechst (2,5'-bi-1 H-benzimidazole, 2'-(4-ethoxyphenyl)-5-(4-methyl-1-piperazinyl), a nuclear DNA stain) reveals that all complexes easily internalize, being mainly localized in the cytoplasm. In order to deepen the mechanism of biological action, the effect of the most cytotoxic complex 2b toward the dynamics of tubulin was explored. This complex displays tubulin depolymerization activity, exhibiting more potent inhibition of microtubule formation in A549 than in HeLa cells, in accordance with its higher antiproliferative activity (IC50 6.98 vs 12.45 µM), placing this complex as a potential antitubulin agent.
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Antineoplásicos/farmacología , Complejos de Coordinación/farmacología , Luminiscencia , Compuestos Organoplatinos/farmacología , Fosfinas/farmacología , Células A549 , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Células HeLa , Humanos , Ligandos , Modelos Moleculares , Estructura Molecular , Imagen Óptica , Compuestos Organoplatinos/síntesis química , Compuestos Organoplatinos/química , Fosfinas/química , Relación Estructura-ActividadRESUMEN
The profile of activation of lipid mediator (LM) pathways in asthmatic airway inflammation remains unclear. This experimental study quantified metabolite levels of ω3-, ω6- and ω9-derived polyunsaturated fatty acids in bronchoalveolar lavage fluid (BALF) after 4-weeks of repeated house dust mite (HDM) exposure in a murine (C57BL/6) asthma model. The challenge induced airway hyperresponsiveness, pulmonary eosinophil infiltration, but with low and unchanged mast cell numbers. Of the 112 screened LMs, 26 were increased between 2 to >25-fold in BALF with HDM treatment (pâ¯<â¯0.05, false discovery rateâ¯=â¯5%). While cysteinyl-leukotrienes were the most abundant metabolites at baseline, their levels did not increase after HDM treatment, whereas elevation of PGD2, LTB4 and multiple 12/15-lipoxygenase products, such as 5,15-DiHETE, 15-HEDE and 15-HEPE were observed. We conclude that this model has identified a global lipoxygenase activation signature, not linked to mast cells, but with aspects that mimic chronic allergic airway inflammation in asthma.
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Araquidonato 12-Lipooxigenasa/inmunología , Araquidonato 15-Lipooxigenasa/inmunología , Araquidonato 5-Lipooxigenasa/inmunología , Asma/inmunología , Mediadores de Inflamación/inmunología , Prostaglandinas/inmunología , Pyroglyphidae/inmunología , Animales , Asma/patología , Lavado Broncoalveolar , Modelos Animales de Enfermedad , Ratones , Ratones TransgénicosRESUMEN
Cycloplatinated complexes based on 2-(4-substituted)benzothiazole ligands of type [Pt(R-PBT-κC,N)Cl(L)] (PBT=2-phenylbenzothiazole; R=Br (1), Me2 N (2); L=dimethyl sulfoxide (DMSO; a), 1,3,5- triaza-7-phosphaadamantane (PTA; b), triphenylphosphine 3,3',3''-trisulfonate (TPPTS; c)) and [Pt(Br-PBT-κC)Cl(PTA)2 ] (3) are presented. On the basis of the photophysical data and time-dependent (TD)-DFT calculations (1 a and 2 a), the low-lying transitions (absorption and emission) were associated with ligand-center (LC) charge transfer, with minor metal-to-ligand charge transfer (MLCT), and intraligand charge transfer (ILCT) [Me2 N-PBTâPBT] excited states, respectively. Simultaneous fluorescence/phosphorescence bands were found in fluid solutions (and also in the solid state for 2 a), which become dominated by triplet emission bands in rigid media at 77â K. The effect of the concentration on emissive behavior of 2 a, b indicated the occurrence of aggregation-induced luminescence properties related to the occurrence of metal-metal and πâ â â π interactions, which are more enhanced in 2 a because of the less bulky DMSO ligand. The behavior of 2 a toward para-toluenesulfonic acid (PTSA) in aerated acetonitrile and to hydrogen chloride gas in the solid state has been evaluated, thus showing a clear reversible change between the 1 ILCT and 3 LC/3 MLCT states due to protonation of the NMe2 group (theoretical calculations on 2 a-H+ ). Solid 2 a undergoes a surprising oxidation of the PtII center to PtIV with concomitant deoxygenation of DMSO, under prolonged reaction with hydrogen chloride gas to afford the PtIV /dimethyl sulfide complex (mer-[Pt(Me2 N-PBT-κC,N)Cl3 (SMe2 )]; mer-4), which evolves in solution to fac-4, as confirmed by X-ray studies. Cytotoxic activity studies on A549 and HeLa cell lines indicated cytotoxic activity of 1 b and 2 a, b. In addition, fluorescent cell microscopy revealed cytoplasmic staining, more visible in perinuclear areas. Inhibition of tubulin polymerization by 1 b in both cells is presented as a preliminary mechanism of its cytotoxic action.
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Antineoplásicos/síntesis química , Benzotiazoles/química , Complejos de Coordinación/síntesis química , Platino (Metal)/química , Células A549 , Antineoplásicos/farmacología , Benzotiazoles/síntesis química , Benzotiazoles/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Células HeLa , Humanos , Ligandos , Luminiscencia , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , TermodinámicaRESUMEN
Asthma is a chronic inflammatory disease characterized by bronchial hyperresponsiveness, mucus overproduction and airway remodeling. Notably, we have recently demonstrated that insulin-like growth factor 1 receptor (IGF1R) deficiency in mice attenuates airway hyperresponsiveness and mucus secretion after chronic house dust mite (HDM) exposure. On this basis, inbred C57BL/6 and Igf1r-deficient mice were given HDM extract to study the acute inflammatory profile and implication of Igf1r in acute asthma pathobiology. Additionally, Igf1r-deficiency was therapeutically induced in mice to evaluate the resolution of HDM-induced inflammation. Acute HDM exposure in inbred C57BL/6 mice led to a progressive increase in inflammation, airway remodeling and associated molecular indicators. Preventively-induced Igf1r-deficiency showed reduced neutrophil and eosinophil numbers in BALF and bone marrow, a significant reduction of airway remodeling and decreased levels of related markers. In addition, therapeutic targeting of Igf1r promoted the resolution of HDM-induced-inflammation. Our results demonstrate for the first time that Igf1r is important in acute asthma pathobiology and resolution of HDM-induced inflammation. Thus, IGF1R is suggested to be a promising candidate for future therapeutic approaches for the treatment and prevention of asthma.
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Asma/terapia , Modelos Animales de Enfermedad , Marcación de Gen , Inflamación/terapia , Receptor IGF Tipo 1/genética , Enfermedad Aguda , Animales , Células de la Médula Ósea , Líquido del Lavado Bronquioalveolar , Ratones , Ratones Endogámicos C57BLRESUMEN
IGF1R (Insulin-like Growth Factor 1 Receptor) is a tyrosine kinase with pleiotropic cellular functions. IGF activity maintains human lung homeostasis and is implicated in pulmonary diseases such as cancer, ARDS, COPD, asthma and fibrosis. Here we report that lung transcriptome analysis in mice with a postnatally-induced Igf1r gene deletion showed differentially expressed genes with potentially protective roles related to epigenetics, redox and oxidative stress. After bleomycin-induced lung injury, IGF1R-deficient mice demonstrated improved survival within a week. Three days post injury, IGF1R-deficient lungs displayed changes in expression of IGF system-related genes and reduced vascular fragility and permeability. Mutant lungs presented reduced inflamed area, down-regulation of pro-inflammatory markers and up-regulation of resolution indicators. Decreased inflammatory cell presence in BALF was reflected in diminished lung infiltration mainly affecting neutrophils, also corroborated by reduced neutrophil numbers in bone marrow, as well as reduced lymphocyte and alveolar macrophage counts. Additionally, increased SFTPC expression together with hindered HIF1A expression and augmented levels of Gpx8 indicate that IGF1R deficiency protects against alveolar damage. These findings identify IGF1R as an important player in murine acute lung inflammation, suggesting that targeting IGF1R may counteract the inflammatory component of many lung diseases.
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Lesión Pulmonar Aguda/etiología , Lesión Pulmonar Aguda/metabolismo , Bleomicina/efectos adversos , Inflamación/etiología , Inflamación/metabolismo , Receptor IGF Tipo 1/deficiencia , Lesión Pulmonar Aguda/patología , Animales , Biomarcadores , Permeabilidad Capilar , Proliferación Celular , Modelos Animales de Enfermedad , Expresión Génica , Perfilación de la Expresión Génica , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Inflamación/patología , Ratones , Ratones Noqueados , Ratones Transgénicos , MutaciónRESUMEN
BACKGROUND: Any strategy designed to decrease the macrophage content in adipose tissue (AT) is of great value as a way to decrease inflammation in this fat depot and also as a way to prevent or treat obesity and associated disorders. Maraviroc (MVC), a CCR5 antagonist approved for the treatment of HIV-infected patients, has beneficial effects on metabolism. The objective of this study was to investigate the effects of MVC on AT macrophage recruitment in a mouse model of obesity. The plausible underlying mechanisms of action were also investigated. METHODS: 32 male C57BL/6 mice were randomly assigned to the following groups: control, MVC (300 mg/l MVC in drinking water), high-fat diet (HFD) or HFD+MVC. After 16 weeks of treatment, histopathological and molecular analyses were performed on epididymal fat. RESULTS: Our results demonstrated that MVC reduced the presence of macrophages in epididymal fat despite the ingestion of an HFD. The inhibition of MCP-1 gene expression and JNK signalling pathway along with the upregulation of protective cytokines such as cardiotrophin-1 could contribute to these actions. MVC effects on AT macrophage recruitment were associated with a lower body weight gain and a partial improvement in insulin resistance despite an HFD. CONCLUSIONS: We have demonstrated the ability of MVC to ameliorate the increased AT macrophage recruitment induced by an HFD in a mouse model of obesity. These actions could be of interest when designing antiretroviral treatments in HIV-patients.
Asunto(s)
Tejido Adiposo/efectos de los fármacos , Fármacos Anti-VIH/farmacología , Antagonistas de los Receptores CCR5/farmacología , Ciclohexanos/farmacología , Dieta Alta en Grasa/efectos adversos , Macrófagos/efectos de los fármacos , Obesidad/tratamiento farmacológico , Triazoles/farmacología , Tejido Adiposo/metabolismo , Tejido Adiposo/patología , Animales , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Resistencia a la Insulina , MAP Quinasa Quinasa 4/genética , MAP Quinasa Quinasa 4/metabolismo , Macrófagos/metabolismo , Macrófagos/patología , Masculino , Maraviroc , Ratones , Ratones Endogámicos C57BL , Obesidad/etiología , Obesidad/metabolismo , Obesidad/patología , Aumento de Peso/efectos de los fármacosRESUMEN
Regeneration of lung epithelium is vital for maintaining airway function and integrity. An imbalance between epithelial damage and repair is at the basis of numerous chronic lung diseases such as asthma, COPD, pulmonary fibrosis and lung cancer. IGF (Insulin-like Growth Factors) signaling has been associated with most of these respiratory pathologies, although their mechanisms of action in this tissue remain poorly understood. Expression profiles analyses of IGF system genes performed in mouse lung support their functional implication in pulmonary ontogeny. Immuno-localization revealed high expression levels of Igf1r (Insulin-like Growth Factor 1 Receptor) in lung epithelial cells, alveolar macrophages and smooth muscle. To further understand the role of Igf1r in pulmonary homeostasis, two distinct lung epithelial-specific Igf1r mutant mice were generated and studied. The lack of Igf1r disturbed airway epithelial differentiation in adult mice, and revealed enhanced proliferation and altered morphology in distal airway club cells. During recovery after naphthalene-induced club cell injury, the kinetics of terminal bronchiolar epithelium regeneration was hindered in Igf1r mutants, revealing increased proliferation and delayed differentiation of club and ciliated cells. Amid airway restoration, lungs of Igf1r deficient mice showed increased levels of Igf1, Insr, Igfbp3 and epithelial precursor markers, reduced amounts of Scgb1a1 protein, and alterations in IGF signaling mediators. These results support the role of Igf1r in controlling the kinetics of cell proliferation and differentiation during pulmonary airway epithelial regeneration after injury.