Reactivity of Schiff base-[C,N,S] pincer palladacycles: hydrolysis renders singular trinuclear, tetranuclear, and heteropentanuclear Pd3W2 coordinated complexes.

Treatment of the Schiff base ligands a-f with Li2[PdCl4]/NaAcO in methanol under reflux gave the single nuclear palladacycles 1a-1f, with the metal atom bonded to a terdentate monoanionic [C,N,S] iminic ligand and to a chloride ligand that completes the palladium coordination sphere. Reaction of 1a-1c with silver perchlorate/triphenylphosphine in acetone at room temperature yielded the single nuclear complexes 2a-2c as the perchlorate salts, after substitution of the chloride ligand by a triphenylphosphine. However, reaction of a-c with Na2[PdCl4]/NaAcO in methanol at room temperature also gave compounds 1a-1c albeit contaminated with small amounts of the corresponding free aldehyde (mixture A). Reaction of mixture A with silver perchlorate/triphenylphosphine in acetone at room temperature gave analogously 2a-2c with some of the corresponding free aldehyde (mixture B). Attempts to purify mixtures A and B via recrystallization produced single crystals of 5 and 6 respectively: two serendipitously formed complexes, bearing thiomethyl aniline and/or acetate ligands, and void of aldehyde or iminic residue; the structures contain eight- and six-membered rings of alternating palladium and nitrogen atoms, respectively. To clarify this situation the aniline itself was reacted with palladium(II) acetate or with Na2[PdCl4]; in the latter case after recrystallization a unique behavior is revealed, giving rise to a tetranuclear complex containing a Pd4N4 ring with three differing coordination environments on the palladium atoms. Treatment of 1d with Ph2PCH2PPh2 (dppm)/AgClO4 or with Ph2PCH2(PPh2)W(CO)5/AgClO4 gave 3d, with a mono-coordinated dppm ligand, and 4d, respectively; complex 3d could not be converted into 4d by reaction with W(CO)5(THF). Recrystallization of 4d gave a still further noticeable species, complex 8: a pentanuclear trans-configured heterometallic mixed valent Pd(II)/W(0) linear complex with the palladium atoms supported by two acetate and two thiomethyl aniline bridging ligands. The complexes were fully characterized by microanalysis, IR, 1H, and 31P NMR spectroscopies, as appropriate. The X-ray single-crystal analyses for compounds 1b, 5, 6, 7 and 8 are described.

Sodium valproate treatment reverses endothelial dysfunction in aorta from rabbits with acute myocardial infarction.

Sodium valproate (VPA), a histone deacetylase (HDAC) inhibitor, could be a promising candidate to treat acute myocardial infarction (AMI). In this study, AMI was induced in New Zealand White rabbits by occluding the left circumflex coronary artery for 1 h, followed by reperfusion. The animals were distributed into three experimental groups: the sham-operated group (SHAM), the AMI group and the AMI + VPA group (AMI treated with VPA 500 mg/kg/day). After 5 weeks, abdominal aorta was removed and used for isometric recording of tension in organ baths or protein expression by Western blot, and plasma for the determination of nitrate/nitrite (NOx) levels by colorimetric assay. Our results indicated that AMI induced a reduction of the endothelium-dependent response to acetylcholine without modifying the endothelium-independent response to sodium nitroprusside, leading to endothelial dysfunction. VPA treatment reversed AMI-induced endothelial dysfunction and even increased NO sensitivity in vascular smooth muscle. This response was consistent with an antioxidant effect of VPA, as it was able to reverse the superoxide dismutase 1 (SOD 1) down-regulation induced by AMI. Our experiments also ruled out that the VPA mechanism was related to eNOS, iNOS, sGC and arginase expression or changes in NOx plasma levels. Therefore, we conclude that VPA improves vasodilation by increasing NO bioavailability, likely due to its antioxidant effect. Since endothelial dysfunction was closely related to AMI, VPA treatment could increase aortic blood flow, making it a potential agent in reperfusion therapy that can prevent the vascular damage.

Improvement of Vascular Insulin Sensitivity by Ranolazine.

Ranolazine (RN) is a drug used in the treatment of chronic coronary ischemia. Different clinical trials have shown that RN behaves as an anti-diabetic drug by lowering blood glucose and glycosylated hemoglobin (HbA1c) levels. However, RN has not been shown to improve insulin (IN) sensitivity. Our study investigates the possible facilitating effects of RN on the actions of IN in the rabbit aorta. IN induced vasodilation of the abdominal aorta in a concentration-dependent manner, and this dilatory effect was due to the phosphorylation of endothelial nitric oxide synthase (eNOS) and the formation of nitric oxide (NO). On the other hand, IN facilitated the vasodilator effects of acetylcholine but not the vasodilation induced by sodium nitroprusside. RN facilitated all the vasodilatory effects of IN. In addition, IN decreased the vasoconstrictor effects of adrenergic nerve stimulation and exogenous noradrenaline. Both effects were in turn facilitated by RN. The joint effect of RN with IN induced a significant increase in the ratio of p-eNOS/eNOS and pAKT/AKT. In conclusion, RN facilitated the vasodilator effects of IN, both direct and induced, on the adrenergic system. Therefore, RN increases vascular sensitivity to IN, thus decreasing tissue resistance to the hormone, a key mechanism in the development of type II diabetes.

An Innovative Structural Rearrangement in Imine Palladacycle Metaloligand Chemistry: From Single-Nuclear to Double-Nuclear Pseudo-Pentacoordinated Complexes.

Treatment of the double nuclear complex 1a, di-µ-cloro-bis[N-(4-formylbenzylidene)cyclohexylaminato-C6, N]dipalladium, with Ph2PCH2CH2)2PPh (triphos) and NH4PF6 gave the single nuclear species 2a, 1-N-(cyclohexylamine)-4-N-(formyl)palladium(triphos)(hexafluorophasphate). Reaction of 2a with Ph2PCH2CH2NH2 in refluxing chloroform via a condensation reaction of the amine and formyl groups to produce the C=N double bond, gave 3a, 1-N-(cyclohexylamine)-4- N-(diphenylphosphinoethylamine)palladium(triphos)(hexafluorophasphate); a potentially bidentate [N,P] metaloligand. However, attempts to coordinate a second metal by treatment of 3a with [PdCl2(PhCN)2] were to no avail. Notwithstanding, complexes 2a and 3a left to stand in solution spontaneously self-transformed to give in either case the double nuclear complex 10, 1,4-N,N-terephthalylidene(cyclohexilamine)-3,6-[bispalladium(triphos)]di(hexafluorophosphate), after undergoing further metalation of the phenyl ring, then bearing two mutually trans [Pd(Ph2PCH2CH2)2PPh)-P,P,P] moieties: an unprecedented and serendipitous result indeed. On the other hand, reaction of the double nuclear complex 1b, di-µ-cloro-bis[N-(3-formylbenzylidene)cyclohexylaminato-C6, N]dipalladium, with Ph2PCH2CH2)2PPh (triphos) and NH4PF6 gave the single nuclear species 2b, 1-N-(cyclohexylamine)-4-N-(formyl)palladium(triphos)(hexafluorophasphate), Treatment of 2b with H2O/glacial MeCOOH gave cleavage of the C=N double bond and of the Pd···N interaction, yielding 5b, isophthalaldehyde-6-palladium(triphos)hexafluorophosphate, which then reacted with Ph2P(CH2)3NH2 to yield complex 6b, N,N-(isophthalylidene(diphenylphosphinopropylamine)-6-(palladiumtriphos)di(hexafluorophosphate), with two pairs of non-coordinated nitrogen and phosphorus donor atoms. Treatment of 6b with [PdCl2(PhCN)2], [PtCl2(PhCN)2], or [PtMe2(COD)] gave the new double nuclear complexes 7b, 8b and 9b, palladiumdichloro-, platinumdichloro- and platinumdimethyl[N,N-(isophthalylidene(diphenylphosphinopropylamine)-6-(palladiumtriphos)(hexafluorophosphate)-P,P], respectively, showing the behavior of 6b as a palladated bidentate [P,P] metaloligand. The complexes were fully characterized by microanalysis, IR, 1H, and 31P NMR spectroscopies, as appropriate. The X-ray single-crystal analyses for compounds 10 and 5b have been previously described as the perchlorate salts by JM Vila et al.

Cerium dioxide nanoparticles modulate antioxidant defences and change vascular response in the human saphenous vein.

Nanoparticles have a promising future in biomedical applications and knowing whether they affect ex vivo vascular reactivity is a necessary step before their use in patients. In this study, we have evaluated the vascular effect of cerium dioxide nanoparticles (CeO2NPs) on the human saphenous vein in response to relaxing and contractile agonists. In addition, we have measured the protein expression of key enzymes related to vascular homeostasis and oxidative stress. We found that CeO2NPs increased expression of both SOD isoforms, and the consequent reduction of superoxide anion would enhance the bioavailability of NO explaining the increased vascular sensitivity to sodium nitroprusside in the presence of CeO2NPs. The NOX4 reduction induced by CeO2NPs may lead to lower H2O2 synthesis associated with vasodilation through potassium channels explaining the lower vasodilation to bradykinin. In addition, we showed for the first time, that CeO2NPs increase the expression of ACE2 in human saphenous vein, and it may be the cause of the reduced contraction to angiotensin II. Moreover, we ruled out that CeO2NPs have effect on the protein expression of eNOS, sGC, BKca channels and angiotensin II receptors or modify the vascular response to noradrenaline, endothelin-1 and TXA2 analogue. In conclusion, CeO2NPs show antioxidant properties, and together with their vascular effect, they could be postulated as adjuvants for the treatment of cardiovascular diseases.

Facilitation of Insulin Effects by Ranolazine in Astrocytes in Primary Culture.

Ranolazine (Rn) is a drug used to treat persistent chronic coronary ischemia. It has also been shown to have therapeutic benefits on the central nervous system and an anti-diabetic effect by lowering blood glucose levels; however, no effects of Rn on cellular sensitivity to insulin (Ins) have been demonstrated yet. The present study aimed to investigate the permissive effects of Rn on the actions of Ins in astrocytes in primary culture. Ins (10-8 M), Rn (10-6 M), and Ins + Rn (10-8 M and 10-6 M, respectively) were added to astrocytes for 24 h. In comparison to control cells, Rn and/or Ins caused modifications in cell viability and proliferation. Rn increased protein expression of Cu/Zn-SOD and the pro-inflammatory protein COX-2 was upregulated by Ins. On the contrary, no significant changes were found in the protein expression of NF-κB and IκB. The presence of Rn produced an increase in p-ERK protein and a significant decrease in COX-2 protein expression. Furthermore, Rn significantly increased the effects of Ins on the expression of p-AKT, p-eNOS, p-ERK, Mn-SOD, and PPAR-γ. In addition, Rn + Ins produced a significant decrease in COX-2 expression. In conclusion, Rn facilitated the effects of insulin on the p-AKT, p-eNOS, p-ERK, Mn-SOD, and PPAR-γ signaling pathways, as well as on the anti-inflammatory and antioxidant effects of the hormone.

Cyclometallated Palladium(II) Complexes: An Approach to the First Dinuclear Bis(iminophosphorane)phosphane-[C,N,S] Metallacycle.

Treatment of bis(iminophosphorane)phosphane ligands 2a-2e with Li2PdCl4 gave a set of novel diphosphane-derived complexes bearing two metallacycle rings, each one enclosing a P=N double bond: the unprecedented bis(iminophosphorane)phosphane-[C,N,S] palladacycles. In the case of the ligand derived from bis(diphenylphosphino)methane, 2a, both the single and the double palladacycle complexes were obtained. Reaction of 3a with bis(diphenylphosphino)ethane did not yield the expected product with the diphosphane bonded to both palladium atoms, but rather the novel coordination compound 5. The crystal structures of 3c and 5 are described.

Cyclometallated Platinum(II) Complexes with Small Crown Ether Rings: Appropriate Choice of the Bridging Diphosphane to Coordinate Potassium Cations.

This account reports the synthesis and structural characterization of the first cyclometallated platinum(II) complex that coordinates a potassium cation in a sandwich arrangement via two 15-crown-5 ether rings within the same molecule. The cooperation of the two small crown ether moieties allows the entrapment of the non-ideal potassium ion. The reaction of the parent thiosemicarbazone ligand 3,4-(C8H16O5)C6H3C(Me)=NN-(H)C(=S)NHMe, 1, containing the crown ether ring, with K2[PtCl4], or alternatively with PtCl2(DMSO)2, and subsequent treatment with the diphosphanes Ph2PCH2PPh2 (dppm) and Ph2PC(=CH2)PPh2 (vdpp) produced the double nuclear platinacycles 3a, 3b, and 4, probably via formation of the 2a and 2b intermediates. Complex 3a with the K+ cation in a sandwich coordination was slightly mixed with 3b lacking any K+. Alternatively, reaction of 1 with K2[PtCl4] or with PtCl2(DMSO)2 followed by the diphosphane Ph2PC(=CH2)PPh2 (vdpp) only gave the dinuclear phosphane-bridged compound 4; this highlights the importance of choosing the right diphosphane ligand. Density functional theory calculations (B3LYP-D3/LANL2DZ-ECP-6.311++G**) revealed similar affinities for both dppm and vdpp derivatives to coordinate potassium cations. Crystal structure analysis was performed for compounds 3a and 4.

Imine Palladacycles: Synthesis, Structural Analysis and Application in Suzuki-Miyaura Cross Coupling in Semi-Aqueous Media.

Treatment of the imines a-c with palladium(II) acetate in acetic acid yielded the µ-acetate dinuclear complexes 1a-c, which readily reacted with sodium chloride or bromide to provide µ-halide analogues. The reaction of the latter with nitrogen, phosphorus and oxygen donor nucleophiles yielded new imine palladacycles following the cleavage of the Pd2X2 unit. The complexes were fully characterized by microanalysis, 1H, 13C and 31P NMR spectroscopies, as appropriate. The compounds were applied as catalysts in the Suzuki-Miyaura coupling reaction in aqueous and semi-aqueous media.

Deleterious effects of levamisole, a cocaine adulterant, in rabbit aorta.

Levamisole, a veterinary anthelmintic drug, is one of the most widely used and dangerous cocaine adulterants. Like cocaine, levamisole acutely blocks noradrenaline reuptake but with much less potency, although its vascular effects are not well known. In this study, we evaluated the vascular effects of levamisole and cocaine in rabbit aortic rings used for isometric recording of tension in organ baths and protein expression by western blot. Our results indicated that levamisole (10-5-10-3 M) induced a concentration-dependent relaxation in rings precontracted with noradrenaline (10-7-3 × 10-7 M). Furthermore, it reduced the contractile response to phenylephrine (10-9-3 × 10-5 M) that was not modified by cocaine (10-5-10-4 M), and reduced α1-adrenergic receptor expression. Levamisole (10-6-10-4 M) produced a potentiation of the electrical field stimulation that was not further enhanced by the combination of both drugs. However, high concentrations of levamisole (10-3 M) abolished adrenergic neurotransmission whether administered alone or with cocaine (10-4 M). In addition, levamisole (10-5-10-3 M) also decreased endothelium-dependent relaxation to acetylcholine that was not further impaired by cocaine (10-4 M), and that was partially reversed by superoxide dismutase (SOD, 200 U/ml). These results demonstrate that levamisole has a dual effect on the adrenergic system, and its effects are independent of the presence of cocaine. At lower concentrations, it enhances the contractile sympathetic response by blocking presynaptic α2-adrenergic receptors, while at high concentrations, the effect of the antagonism of α1-adrenergic receptor prevails. In addition, levamisole induces endothelial dysfunction by reducing NO bioavailability, and this effect could be in part mediated by oxidative stress.

EpCAM and microvascular obstruction in patients with STEMI: a cardiac magnetic resonance study.

INTRODUCTION AND OBJECTIVES: Microvascular obstruction (MVO) is negatively associated with cardiac structure and worse prognosis after ST-segment elevation myocardial infarction (STEMI). Epithelial cell adhesion molecule (EpCAM), involved in epithelium adhesion, is an understudied area in the MVO setting. We aimed to determine whether EpCAM is associated with the appearance of cardiac magnetic resonance (CMR)-derived MVO and long-term systolic function in reperfused STEMI. METHODS: We prospectively included 106 patients with a first STEMI treated with percutaneous coronary intervention, quantifying serum levels of EpCAM 24hours postreperfusion. All patients underwent CMR imaging 1 week and 6 months post-STEMI. The independent correlation of EpCAM with MVO, systolic volume indices, and left ventricular ejection fraction was evaluated. RESULTS: The mean age of the sample was 59±13 years and 76% were male. Patients were dichotomized according to median EpCAM (4.48 pg/mL). At 1-week CMR, lower EpCAM was related to extensive MVO (P=.021) and larger infarct size (P=.019). At presentation, EpCAM values were significantly associated with the presence of MVO in univariate (OR, 0.58; 95%CI, 0.38-0.88; P=.011) and multivariate logistic regression models (OR, 0.55; 95%CI, 0.35-0.87; P=.010). Although MVO tends to resolve at chronic phases, decreased EpCAM was associated with worse systolic function: reduced left ventricular ejection fraction (P=.009) and higher left ventricular end-systolic volume (P=.043). CONCLUSIONS: EpCAM is associated with the occurrence of CMR-derived MVO at acute phases and long-term adverse ventricular remodeling post-STEMI.

PPARγ as an indicator of vascular function in an experimental model of metabolic syndrome in rabbits.

BACKGROUND AND AIMS: Underlying mechanisms associated with vascular dysfunction in metabolic syndrome (MetS) remain unclear and can even vary from one vascular bed to another. METHODS: In this study, MetS was induced by a high-fat, high-sucrose diet, and after 28 weeks, aorta and renal arteries were removed and used for isometric recording of tension in organ baths, protein expression by Western blot, and histological analysis to assess the presence of atherosclerosis. RESULTS: MetS induced a mild hypertension, pre-diabetes, central obesity and dyslipidaemia. Our results indicated that MetS did not change the contractile response in either the aorta or renal artery. Conversely, vasodilation was affected in both arteries in a different way. The aorta from MetS showed vascular dysfunction, including lower response to acetylcholine and sodium nitroprusside, while the renal artery from MetS presented a preserved relaxation to acetylcholine and an increased sensitivity to sodium nitroprusside. We did not find vascular oxidative stress in the aorta from MetS, but we found a significant decrease in PPARγ, phospho-Akt (p-Akt) and phospho-eNOS (p-eNOS) protein expression. On the other hand, we found oxidative stress in the renal artery from MetS, and PPARγ, Akt and p-Akt were overexpressed. No evidence of atherosclerosis was found in arteries from MetS. CONCLUSIONS: MetS affects vascular function differently depending on the vessel. In the aorta, it decreases both the vasodilation and the expression of the PPARγ/Akt/eNOS pathway, while in the renal artery, it increases the expression of PPARγ/Akt signalling pathway without decreasing the vasodilation.

Ischemia-reperfusion injury to coronary arteries: Comprehensive microscopic study after reperfused myocardial infarction.

BACKGROUND: Coronary arteries supply oxygen and nutrients to the heart. We evaluated the dynamics of microscopic damage throughout the ischemia-reperfusion process in the wall of coronary arteries following myocardial infarction (MI). METHODS: In a swine model of reperfused MI, animals were divided into one control and four MI groups: 90-min ischemia without reperfusion, or followed by one minute, one week or one month reperfusion. Left anterior descending (LAD; infarct-related artery) and control right coronary arteries (RCA) were isolated. Taking the balloon inflation region as a reference, we isolated the proximal and distal LAD areas, performing histological staining and immunohistochemistry. RESULTS: Although mild changes in tunica intima were observed during ischemia, an almost complete absence of endothelium, and abnormal breaks in the internal elastic layer were found post-revascularization. In tunica media, increased thickness was observed soon after reperfusion, whereas larger thickness, disorganized muscle cell distribution and edema were found one week after reperfusion. This damage was more pronounced in distal rather than proximal LAD, whereas no changes were detected in RCA. In the tunica adventitia, vasa vasorum density decayed during ischemia in both LAD regions, but was restored after one month. Leukocyte adhesion to the artery was observed post-revascularization, developing into a massive presence in the three layers one week post-reperfusion. CONCLUSIONS: Ischemia-reperfusion can itself induce damage in the wall of the epicardial coronary artery, becoming more pronounced in the region distal to balloon inflation. Exploring these abnormalities will provide insight into the pathophysiology of coronary circulation and MI.

Overexpression of genes involved in lymphocyte activation and regulation are associated with reduced CRM-derived cardiac remodelling after STEMI.

AIMS: Lymphopenia after ST-segment elevation myocardial infarction (STEMI) correlates with deleterious cardiac consequences and worse prognosis. An in-depth examination of genes implicated in lymphocyte proliferation, activation and regulation and their association with short- and long-term cardiac structure and function is therefore of great interest. METHODS: Peripheral blood mononuclear cells were isolated from 10 control subjects and 64 patients with a first STEMI treated with primary percutaneous coronary intervention and submitted to cardiac magnetic resonance after 1 week and 6 months. mRNA expression of genes implicated in lymphocyte activation (CD25 and CD69) and regulation [programmed death (PD)-1 and cytotoxic T-lymphocyte antigen (CTLA)-4] were determined by qRT-PCR. RESULTS: In comparison to controls, STEMI patients showed heightened mRNA expression of CD25 and lower PD-1 and CTLA-4 96 h after coronary reperfusion. Patients with extensive infarctions (>30% of left ventricular mass) at 1 week displayed a notable reduction in CD25, CD69, PD-1, and CTLA-4 expression (p < 0.05). However, CD25 was the only predictor of 1-week extensive infarct size in multivariate logistic regression analysis (odds ratio 0.019; 95% confidence interval [0.001-0.505]; p = 0.018). Regarding long-term ventricular function, mRNA expression of CD25 under the mean value was associated with worse ventricular function and more adverse remodelling. CONCLUSIONS: Following STEMI, heightened expression of genes expressed in regulatory T cells (CD25 and CD69) and immune checkpoints (PD-1 and CTLA-4) correlates with a better short- and long-term cardiac structure and function. Advancing understanding of the pathophysiology of lymphopenia and evaluating novel immunomodulatory therapies will help translate these results into future clinical trials.

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.

Implicación de la isoforma antiangiogénica VEGF-A165b en la angiogénesis y la función sistólica tras un infarto de miocardio reperfundido / Role of antiangiogenic VEGF-A165b in angiogenesis and systolic function after reperfused myocardial infarction

Introducción y objetivos La angiogénesis participa en la restauración de la microcirculación después de un infarto agudo de miocardio (IAM). El objetivo de este estudio es explorar el papel que juega la isoforma anti-angiogénica del factor de crecimiento endotelial vascular (VEGF)-A165b y explorar su potencial como terapia coadyuvante a la reperfusión coronaria. Métodos Se realizaron dos modelos murinos de IAM: a) ligadura permanente de la arteria coronaria (IAM no reperfundido) y b) oclusión transitoria durante 45 minutos de la arteria coronaria seguida de reperfusión (IAM reperfundido); en ambos modelos, se realizó a los animales una ecocardiografía previa a la eutanasia el día 21 pos-IAM. Se determinaron los niveles séricos y miocárdicos de VEGF- A165b. En ambos modelos experimentales se evaluó la implicación funcional y estructural del bloqueo de esta isoforma. En una cohorte de 104 pacientes con IAM con elevación del segmento ST se cuantificaron los niveles circulantes de VEGF-A165b y se estudió su asociación con la fracción de eyección del ventrículo izquierdo determinada mediante resonancia magnética cardiaca a los 6 meses del IAM, así como con la aparición de eventos adversos (muerte, insuficiencia cardiaca o reinfarto) durante el seguimiento. Resultados En ambos modelos, los niveles séricos y tisulares de VEGF-A165b habían aumentado a los 21 días de la inducción del IAM. Además, existía una correlación negativa entre los valores circulantes de VEGF-A165b y la función sistólica evaluada mediante ecocardiografía. El bloqueo in vivo de VEGF-A165b se relacionó con una mayor densidad microvascular, menor tamaño de infarto y mejor fracción de eyección en el modelo de IAM reperfundido, pero no en el modelo de IAM no reperfundido. En la cohorte de pacientes, aquellos con unos niveles séricos elevados de VEGF-A165b presentaron una fracción de eyección deprimida y una mayor tasa de eventos adversos. Conclusiones ... (AU)

Introduction and objectives Angiogenesis helps to reestablish microcirculation after myocardial infarction (MI). In this study, we aimed to further understand the role of the antiangiogenic isoform vascular endothelial growth factor (VEGF)-A165b after MI and to explore its potential as a coadjuvant therapy to coronary reperfusion. Methods Two mice MI models were formed: a) permanent coronary ligation (nonreperfused MI); b) transient 45-minute coronary occlusion followed by reperfusion (reperfused MI); in both models, animals underwent echocardiography before euthanasia at day 21 after MI induction. We determined serum and myocardial VEGF-A165b levels. In both experimental MI models, we assessed the functional and structural role of VEGF-A165b blockade. In a cohort of 104 ST-segment elevation MI patients, circulating VEGF-A165b levels were correlated with cardiovascular magnetic resonance-derived left ventricular ejection fraction at 6 months and with the occurrence of adverse events (death, heart failure, and/or reinfarction). Results In both models, circulating and myocardial VEGF-A165b levels were increased 21 days after MI induction. Serum VEGF-A165b levels inversely correlated with systolic function evaluated by echocardiography. VEGF-A165b blockade increased capillary density, reduced infarct size, and enhanced left ventricular function in reperfused, but not in nonreperfused, MI experiments. In patients, higher VEGF-A165b levels correlated with depressed ejection fraction and worse outcomes. Conclusions In experimental and clinical studies, higher serum VEGF-A165b levels are associated with worse systolic function. Their blockade enhances neoangiogenesis, reduces infarct size, and increases ejection fraction in reperfused, but not in nonreperfused, MI experiments. Therefore, VEGF-A165b neutralization represents a potential coadjuvant therapy to coronary reperfusion. (AU)

Role of antiangiogenic VEGF-A165b in angiogenesis and systolic function after reperfused myocardial infarction.

INTRODUCTION AND OBJECTIVES: Angiogenesis helps to reestablish microcirculation after myocardial infarction (MI). In this study, we aimed to further understand the role of the antiangiogenic isoform vascular endothelial growth factor (VEGF)-A165b after MI and to explore its potential as a coadjuvant therapy to coronary reperfusion. METHODS: Two mice MI models were formed: a) permanent coronary ligation (nonreperfused MI); b) transient 45-minute coronary occlusion followed by reperfusion (reperfused MI); in both models, animals underwent echocardiography before euthanasia at day 21 after MI induction. We determined serum and myocardial VEGF-A165b levels. In both experimental MI models, we assessed the functional and structural role of VEGF-A165b blockade. In a cohort of 104 ST-segment elevation MI patients, circulating VEGF-A165b levels were correlated with cardiovascular magnetic resonance-derived left ventricular ejection fraction at 6 months and with the occurrence of adverse events (death, heart failure, and/or reinfarction). RESULTS: In both models, circulating and myocardial VEGF-A165b levels were increased 21 days after MI induction. Serum VEGF-A165b levels inversely correlated with systolic function evaluated by echocardiography. VEGF-A165b blockade increased capillary density, reduced infarct size, and enhanced left ventricular function in reperfused, but not in nonreperfused, MI experiments. In patients, higher VEGF-A165b levels correlated with depressed ejection fraction and worse outcomes. CONCLUSIONS: In experimental and clinical studies, higher serum VEGF-A165b levels are associated with worse systolic function. Their blockade enhances neoangiogenesis, reduces infarct size, and increases ejection fraction in reperfused, but not in nonreperfused, MI experiments. Therefore, VEGF-A165b neutralization represents a potential coadjuvant therapy to coronary reperfusion.

Chemistry of Tetradentate [C,N : C,N] Iminophosphorane Palladacycles: Preparation, Reactivity and Theoretical Calculations.

A theoretical and experimental study of tetradentate [C,N : C,N] iminophosphorane palladacycles was carried out for the purpose of elucidating their behavior as compared to the parent Schiff base analogues to determine the prospect of encountering new A-frame structures for the iminophosphorane derivatives. The DFT calculations were in agreement with the experimental results regarding the performance of these ligands. New insights into the chemistry of the related dinuclear species have been obtained.

Similar Clinical Course and Significance of Circulating Innate and Adaptive Immune Cell Counts in STEMI and COVID-19.

This study aimed to assess the time course of circulating neutrophil and lymphocyte counts and their ratio (NLR) in ST-segment elevation myocardial infarction (STEMI) and coronavirus disease (COVID)-19 and explore their associations with clinical events and structural damage. Circulating neutrophil, lymphocyte and NLR were sequentially measured in 659 patients admitted for STEMI and in 103 COVID-19 patients. The dynamics detected in STEMI (within a few hours) were replicated in COVID-19 (within a few days). In both entities patients with events and with severe structural damage displayed higher neutrophil and lower lymphocyte counts. In both scenarios, higher maximum neutrophil and lower minimum lymphocyte counts were associated with more events and more severe organ damage. NLR was higher in STEMI and COVID-19 patients with the worst clinical and structural outcomes. A canonical deregulation of the immune response occurs in STEMI and COVID-19 patients. Boosted circulating innate (neutrophilia) and depressed circulating adaptive immunity (lymphopenia) is associated with more events and severe organ damage. A greater understanding of these critical illnesses is pivotal to explore novel alternative therapies.

The Role of Chemokines in Alzheimer's Disease.

OBJECTIVE: The most common multifactorial neurodegenerative disorder occurring in old age is Alzheimer's disease. The neuropathological hallmarks of that disorder are amyloid plaques with the presence of ß -amyloid aggregates, intraneuronal tau protein tangles, and chronic inflammation. Brain cells such as microglia and astrocytes are inflammatory cells associated with Alzheimer's disease and involved in the production of inflammatory mediators, such as cytokines and chemokines. Chemokines consist of a large family of protein mediators with low molecular weight, which able to control the migration and residence of all immune cells. In pathological conditions, such as Alzheimer's disease, chemokines contribute to the inflammatory response by recruiting T cells and controlling microglia/ macrophages activation. METHODS: The present study focuses on the role that chemokines and their receptors play in Alzheimer's disease and in processes such as inflammation and oxidative stress. RESULTS: Chemokines are important mediators in AD and inflammation. They promote Aß deposition and TAU hyperphosphorylation aggravating and increasing the progression of AD. Moreover, they affect the processing of senile plaques and produce abnormal TAU phosphorylation. CONCLUSION: There is no cure for AD but the therapeutic potential of chemokines to control the development of the disease may be a field of study to consider in the future.