Cardiovascular diseases (CVDs), including atherosclerosis, are globally the leading cause of death. Key factors contributing to onset and progression of atherosclerosis include the pro-inflammatory ...cytokines Interferon (IFN)α and IFNγ and the Pattern Recognition Receptor (PRR) Toll-like receptor 4 (TLR4). Together, they trigger activation of Signal Transducer and Activator of Transcription (STAT)s. Searches for compounds targeting the pTyr-SH2 interaction area of STAT3, yielded many small molecules, including STATTIC and STX-0119. However, many of these inhibitors do not seem STAT3-specific. We hypothesized that multi-STAT-inhibitors that simultaneously block STAT1, STAT2, and STAT3 activity and pro-inflammatory target gene expression may be a promising strategy to treat CVDs. Using comparative
docking of multiple STAT-SH2 models on multi-million compound libraries, we identified the novel multi-STAT inhibitor, C01L_F03. This compound targets the SH2 domain of STAT1, STAT2, and STAT3 with the same affinity and simultaneously blocks their activity and expression of multiple STAT-target genes in HMECs in response to IFNα. The same
and
multi-STAT inhibiting capacity was shown for STATTIC and STX-0119. Moreover, C01L_F03, STATTIC and STX-0119 were also able to affect genome-wide interactions between IFNγ and TLR4 by commonly inhibiting pro-inflammatory and pro-atherogenic gene expression directed by cooperative involvement of STATs with IRFs and/or NF-κB. Moreover, we observed that multi-STAT inhibitors could be used to inhibit IFNγ+LPS-induced HMECs migration, leukocyte adhesion to ECs as well as impairment of mesenteric artery contractility. Together, this implicates that application of a multi-STAT inhibitory strategy could provide great promise for the treatment of CVDs.
In HIV-1/HCV-coinfected patients, chronic HCV infection leads to an increased T-lymphocyte immune activation compared to HIV-monoinfected patients, thereby likely contributing to increase HIV-1 ...reservoir that is the major barrier for its eradication. Our objective was to evaluate the influence of HCV coinfection in HIV-1 viral reservoir size in resting (r) CD4+ T-cells (CD25-CD69-HLADR-). Multicenter cross-sectional study of 97 cART-treated HIV-1 patients, including 36 patients with HIV and HCV-chronic co-infection without anti-HCV treatment, 32 HIV patients with HCV spontaneous clearance and 29 HIV-monoinfected patients. rCD4+ T-cells were isolated and total DNA was extracted. HIV viral reservoir was measured by Alu-LTR qPCR. Differences between groups were calculated with a generalized linear model. Overall, 63.9% were men, median age of 41 years and Caucasian. Median CD4+ and CD8+ T-lymphocytes were 725 and 858 cells/mm
, respectively. CD4+ T nadir cells was 305 cells/mm
. Proviral HIV-1 DNA size was significantly increased in chronic HIV/HCV-coinfected compared to HIV-monoinfected patients (206.21 ± 47.38 vs. 87.34 ± 22.46, respectively; P = 0.009), as well as in spontaneously clarified HCV co-infected patients when compared to HIV-monoinfected individuals (136.20 ± 33.20; P = 0.009). HIV-1/HCV co-infected patients showed a larger HIV-1 reservoir size in comparison to HIV-monoinfected individuals. This increase could lead to a greater complexity in the elimination of HIV-1 reservoir in HIV-1/HCV-coinfected individuals, which should be considered in the current strategies for the elimination of HIV-1 reservoir.
Sialodochitis fibrinosa is a rare disease which is characterized by recurring episodes of pain and swelling of the salivary glands due to the formation of mucofibrinous plugs. Analytic studies ...ascertain elevated levels of eosinophils and immunoglobulin E (IgE). Imaging studies such as magnetic resonance imaging (MRI) and sialography reveal dilation of the main salivary duct (duct ectasia). Treatment is initially supportive, consisting of compressive massages, and use of antihistamines and/or corticosteroids.
In the following, 3 cases of sialodochitis fibrinosa are presented which were diagnosed in a third level hospital during the period of 2008 and 2016, as well as a literature review of all cases reported to our knowledge.
Of the 41 cases found, including the 3 of this article, 66% were women with an average age of 45 years old. However, 75% of reported cases were of Japanese heritage. Involvement of the parotid glands was more frequent than the submandibular glands. In more than half of all cases treatment with compressive massages, antihistamines and/or corticosteroids was effective.
Clinicians should consider sialodochitis fibrinosa as a diagnostic possibility when presented with cases of recurring parotid and submandibular gland tumescence.
In this work we report on water-free proton conductivity in liquid-crystal pyridylpyrazolate-based Pt(II) and Pd(II) complexes M(pzR(n,n)py)2 (pzR(n,n)py = ...3-(3,5-dialkyloxyphenyl)-5-(pyridin-2-yl)pyrazolate, R(n,n) = C6H3(OC n H2n+1)2; n = 4, 12, 16, M = Pd; n = 12, M = Pt) with potential application as electrolyte materials in proton exchange membrane fuel cells. The columnar ordering of the complexes in the liquid-crystalline phase opens nanochannels, which are used for fast proton exchange as detected by impedance spectroscopy and NMR. The NMR spectra indicate that the proton conduction mechanism is associated with a novel C–H···N proton transfer, which persists above the clearing point of the material. The highest conductivity of ∼0.5 μS cm–1 at 180 °C with an activation energy of 1.2 eV is found for the Pt(II) compound in the mesophase. The Pd(II) complexes with different chain length (n = 4, 12, and 16) show lower conductivity but smaller activation energies, in the range of 0.74–0.93 eV.
The aim of this study was to establish guidelines for the optimization of biologic therapies for health professionals involved in the management of patients with RA, AS and PsA.
Recommendations were ...established via consensus by a panel of experts in rheumatology and hospital pharmacy, based on analysis of available scientific evidence obtained from four systematic reviews and on the clinical experience of panellists. The Delphi method was used to evaluate these recommendations, both between panellists and among a wider group of rheumatologists.
Previous concepts concerning better management of RA, AS and PsA were reviewed and, more specifically, guidelines for the optimization of biologic therapies used to treat these diseases were formulated. Recommendations were made with the aim of establishing a plan for when and how to taper biologic treatment in patients with these diseases.
The recommendations established herein aim not only to provide advice on how to improve the risk:benefit ratio and efficiency of such treatments, but also to reduce variability in daily clinical practice in the use of biologic therapies for rheumatic diseases.
Antibiotic resistance is a global current threat of increasing importance. Moreover, biofilms represent a medical challenge since the inherent antibiotic resistance of their producers demands the use ...of high doses of antibiotics over prolonged periods. Frequently, these therapeutic measures fail, contributing to bacterial persistence, therefore demanding the development of novel antimicrobials. Esters of bicyclic amines (EBAs), which are strong inhibitors of Streptococcus pneumoniae growth, were initially designed as inhibitors of pneumococcal choline-binding proteins on the basis of their structural analogy to the choline residues in the cell wall. However, instead of mimicking the characteristic cell chaining phenotype caused by exogenously added choline on planktonic cultures of pneumococcal cells, EBAs showed an unexpected lytic activity. In this work we demonstrate that EBAs display a second, and even more important, function as cell membrane destabilizers. We then assayed the inhibitory and disintegrating activity of these molecules on pneumococcal biofilms. The selected compound (EBA 31) produced the highest effect on S. pneumoniae (encapsulated and non-encapsulated) biofilms at very low concentrations. EBA 31 was also effective on mixed biofilms of non-encapsulated S. pneumoniae plus non-typeable Haemophilus influenzae, two pathogens frequently forming a self-produced biofilm in the human nasopharynx. These results support the role of EBAs as a promising alternative for the development of novel, broad-range antimicrobial drugs encompassing both Gram-positive and Gram-negative pathogens.
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•Esters of bicyclic amines (EBAs) destabilize the bacterial membrane.•EBAs trigger the premature autolysis of Streptococcus pneumoniae by LytA autolysin.•EBAs disrupt mixed biofilms formed by S. pneumoniae and Haemophilus influenzae.•Broad-spectrum effect of EBAs is useful to fight antimicrobial resistance.
The aim of this study is to assess the effects of the addition of aluminum (NaAlO2) into the activating solution on the geopolymerization reactions and the characteristics of the porous network. It ...was established by liquid state NMR that the speciation of the aluminosilicate oligomers and then the mean degree of polymerization were modified by the addition of sodium aluminate in the activating solution. Time-resolved SAXS and rheology results on geopolymer pastes showed that the molar ratios Si/Al and (Si+Al)/Na2O in the activating solution play a major role in the geopolymer properties at liquid and solid state. Indeed, the geopolymer percolating network appeared sooner and the properties of the porous network were dramatically changed with the addition of the NaAlO2. On the other hand, two geopolymers having identical final chemical composition but a different activating solution composition, showed to the same setting time and the same porous network characteristics.
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Porphyria cutanea tarda (PCT) is common and usually associated with HCV chronic infection and HFE polymorphisms. Since DAA IFN-free regimens availability, SVR for HCV is nearly a constant and we ...wonder whether HCV SVR determine PCT evolution.
Retrospective observational study including patients with HCV associated PCT from the Gastroenterology and Infectious Diseases Departments at our Hospital, treated with DAA (Apr/2015–Apr/2017). Clinical variables of PCT were collected at PCT diagnosis, after PCT treatment, before DAA use and after SVR achievement. UROD activity and C282Y/H63D polymorphisms were registered. SPSS 22.0.
13 HCV-PCT patients included: median age 52.5 years; 4 females; 8 HCV/HIV co-infected (all on undetectable viral load). Classical PCT factors: 12 smoked, 9 alcohol abuse, 6 former IDU. 10 type I PCT and 1 type II PCT. HFE polymorphism: 2 cases with C282Y/H63D; H63D polymorphism in 8. PCT manifestations resolved with PCT treatment in 4 patients, almost completely in 7 patients, 1 patient referred stabilization and one worsened. After DAA treatment all the residual lesions resolved, what always led to specific treatment interruption.
Our series of cases of HCV-associated PCT shows that SVR after DAA treatment leads to PCT resolution. Porphyrin levels are not needed after ending PCT specific treatment interruption when there are no residual skin lesions in HCV-associated PCT.
La porfiria cutánea tarda (PCT) es un trastorno frecuentemente asociado con la infección por VHC y los polimorfismos HFE. Desde la aparición de los AAD en regímenes libres de IFN, la RVS para el VHC es casi universal. Nos preguntamos si la RVS del VHC determina la evolución de la PCT asociada al VHC.
Estudio observacional retrospectivo con pacientes con PCT asociada al VHC atendidos en Gastroenterología y Enfermedades Infecciosas en nuestro centro, tratados con AAD (abril 2015 - abril 2017). Se registra información relacionada con la PCT en el momento del diagnóstico, tras iniciar tratamiento para la PCT, antes de AAD y tras RVS. Analizamos la actividad UROD y los polimorfismos C282Y/H63D. SPSS 22.0.
Se incluyen 13 pacientes con PCT asociada al VHC: edad mediana 52,5 años; 4 mujeres; 8 coinfectados VHC/VIH (todos con VIH indetectable). Factores asociados a PCT: 12 fumadores, 9 alcohol, 6 ADVP. Hubo 10 PCT clasificadas como tipo I y una PCT tipo II. HFE: 2 casos C282Y/H63D; H63D presente en 8. Tras iniciar tratamiento clásico para PCT los síntomas se resolvieron completamente en 4 casos, casi completamente en 7, se estabilizaron en un paciente y empeoraron en un paciente. Tras la RVS con AAD desaparecieron las lesiones residuales en los pacientes que las presentaban, lo que llevó a interrumpir todos los tratamientos para la PCT.
Nuestra serie de casos de PCT asociada al VHC muestra que la RVS para el VHC tras AAD conduce siempre a la curación de la PCT. Según esto no sería necesaria la determinación de porfirinas tras finalizar la terapia específica para la PCT cuando no haya lesiones cutáneas residuales en la PCT asociada al VHC.
Choline-binding proteins (CBPs) from Streptococcus pneumoniae comprise a family of modular polypeptides involved in essential events of this pathogen. They recognize the choline residues present in ...the teichoic and lipoteichoic acids of the cell wall using the so-called choline-binding modules (CBMs). The importance of CBPs in pneumococcal physiology points to them as novel targets to combat antimicrobial resistances shown by this organism. In this work we have tested the ability of exogenously added CBMs to act as CBP inhibitors by competing with the latter for the binding to the choline molecules in the bacterial surface. First, we carried out a thorough physicochemical characterization of three native CBMs, namely C-LytA, C-Cpl1, and C-CbpD, and assessed their affinity for choline and macromolecular, pneumococcal cell-wall mimics. The interaction with these substrates was evaluated by molecular modeling, analytical ultracentrifugation, surface plasmon resonance, and fluorescence and circular dichroism spectroscopies. Van’t Hoff thermal analyses unveiled the existence of one noncanonical choline binding site in each of the C-Cpl1 and C-CbpD proteins, leading in total to 5 ligand-binding sites per dimer and 4 sites per monomer, respectively. Remarkably, the binding affinities of the CBMs do not directly correlate with their native oligomeric state or with the number of choline-binding sites, suggesting that choline recognition by these modules is a complex phenomenon. On the other hand, the exogenous addition of CBMs to pneumococcal planktonic cultures caused extensive cell-chaining probably as a consequence of the inhibition of CBP attachment to the cell wall. This was accompanied by bacterial aggregation and sedimentation, causing an enhancement of bacterial phagocytosis by peritoneal macrophages. In addition, the rational design of an oligomeric variant of a native CBM led to a substantial increase in its antibacterial activity by multivalency effects. These results suggest that CBMs might constitute promising nonlytic antimicrobial candidates based on the natural induction of the host defense system.
Cardiovascular disease (CVD) is a major comorbidity in chronic obstructive pulmonary disease (COPD). Although the mechanism of its development remains largely unknown, it appears to be associated ...with cigarette consumption and reduced lung function. Therefore, the aim of this study was to investigate the potential link between water-soluble cigarette smoke extract (CSE)-induced endothelial dysfunction and the function of CXCL16/CXCR6 axis on the initial attachment of leukocytes, in addition to its possible impact on COPD-associated systemic inflammation. To do this, we employed several experimental approaches, including RNA silencing and flow cytometry analysis, the dynamic flow chamber technique, and intravital microscopy in the cremasteric arterioles of animals exposed to cigarette smoke (CS). CSE-induced arterial CXCL16 expression, leading to increased platelet-leukocyte and mononuclear cell adhesiveness. CSE-induced CXCL16 expression was dependent on Nox5 expression and subsequent RhoA/p38 MAPK/NF-κB activation. Flow cytometry analysis revealed that COPD patients (
= 35) presented greater numbers of activated circulating platelets (PAC-1
and P-selectin
) expressing CXCL16 and CXCR6 as compared with age-matched controls (
= 17), with a higher number of CXCR6
-platelets in the smoking COPD group than in ex-smokers. This correlated with enhanced circulating CXCR6
-platelet-leukocyte aggregates in COPD patients. The increase in circulating numbers of CXCR6-expressing platelets and mononuclear cells resulted in enhanced platelet-leukocyte and leukocyte adhesiveness to CSE-stimulated arterial endothelium, which was greater than that found in age-matched controls and was partly dependent on endothelial CXCL16 upregulation. Furthermore, CS exposure provoked CXCL16-dependent leukocyte-arteriolar adhesion in cremasteric arterioles, which was significantly reduced in animals with a nonfunctional CXCR6 receptor. In conclusion, we provide the first evidence that increased numbers of CXCR6-expressing circulating platelets and mononuclear leukocytes from patients with COPD might be a marker of systemic inflammation with potential consequences in CVD development. Accordingly, CXCL16/CXCR6 axis blockade might constitute a new therapeutic approach for decreasing the risk of CVD in COPD patients.
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