Systemic Immune Responses in Alzheimer’s Disease: In Vitro Mononuclear Cell Activation and Cytokine Production

To investigate the systemic signs of immune-inflammatory responses in Alzheimer’s disease (AD), in the present study we have analyzed blood lymphocyte subsets and the expression of activation markers on peripheral blood mononuclear cells (PBMCs) fromADpatients and age-matched healthy controls (HC) activated in vitro by recombinant amyloid-β peptide (rAβ42). Our study of AD lymphocyte subpopulations confirms the already described decrease of the absolute number and percentage of B cells when compared to HC lymphocytes, whereas the other subsets are not significantly different in patients and controls. We report the increased expression of the activation marker CD69 and of the chemokine receptors CCR2 and CCR5 on T cells but no changes of CD25 after activation. B cells are also activated by rAβ42 as demonstrated by the enhanced expression of CCR5. Moreover, rAβ42 induces an increased expression of the scavenger receptor CD36 on monocytes. Some activation markers and chemokine receptors are overexpressed in unstimulated AD cells when compared to controls. This is evidence of the pro-inflammatory status of AD. Stimulation by rAβ42 also induces the production of the pro-inflammatory cytokines IL-1β, IL-6, IFN-γ, and TNF-α, and of the anti-inflammatory cytokines IL-10 and IL-1Ra. The chemokines RANTES, MIP-1β, and eotaxin as well as some growth factors (GM-CSF, G-CSF) are also overproduced by AD-derived PBMC activated by rAβ42. These results support the involvement of systemic immunity in AD patients. However, our study is an observational one so we cannot draw a conclusion about its contribution to the pathophysiology of the disease

Facile Preparation of N-Glycosylated 10-Piperazinyl Artemisinin Derivatives and Evaluation of Their Antimalarial and Cytotoxic Activities

According to the precepts that C-10 amino-artemisinins display optimum biological activities for the artemisinin drug class, and that attachment of a sugar enhances specificity of drug delivery, polarity and solubility so as to attenuate toxicity, we assessed the effects of attaching sugars to N-4 of the dihydroartemisinin (DHA)-piperazine derivative prepared in one step from DHA and piperazine. N-Glycosylated DHA-piperazine derivatives were obtained according to the Kotchetkov reaction by heating the DHA-piperazine with the sugar in a polar solvent. Structure of the D-glucose derivative is secured by X-ray crystallography. The D-galactose, L-rhamnose and D-xylose derivatives displayed IC50 values of 0.58\u20130.87 nM against different strains of Plasmodium falciparum (Pf ) and selectivity indices (SI) >195, on average, with respect to the mouse fibroblast WEHI-164 cell line. These activities are higher than those of the amino-artemisinin, artemisone (IC50 0.9\u20131.1 nM). Notably, the D-glucose, D-maltose and D-ribose derivatives were the most active against the myelogenous leukemia K562 cell line with IC50 values of 0.78\u20130.87 M and SI > 380 with respect to the human dermal fibroblasts (HDF). In comparison, artemisone has an IC50 of 0.26 M, and a SI of 88 with the same cell lines. Overall, the N-glycosylated DHA-piperazine derivatives display antimalarial activities that are greatly superior to O-glycosides previously obtained from DHA

Salinomycin and Other Ionophores as a New Class of Antimalarial Drugs with Transmission-Blocking Activity

The drug target profile proposed by the Medicines for Malaria Venture for a malaria elimination/eradication policy focuses on molecules active on both asexual and sexual stages of Plasmodium, thus with both curative and transmission-blocking activities. The aim of the present work was to investigate whether the class of monovalent ionophores, which includes drugs used in veterinary medicine and that were recently proposed as human anticancer agents, meets these requirements. The activity of salinomycin, monensin, and nigericin on Plasmodium falciparum asexual and sexual erythrocytic stages and on the development of the Plasmodium berghei and P. falciparum mosquito stages is reported here. Gametocytogenesis of the P. falciparum strain 3D7 was induced in vitro, and gametocytes at stage II and III or stage IV and V of development were treated for different lengths of time with the ionophores and their viability measured with the parasite lactate dehydrogenase (pLDH) assay. The monovalent ionophores efficiently killed both asexual parasites and gametocytes with a nanomolar 50% inhibitory concentration (IC50). Salinomycin showed a fast speed of kill compared to that of standard drugs, and the potency was higher on stage IV and V than on stage II and III gametocytes. The ionophores inhibited ookinete development and subsequent oocyst formation in the mosquito midgut, confirming their transmission-blocking activity. Potential toxicity due to hemolysis was excluded, since only infected and not normal erythrocytes were damaged by ionophores. Our data strongly support the downstream exploration of monovalent ionophores for repositioning as new antimalarial and transmission-blocking leads

Salinomycin and other ionophores as a new class of antimalarial drugs with transmission-blocking activity

The drug target profile proposed by the Medicines for Malaria Venture for a malaria elimination/eradication policy focuses on molecules active on both asexual and sexual stages of Plasmodium, thus with both curative and transmission-blocking activities. The aim of the present work was to investigate whether the class of monovalent ionophores, which includes drugs used in veterinary medicine and that were recently proposed as human anticancer agents, meets these requirements. The activity of salinomycin, monensin, and nigericin on Plasmodium falciparum asexual and sexual erythrocytic stages and on the development of the Plasmodium berghei and P. falciparum mosquito stages is reported here. Gametocytogenesis of the P. falciparum strain 3D7 was induced in vitro, and gametocytes at stage II and III or stage IV and V of development were treated for different lengths of time with the ionophores and their viability measured with the parasite lactate dehydrogenase (pLDH) assay. The monovalent ionophores efficiently killed both asexual parasites and gametocytes with a nanomolar 50% inhibitory concentration (IC50). Salinomycin showed a fast speed of kill compared to that of standard drugs, and the potency was higher on stage IV and V than on stage II and III gametocytes. The ionophores inhibited ookinete development and subsequent oocyst formation in the mosquito midgut, confirming their transmission-blocking activity. Potential toxicity due to hemolysis was excluded, since only infected and not normal erythrocytes were damaged by ionophores. Our data strongly support the downstream exploration of monovalent ionophores for repositioning as new antimalarial and transmission-blocking leads

The T.O.S.C.A. Project: Research, Education and Care

Despite recent and exponential improvements in diagnostic- therapeutic pathways, an existing “GAP” has been revealed between the “real world care” and the “optimal care” of patients with chronic heart failure (CHF). We present the T.O.S.CA. Project (Trattamento Ormonale dello Scompenso CArdiaco), an Italian multicenter initiative involving different health care professionals and services aiming to explore the CHF “metabolic pathophysiological model” and to improve the quality of care of HF patients through research and continuing medical education

Последовательность действий при визуализации кровоизлияний/гематом мягких тканей у пожилых больных, инфицированных SARS-CoV-2

Aim. To determine ultrasound, computed tomography and angiographic image characteristics for soft tissue hemorrhages/hematomas, the sequence of using imaging methods in patients infected with SARS-CoV-2, to study the morphology of changes in soft tissues, to determine the essence of the concept and to develop treatment tactics for this complication of COVID-19.Material and methods. During 4 months of treatment of elderly patients (+60) infected with SARS-CoV-2, 40 patients were identified with soft tissue hemorrhages/hematomas, of which 26 (65%) patients with large hematomas (>10 cm in size and > 1000 ml in volume). The analysis of clinical and laboratory parameters, methods of instrumental diagnostics (ultrasound – 26 patients, CT – 10 patients, angiography – 9 patients, punctures – 6 patients) was carried out; autopsy material was studied in 11 cases.Results. Image characteristics of hemorrhages/hematomas of soft tissue density were obtained using modern instrumental methods, and the sequence of application of visualization methods was determined. A tactic for managing a patient with stopped and ongoing bleeding has been developed. The morphological substrate of hemorrhagic complications in a new viral infection was studied. All patients were treated with conservative and minimally invasive procedures (embolization, puncture with pressure bandage). 15 patients (57.7%) recovered, 11 patients (42.3%) died from the progression of COVID-19 complications.Conclusion. Comprehensive clinical and laboratory sequential instrumental diagnosis of soft tissue hemorrhages in COVID-19. Treatment should be conservative and significantly invasive. The use of the term “soft tissue hematoma” in SARS-CoV-2 infected patients is not a natural quality of the normal pathological process and should not be observed from our point of view.Цель исследования: определить визуальные ультразвуковые, компьютерно-томографические и ангиографические критерии мягкотканных кровоизлияний/гематом, последовательность использования методов визуализации у больных, инфицированных SARS-CoV-2, изучить морфологию изменений в мягких тканях, определить суть понятия и выработать лечебную тактику при таком осложнении COVID-19.Материал и методы. За 4 мес лечения пожилых больных (+60), инфицированных SARS-CoV-2, выявлено 40 пациентов с мягкотканными кровоизлияниями/гематомами, из них 26 (65%) пациентов с большими гематомами (размер >10 см и объем> 1000 мл). Проведен анализ клинико-лабораторных показателей, методов инструментальной диагностики (УЗИ – 26 пациентов, КТ – 10 пациентов, ангиография – 9 больных, пункции – 6 пациентов), в 11 случаях изучен материал аутопсии.Результаты. Современными инструментальными методами получена визуальная характеристика крово излияний/гематом мягкотканной плотности, определена последовательность применения методов визуализации. Разработана тактика ведения пациента при остановившемся и продолжающемся кровотечении. Изучен морфологический субстрат геморрагического осложнения при новой вирусной инфекции. Все больные пролечены консервативными и минимально инвазивными процедурами (эмболизация, пункция с давящей повязкой). Выздоровели 15 (57,7%) пациентов, умерли от прогрессирования осложнений COVID-19 11 (42,3%) больных.Заключение. Комплексная клинико-лабораторная последовательная инструментальная диагностика мягкотканных кровоизлияний при COVID-19-инфекции позволяет своевременно установить топический диагноз, оценить тяжесть кровопотери, ее остановку или продолжение кровотечения. Лечение должно носить консервативный и минимально инвазивный характер. Использование термина “гематома” мягких тканей у инфицированных SARS-CoV-2 больных не отражает суть происходящего патологического процесса и, с нашей точки зрения, не должно использоваться

Indole derivatives useful for treating resistance to antitumor agents

The use of a group of indole compounds of formula (I) is described for treating tumours which have developed resistance to antitumour drugs. The compounds of formula (I) can be used in monotherapy, to treat tumours affected by drug resistance, or in co-therapy, as synergistic enhancers of the action of the aforesaid antitumour drugs. In addition, pharmaceutical compositions are described which comprise the indole derivatives of formula (I) in association with antitumour drugs the activity of which is to be enhance

Indole and Azaindole Derivatives For the Treatment of Inflammatory and Autoimmune Diseases

The use is described of compounds of formula (I) wherein A is chosen from a phenyl or a heterocyclic ring with 5 or 6 members containing up to two heteroatoms chosen from nitrogen, oxygen and sulfur, X and Y represent carbon or nitrogen, and R1-R6 are as described in the specification, in the prevention and/or treatment of inflammatory and autoimmune diseases