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1.
BMC Immunol ; 25(1): 49, 2024 Jul 26.
Artículo en Inglés | MEDLINE | ID: mdl-39061002

RESUMEN

BACKGROUND: The systemic inflammatory syndrome called "cytokine storm" has been described in COVID-19 pathogenesis, contributing to disease severity. The analysis of cytokine and chemokine levels in the blood of 21 SARS-CoV-2 positive patients throughout the phases of the pandemic has been studied to understand immune response dysregulation and identify potential disease biomarkers for new treatments. The present work reports the cytokine and chemokine levels in sera from a small cohort of individuals primarily infected with SARS-CoV-2 during the first wave of the COVID-19 pandemic in Milan (Italy). RESULTS: Among the 27 cytokines and chemokines investigated, a significant higher expression of Interleukin-9 (IL-9), IP-10 (CXCL10), MCP-1 (CCL2) and RANTES (CCL-5) in infected patients compared to uninfected subjects was observed. When the change in cytokine/chemokine levels was monitored over time, from the hospitalization day to discharge, only IL-6 and IP-10 showed a significant decrease. Consistent with these findings, a significant negative correlation was observed between IP-10 and anti-Spike IgG antibodies in infected individuals. In contrast, IL-17 was positively correlated with the production of IgG against SARS-CoV-2. CONCLUSIONS: The cytokine storm and the modulation of cytokine levels by SARS-CoV-2 infection are hallmarks of COVID-19. The current global immunity profile largely stems from widespread vaccination campaigns and previous infection exposures. Consequently, the immunological features and dynamic cytokine profiles of non-vaccinated and primarily-infected subjects reported here provide novel insights into the inflammatory immune landscape in the context of SARS-CoV-2 infection, and offer valuable knowledge for addressing future viral infections and the development of novel treatments.


Asunto(s)
COVID-19 , Quimiocinas , Citocinas , SARS-CoV-2 , Humanos , COVID-19/inmunología , COVID-19/sangre , COVID-19/epidemiología , Italia/epidemiología , SARS-CoV-2/inmunología , Femenino , Masculino , Persona de Mediana Edad , Citocinas/sangre , Anciano , Quimiocinas/sangre , Adulto , Síndrome de Liberación de Citoquinas/sangre , Síndrome de Liberación de Citoquinas/inmunología , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Biomarcadores/sangre , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Pandemias
2.
Antimicrob Agents Chemother ; 68(7): e0014324, 2024 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-38899927

RESUMEN

In response to the spread of artemisinin (ART) resistance, ART-based hybrid drugs were developed, and their activity profile was characterized against drug-sensitive and drug-resistant Plasmodium falciparum parasites. Two hybrids were found to display parasite growth reduction, stage-specificity, speed of activity, additivity of activity in drug combinations, and stability in hepatic microsomes of similar levels to those displayed by dihydroartemisinin (DHA). Conversely, the rate of chemical homolysis of the peroxide bonds is slower in hybrids than in DHA. From a mechanistic perspective, heme plays a central role in the chemical homolysis of peroxide, inhibiting heme detoxification and disrupting parasite heme redox homeostasis. The hybrid exhibiting slow homolysis of peroxide bonds was more potent in reducing the viability of ART-resistant parasites in a ring-stage survival assay than the hybrid exhibiting fast homolysis. However, both hybrids showed limited activity against ART-induced quiescent parasites in the quiescent-stage survival assay. Our findings are consistent with previous results showing that slow homolysis of peroxide-containing drugs may retain activity against proliferating ART-resistant parasites. However, our data suggest that this property does not overcome the limited activity of peroxides in killing non-proliferating parasites in a quiescent state.


Asunto(s)
Antimaláricos , Artemisininas , Plasmodium falciparum , Artemisininas/farmacología , Antimaláricos/farmacología , Plasmodium falciparum/efectos de los fármacos , Resistencia a Medicamentos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Humanos , Pruebas de Sensibilidad Parasitaria , Animales , Peróxidos/farmacología
3.
Chemistry ; 29(55): e202301642, 2023 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-37427863

RESUMEN

Malaria is the one of the deadliest infectious diseases worldwide. Chemically, quinolines are excellent ligands for metal coordination and are deployed as drugs for malaria treatment. There is a growing body of evidence indicating that metal complexes can be conjugated with antimalarial quinolines to be used as chemical tools to overcome the disadvantages of quinolines, improving their bioactive speciation, cellular distribution, and subsequently broadening the spectrum of activity to multiple stages of the complex Plasmodium life cycle. In this study, four novel complexes of ruthenium(II)- and gold(I)-containing amodiaquine (AQ) were synthesized, and a careful chemical characterization revealed the precise coordination site of AQ to the metals. Their speciation in solution was investigated, demonstrating the stability of the quinoline-metal bond. RuII - and AuI -AQ complexes were demonstrated to be potent and efficacious in inhibiting parasite growth in multiple stages of the Plasmodium life cycle as assayed in vitro and in vivo. These properties could be attributed to the ability of the metal-AQ complexes to reproduce the suppression of heme detoxification induced by AQ, while also inhibiting other processes in the parasite life cycle; this can be attributed to the action of the metallic species. Altogether, these findings indicate that metal coordination with antimalarial quinolines is a potential chemical tool for drug design and discovery in malaria and other infectious diseases susceptible to quinoline treatment.


Asunto(s)
Antimaláricos , Complejos de Coordinación , Malaria , Plasmodium , Quinolinas , Humanos , Antimaláricos/farmacología , Antimaláricos/uso terapéutico , Amodiaquina/farmacología , Complejos de Coordinación/farmacología , Complejos de Coordinación/uso terapéutico , Malaria/tratamiento farmacológico , Quinolinas/farmacología , Quinolinas/uso terapéutico , Plasmodium falciparum
4.
Mol Divers ; 2023 Jul 22.
Artículo en Inglés | MEDLINE | ID: mdl-37480422

RESUMEN

In recent years, the viral outbreak named COVID-19 showed that infectious diseases have a huge impact on both global health and the financial and economic sectors. The lack of efficacious antiviral drugs worsened the health problem. Based on our previous experience, we investigated in vitro and in silico a series of quinoline-3-carboxylate derivatives against a SARS-CoV-2 isolate. In the present study, the in-vitro antiviral activity of a series of quinoline-3-carboxylate compounds and the in silico target-based molecular dynamics (MD) and metabolic studies are reported. The compounds' activity against SARS-CoV-2 was evaluated using plaque assay and RT-qPCR. Moreover, from the docking scores, it appears that the most active compounds (1j and 1o) exhibit stronger binding affinity to the primary viral protease (NSP5) and the exoribonuclease domain of non structural protein 14 (NSP14). Additionally, the in-silico metabolic analysis of 1j and 1o defines CYP2C9 and CYP3A4 as the major P450 enzymes involved in their metabolism.

5.
Molecules ; 28(4)2023 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-36838701

RESUMEN

Pyrazole core represents a privilege scaffold in medicinal chemistry; a number of pyrazole compounds are endowed with various pharmacological activities in different therapeutic areas including antimalarial treatment. Supported by this evidence, a series of 5-anilino-3-(hetero)arylpyrazoles were evaluated for their antiplasmodial activity in in vitro assays. The compounds were synthesized according to regioselective and versatile protocols that combine active methylene reagents, aryl isothiocyanates and (substituted)hydrazines. The considered derivatives 2 allowed the definition of consistent structure-activity relationships and compounds 2b,e,k,l were identified as the most interesting derivatives of the series showing micromolar IC50 values against chloroquine-sensitive and chloroquine-resistant Plasmodium strains. Additionally, the most active anilino-pyrazoles did not show any cytotoxicity against tumor and normal cells and were predicted to have favorable drug-like and pharmacokinetic properties.


Asunto(s)
Antimaláricos , Antimaláricos/farmacología , Cloroquina/farmacología , Relación Estructura-Actividad , Indicadores y Reactivos , Plasmodium falciparum
6.
Molecules ; 28(6)2023 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-36985820

RESUMEN

Lysozyme (E.C. 3.2.1.17), an about 14 kDa protein and pI 11, widely spread in nature, is present in humans mainly in milk, saliva, and intestinal mucus as a part of innate defense mechanisms. It is endowed with antimicrobial activity due to its action as an N-acetylmuramidase, cleaving the 1-4ß glycosidic linkage in the peptidoglycan layer of Gram-positive bacteria. This antimicrobial activity is exerted only against a limited number of Gram-negative bacteria. Different action mechanisms are proposed to explain its activity against Gram-negative bacteria, viruses, and fungi. The antiviral activity prompted the study of a possible application of lysozyme in the treatment of SARS-CoV-2 infections. Among the different sources of lysozyme, the chicken egg albumen was chosen, being the richest source of this protein (c-type lysozyme, 129 amino acids). Interestingly, the activity of lysozyme hydrochloride against SARS-CoV-2 was related to the heating (to about 100 °C) of this molecule. A chemical-physical characterization was required to investigate the possible modifications of native lysozyme hydrochloride by heat treatment. The FTIR analysis of the two preparations of lysozyme hydrochloride showed appreciable differences in the secondary structure of the two protein chains. HPLC and NMR analyses, as well as the enzymatic activity determination, did not show significant modifications.


Asunto(s)
COVID-19 , Muramidasa , Humanos , Muramidasa/química , Calor , SARS-CoV-2/metabolismo , Bacterias Gramnegativas/metabolismo , Antivirales/farmacología
7.
Molecules ; 28(7)2023 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-37049935

RESUMEN

Chiral natural compounds are often biosynthesized in an enantiomerically pure fashion, and stereochemistry plays a pivotal role in biological activity. Herein, we investigated the significance of chirality for nature-inspired 3-Br-acivicin (3-BA) and its derivatives. The three unnatural isomers of 3-BA and its ester and amide derivatives were prepared and characterized for their antimalarial activity. Only the (5S, αS) isomers displayed significant antiplasmodial activity, revealing that their uptake might be mediated by the L-amino acid transport system, which is known to mediate the acivicin membrane's permeability. In addition, we investigated the inhibitory activity towards Plasmodium falciparum glyceraldehyde 3-phosphate dehydrogenase (PfGAPDH) since it is involved in the multitarget mechanism of action of 3-BA. Molecular modeling has shed light on the structural and stereochemical requirements for an efficient interaction with PfGAPDH, leading to covalent irreversible binding and enzyme inactivation. While stereochemistry affects the target binding only for two subclasses (1a-d and 4a-d), it leads to significant differences in the antimalarial activity for all subclasses, suggesting that a stereoselective uptake might be responsible for the enhanced biological activity of the (5S, αS) isomers.


Asunto(s)
Antimaláricos , Antimaláricos/farmacología , Antimaláricos/química , Isoxazoles/química , Plasmodium falciparum , Modelos Moleculares
8.
J Neurovirol ; 28(1): 113-122, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34997473

RESUMEN

Here we described the virological and serological assessment of 23 COVID-19 patients hospitalized and followed up in Milan, Italy, during the first wave of COVID-19 pandemic. Nasopharyngeal (NPS), anal swabs, and blood samples were collected from 23 COVID-19 patients, at hospital admission, and periodically up to discharge, for a median time of 20 days (3-83 days). RNA was isolated and tested for SARS-CoV-2 by qRT-PCR; anti-SARS-CoV-2 IgM and IgG antibody titers were evaluated in serum samples by ELISA. SARS-CoV-2 genome was detected in the NPS swabs of the 23 patients, at the admission, and 8/19 (42.1%) were still positive at the discharge. Anal swabs were positive to SARS-CoV-2 RNA detection in 20/23 (86.9%) patients; 6/19 (31.6%) were still positive at discharge. The mean time of RNA negative conversion was 17 days (4-36 days) and 33 days (4-77 days), for NPS and anal swabs, respectively. SARS-CoV-2-RNA was detected in the blood of 6/23 (26.1%) patients. Thirteen/23 (56.5%) and 17/23 (73.9%) patients were seropositive for IgM and IgG, respectively, at the admission, and the median IgM and IgG levels significantly (p < 0.05) increased after 13 days. Although the limited cohort size, our report provides evidence that SARS-CoV-2 is shed through multiple routes, with important implications in healthcare settings.


Asunto(s)
COVID-19 , Anticuerpos Antivirales , COVID-19/diagnóstico , Humanos , Inmunoglobulina G , Inmunoglobulina M , Pandemias , ARN Viral/genética , SARS-CoV-2
9.
Ann Vasc Surg ; 82: 325-333, 2022 May.
Artículo en Inglés | MEDLINE | ID: mdl-34902464

RESUMEN

BACKGROUND: To investigate the presence of genetic material of viral agents and the serum level of inflammatory cytokines in patients submitted to carotid endarterectomy having vulnerable versus stable atherosclerotic plaques. METHODS: Data of patients consecutively submitted to carotid endarterectomy for a significant stenosis from July 2019 to December 2019 were prospectively collected. The genetic material of Epstein-Barr (EBV), CitoMegalo (CMV), Herpes Simplex (HSV), Varicella-Zoster (VZV) and Influenza (IV) Viruses was searched in the patient's plaques, both in the "mid" of the plaque and in an adjacent lateral portion of no-plaque area. The serum levels of TNF-α, IL-1ß, IL-6, IL10 and CCL5 were determined. The obtained results were then correlated to the histologic vulnerability of the removed carotid plaque. P values < 0.05 were considered statistically significant. RESULTS: Data of 50 patients were analyzed. A vulnerable plaque was found in 31 patients (62%). The genome of CMV, HSV, VZV and IV was not found in any of the vascular samples, while the EBV genome was found in the "mid" of 2 vulnerable plaques, but not in their respective control area. Eighty-two percent of patients who did not receive anti-IV vaccination (23/28) had vulnerable carotid plaque, compared with 36% of vaccinated patients (8/22, P = 0.001). Serum levels of TNF-α and IL-6 were higher in patients with a vulnerable plaque compared to patients with a stable plaque (73.6 ± 238.2 vs. 3.9 ± 13.1 pg/ml, P= 0.01, and 45.9 ± 103.6 vs. 10.1 ± 25.3 pg/ml, P= 0.01, respectively), independent of comorbidities, viral exposure or flu vaccination. CONCLUSIONS: The EBV genome was found in the "core" of 2 vulnerable carotid plaques, but not in their respective adjacent control. Influenza vaccination was associated with a lower incidence of carotid plaque vulnerability. Serum levels of TNF-α and IL-6 were higher in patients with a vulnerable plaque compared to patients with a stable plaque.


Asunto(s)
Estenosis Carotídea , Citocinas , Infecciones por Citomegalovirus , Endarterectomía Carotidea , Interleucina-6 , Placa Aterosclerótica , Factor de Necrosis Tumoral alfa , Estenosis Carotídea/diagnóstico por imagen , Citocinas/sangre , Infecciones por Citomegalovirus/diagnóstico , Infecciones por Citomegalovirus/genética , Endarterectomía Carotidea/efectos adversos , Infecciones por Virus de Epstein-Barr/diagnóstico , Infecciones por Virus de Epstein-Barr/genética , Humanos , Inflamación/diagnóstico , Gripe Humana/diagnóstico , Gripe Humana/genética , Interleucina-6/sangre , Placa Aterosclerótica/genética , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/sangre
10.
Int J Mol Sci ; 23(7)2022 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-35409421

RESUMEN

In the novel pandemic of Coronavirus Disease 2019, high levels of pro-inflammatory cytokines lead to endothelial activation and dysfunction, promoting a pro-coagulative state, thrombotic events, and microvasculature injuries. The aim of the present work was to investigate the effect of SARS-CoV-2 on pro-inflammatory cytokines, tissue factor, and chemokine release, with Human Microvascular Endothelial Cells (HMEC-1). ACE2 receptor expression was evaluated by western blot analysis. SARS-CoV-2 infection was assessed by one-step RT-PCR until 7 days post-infection (p.i.), and by Transmission Electron Microscopy (TEM). IL-6, TNF-α, IL-8, IFN-α, and hTF mRNA expression levels were detected by RT-PCR, while cytokine release was evaluated by ELISA. HMEC-1 expressed ACE2 receptor and SARS-CoV-2 infection showed a constant viral load. TEM analysis showed virions localized in the cytoplasm. Expression of IL-6 at 24 h and IFN-α mRNA at 24 h and 48 h p.i. was higher in infected than uninfected HMEC-1 (p < 0.05). IL-6 levels were significantly higher in supernatants from infected HMEC-1 (p < 0.001) at 24 h, 48 h, and 72 h p.i., while IL-8 levels were significantly lower at 24 h p.i. (p < 0.001). These data indicate that in vitro microvascular endothelial cells are susceptible to SARS-CoV-2 infection but slightly contribute to viral amplification. However, SARS-CoV-2 infection might trigger the increase of pro-inflammatory mediators.


Asunto(s)
COVID-19 , Enzima Convertidora de Angiotensina 2 , Quimiocinas/genética , Quimiocinas/metabolismo , Citocinas/metabolismo , Células Endoteliales/metabolismo , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , SARS-CoV-2
11.
Molecules ; 27(2)2022 Jan 11.
Artículo en Inglés | MEDLINE | ID: mdl-35056779

RESUMEN

The potential of natural and synthetic chalcones as therapeutic leads against different pathological conditions has been investigated for several years, and this class of compounds emerged as a privileged chemotype due to its interesting anti-inflammatory, antimicrobial, antiviral, and anticancer properties. The objective of our study was to contribute to the investigation of this class of natural products as anti-leishmanial agents. We aimed at investigating the structure-activity relationships of the natural chalcone lophirone E, characterized by the presence of benzofuran B-ring, and analogues on anti-leishmania activity. Here we describe an effective synthetic strategy for the preparation of the natural chalcone lophirone E and its application to the synthesis of a small set of chalcones bearing different substitution patterns at both the A and heterocyclic B rings. The resulting compounds were investigated for their activity against Leishmania infantum promastigotes disclosing derivatives 1 and 28a,b as those endowed with the most interesting activities (IC50 = 15.3, 27.2, 15.9 µM, respectively). The synthetic approaches here described and the early SAR investigations highlighted the potential of this class of compounds as antiparasitic hits, making this study worthy of further investigation.


Asunto(s)
Antiparasitarios/química , Antiparasitarios/farmacología , Benzofuranos/química , Biflavonoides/síntesis química , Chalconas/síntesis química , Indoles/química , Biflavonoides/química , Chalconas/química , Fenómenos Químicos , Técnicas de Química Sintética , Humanos , Leishmania infantum , Estructura Molecular , Relación Estructura-Actividad
12.
Malar J ; 20(1): 81, 2021 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-33568138

RESUMEN

BACKGROUND: The innate immune response against various life cycle stages of the malaria parasite plays an important role in protection against the disease and regulation of its severity. Phagocytosis of asexual erythrocytic stages is well documented, but little and contrasting results are available about phagocytic clearance of sexual stages, the gametocytes, which are responsible for the transmission of the parasites from humans to mosquitoes. Similarly, activation of host macrophages by gametocytes has not yet been carefully addressed. METHODS: Phagocytosis of early or late Plasmodium falciparum gametocytes was evaluated through methanol fixed cytospin preparations of immortalized mouse C57Bl/6 bone marrow-derived macrophages treated for 2 h with P. falciparum and stained with Giemsa, and it was confirmed through a standardized bioluminescent method using the transgenic P. falciparum 3D7elo1-pfs16-CBG99 strain. Activation was evaluated by measuring nitric oxide or cytokine levels in the supernatants of immortalized mouse C57Bl/6 bone marrow-derived macrophages treated with early or late gametocytes. RESULTS: The results showed that murine bone marrow-derived macrophages can phagocytose both early and late gametocytes, but only the latter were able to induce the production of inflammatory mediators, specifically nitric oxide and the cytokines tumour necrosis factor and macrophage inflammatory protein 2. CONCLUSIONS: These results support the hypothesis that developing gametocytes interact in different ways with innate immune cells of the host. Moreover, the present study proposes that early and late gametocytes act differently as targets for innate immune responses.


Asunto(s)
Activación de Macrófagos/inmunología , Macrófagos/inmunología , Fagocitosis/inmunología , Plasmodium falciparum/fisiología , Animales , Ratones , Ratones Endogámicos C57BL
13.
Int J Mol Sci ; 22(24)2021 Dec 17.
Artículo en Inglés | MEDLINE | ID: mdl-34948361

RESUMEN

Malaria is still one of the most dangerous infectious diseases and the emergence of drug resistant parasites only worsens the situation. A series of new tetrahydro-ß-carbolines were designed, synthesized by the Pictet-Spengler reaction, and characterized. Further, the compounds were screened for their in vitro antiplasmodial activity against chloroquine-sensitive (D10) and chloroquine-resistant (W2) strains of Plasmodium falciparum. Moreover, molecular modeling studies were performed to assess the potential action of the designed molecules and toxicity assays were conducted on the human microvascular endothelial (HMEC-1) cell line and human red blood cells. Our studies identified N-(3,3-dimethylbutyl)-1-octyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b] indole-3-carboxamide (7) (a mixture of diastereomers) as the most promising compound endowed with the highest antiplasmodial activity, highest selectivity, and lack of cytotoxicity. In silico simulations carried out for (1S,3R)-7 provided useful insights into its possible interactions with enzymes essential for parasite metabolism. Further studies are underway to develop the optimal nanosized lipid-based delivery system for this compound and to determine its precise mechanism of action.


Asunto(s)
Antimaláricos/química , Antimaláricos/farmacología , Carbolinas/química , Carbolinas/farmacología , Plasmodium falciparum/efectos de los fármacos , Antimaláricos/síntesis química , Carbolinas/síntesis química , Línea Celular , Diseño de Fármacos , Humanos , Malaria Falciparum/tratamiento farmacológico , Simulación del Acoplamiento Molecular , Plasmodium falciparum/enzimología , Plasmodium falciparum/metabolismo
14.
Int J Mol Sci ; 22(16)2021 Aug 17.
Artículo en Inglés | MEDLINE | ID: mdl-34445543

RESUMEN

The current SARS-CoV-2 pandemic causes serious public health, social, and economic issues all over the globe. Surface transmission has been claimed as a possible SARS-CoV-2 infection route, especially in heavy contaminated environmental surfaces, including hospitals and crowded public places. Herein, we studied the deactivation of SARS-CoV-2 on photoactive AgNPs@TiO2 coated on industrial ceramic tiles under dark, UVA, and LED light irradiations. SARS-CoV-2 inactivation is effective under any light/dark conditions. The presence of AgNPs has an important key to limit the survival of SARS-CoV-2 in the dark; moreover, there is a synergistic action when TiO2 is decorated with Ag to enhance the virus photocatalytic inactivation even under LED. The radical oxidation was confirmed as the the central mechanism behind SARS-CoV-2 damage/inactivation by ESR analysis under LED light. Therefore, photoactive AgNPs@TiO2 ceramic tiles could be exploited to fight surface infections, especially during viral severe pandemics.


Asunto(s)
Cerámica/química , Nanopartículas del Metal/química , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/efectos de la radiación , Titanio/química , Antivirales/farmacología , COVID-19/virología , Humanos , Luz , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/efectos de la radiación , Pandemias , Tamaño de la Partícula , SARS-CoV-2/metabolismo , Propiedades de Superficie , Inactivación de Virus/efectos de los fármacos , Inactivación de Virus/efectos de la radiación
15.
Brain Behav Immun ; 88: 597-605, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32335194

RESUMEN

Activation of the NLRP3 inflammasome has been shown to play a major role in the neuroinflammation that accompanies Alzheimer's disease (AD); interventions that down regulate the NLRP3 inflammasome could thus be beneficial in AD. Parasite infections were recently shown to be associated with improved cognitive functions in Apolipoprotein E4 (ApoE4)-expressing members of an Amazonian tribe. We verified in an in vitro model whether Leishmania infantum infection could reduce NLRP3. Results obtained in an initial experimental model in which PBMC were LPS primed and nigericin-stimulated showed that L. infantum infection significantly reduced ASC-speck formation (i.e. intracellular inflammasome proteins assembly), as well as the production of activated caspase 5 and IL-1ß, but increased that of activated caspase 1 and IL-18. Moreover, L. infantum infection induced the generation of an anti-inflammatory milieu by suppressing the production of TNFα and increasing that of IL-10. These results were replicated when cells that had been LPS-primed were stimulated with Aß42 and infected with L. infantum. Results herein indicate that Leishmania infection favors an anti-inflammatory milieu, which includes the down-regulation of NLRP3 inflammasome activation, possibly to facilitate its survival inside host cells. A side effect of Leishmaniasis would be the hampering of neuroinflammation; this could play a protective role against AD development.


Asunto(s)
Leishmaniasis , Péptidos beta-Amiloides , Caspasa 1 , Humanos , Inflamasomas , Interleucina-1beta , Leishmania infantum , Leucocitos Mononucleares , Proteína con Dominio Pirina 3 de la Familia NLR
16.
Pharmacol Res ; 161: 105288, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-33160070

RESUMEN

Leishmaniases are severe vector-borne diseases affecting humans and animals, caused by Leishmania protozoans. Over one billion people and millions of dogs live in endemic areas for leishmaniases and are at risk of infection. Immune polarization plays a major role in determining the outcome of Leishmania infections: hosts displaying M1-polarized macrophages are protected, while those biased on the M2 side acquire a chronic infection that could develop into a deadly disease. The identification of the factors involved in M1 polarization is essential for the design of therapeutic and prophylactic interventions, including vaccines. Infection by the filarial nematode Dirofilaria immitis could be one of the factors that interfere with leishmaniasis in dogs. Indeed, filarial nematodes induce a partial skew of the immune response towards M1, likely caused by their bacterial endosymbionts, Wolbachia. Here we have examined the potential of AsaiaWSP, a bacterium engineered for the expression of the Wolbachia surface protein (WSP), as an inductor of M1 macrophage activation and Leishmania killing. Macrophages stimulated with AsaiaWSP displayed a strong leishmanicidal activity, comparable to that determined by the choice-drug amphotericin B. Additionally, AsaiaWSP determined the expression of markers of classical macrophage activation, including M1 cytokines, ROS and NO, and an increase in phagocytosis activity. Asaia not expressing WSP also induced macrophage activation, although at a lower extent compared to AsaiaWSP. In summary, the results of the present study confirm the immunostimulating properties of WSP highlighting a potential therapeutic efficacy against Leishmania parasites. Furthermore, Asaia was designed as a delivery system for WSP, thus developing a novel type of immunomodulating agent, worthy of being investigated for immuno-prophylaxis and -therapy of leishmaniases and other diseases that could be subverted by M1 macrophage activation.


Asunto(s)
Acetobacteraceae/inmunología , Proteínas de la Membrana Bacteriana Externa/inmunología , Inmunidad Innata , Leishmania infantum/inmunología , Vacunas contra la Leishmaniasis/inmunología , Activación de Macrófagos , Macrófagos/microbiología , Macrófagos/parasitología , Acetobacteraceae/genética , Acetobacteraceae/metabolismo , Animales , Proteínas de la Membrana Bacteriana Externa/genética , Proteínas de la Membrana Bacteriana Externa/metabolismo , Línea Celular , Citocinas/metabolismo , Vectores Genéticos , Interacciones Huésped-Parásitos , Leishmania infantum/crecimiento & desarrollo , Leishmania infantum/ultraestructura , Vacunas contra la Leishmaniasis/genética , Vacunas contra la Leishmaniasis/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Óxido Nítrico/metabolismo , Fagocitosis , Fenotipo , Especies Reactivas de Oxígeno/metabolismo , Vacunas de ADN/inmunología
17.
Mar Drugs ; 18(2)2020 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-32075136

RESUMEN

The chemical analysis of the sponge Dysidea avara afforded the known sesquiterpene quinone avarone, along with its reduced form avarol. To further explore the role of the thiazinoquinone scaffold as an antiplasmodial, antileishmanial and antischistosomal agent, we converted the quinone avarone into the thiazinoquinone derivative thiazoavarone. The semisynthetic compound, as well as the natural metabolites avarone and avarol, were pharmacologically investigated in order to assess their antiparasitic properties against sexual and asexual stages of Plasmodium falciparum, larval and adult developmental stages of Schistosoma mansoni (eggs included), and also against promastigotes and amastigotes of Leishmania infantum and Leishmania tropica. Furthermore, in depth computational studies including density functional theory (DFT) calculations were performed. A toxic semiquinone radical species which can be produced starting both from quinone- and hydroquinone-based compounds could mediate the anti-parasitic effects of the tested compounds.


Asunto(s)
Ciclohexenos/farmacología , Leishmania/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Quinonas/farmacología , Schistosoma mansoni/efectos de los fármacos , Sesquiterpenos/farmacología , Tiazinas/farmacología , Animales , Antiparasitarios/farmacología , Dysidea/química , Leishmania infantum/efectos de los fármacos , Leishmania tropica/efectos de los fármacos
18.
Molecules ; 25(15)2020 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-32752056

RESUMEN

Artemisinin combination therapy (ACT) is recommended by the World Health Organization (WHO) as first line treatment for uncomplicated malaria both in adults and children. During pregnancy, ACT is considered safe only in the second and third trimester, since animal studies have demonstrated that artemisinin derivatives can cause foetal death and congenital malformation within a narrow time window in early embryogenesis. During this period, artemisinin derivatives induce defective embryonic erythropoiesis and vasculogenesis/angiogenesis in experimental models. However, clinical data on the safety profile of ACT in pregnant women have not shown an increased risk of miscarriage, stillbirth, or congenital malformation, nor low birth weight, associated with exposure to artemisinins in the first trimester. Although further studies are needed, the evidence collected up to now is prompting the WHO towards a change in the guidelines for the treatment of uncomplicated malaria, allowing the use of ACT also in the first trimester of pregnancy.


Asunto(s)
Antimaláricos/efectos adversos , Artemisininas/efectos adversos , Animales , Antimaláricos/farmacología , Antimaláricos/uso terapéutico , Artemisininas/farmacología , Artemisininas/uso terapéutico , Femenino , Guías como Asunto , Hematopoyesis/efectos de los fármacos , Humanos , Malaria/tratamiento farmacológico , Malaria/patología , Embarazo , Primer Trimestre del Embarazo
19.
Molecules ; 25(7)2020 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-32230894

RESUMEN

Malaria is a life-threatening disease and, what is more, the resistance to available antimalarial drugs is a recurring problem. The resistance of Plasmodium falciparum malaria parasites to previous generations of medicines has undermined malaria control efforts and reversed gains in child survival. This paper describes a continuation of our ongoing efforts to investigate the effects against Plasmodium falciparum strains and human microvascular endothelial cells (HMEC-1) of a series of methoxy p-benzyl-substituted thiazinoquinones designed starting from a pointed antimalarial lead candidate. The data obtained from the newly tested compounds expanded the structure-activity relationships (SARs) of the thiazinoquinone scaffold, indicating that antiplasmodial activity is not affected by the inductive effect but rather by the resonance effect of the introduced group at the para position of the benzyl substituent. Indeed, the current survey was based on the evaluation of antiparasitic usefulness as well as the selectivity on mammalian cells of the tested p-benzyl-substituted thiazinoquinones, upgrading the knowledge about the active thiazinoquinone scaffold.


Asunto(s)
Antimaláricos/farmacología , Células Endoteliales/efectos de los fármacos , Malaria/tratamiento farmacológico , Plasmodium falciparum/efectos de los fármacos , Quinonas/química , Quinonas/farmacología , Células Endoteliales/parasitología , Concentración 50 Inhibidora , Pruebas de Sensibilidad Parasitaria , Quinonas/síntesis química , Relación Estructura-Actividad
20.
Parasitology ; 146(3): 399-406, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30269694

RESUMEN

Haemozoin is a by-product of haemoglobin digestion by intraerythrocytic malaria parasites, which induces immunologic responses on different tissues, including endothelial cells. In the present paper, the incubation of human microvascular endothelial cells with haemozoin significantly inhibited MTT reduction, a measure of cytotoxicity, without increasing the release of cytoplasmic lactate dehydrogenase. Moreover, haemozoin did not induce apoptosis or cell cycle arrest nor decreased the number of live cells, suggesting that cells viability itself was not affected and that the inhibition of MTT reduction was only apparent and probably due to accelerated MTT-formazan exocytosis. After 30 min of MTT addition, a significant increase in the % of cells exocytosing MTT formazan crystals was observed in haemozoin-treated cells compared with control cells. Such an effect was partially reversed by the addition of genistein, an inhibitor of MTT-formazan exocytosis. The rapid release of CXCL-8, a preformed chemokine contained in Weibel-Palade bodies, confirmed that haemozoin induces a perturbation of the intracellular endothelial trafficking, including the exocytosis of MTT-formazan containing vesicles. The haem moiety of haemozoin is responsible for the observed effect. Moreover, this work underlines that MTT assay should not be used to measure cytotoxicity induced by haemozoin and other methods should be preferred.


Asunto(s)
Células Endoteliales/fisiología , Exocitosis/fisiología , Formazáns/química , Hemoproteínas/metabolismo , Pigmentos Biológicos/metabolismo , Plasmodium falciparum/fisiología , Sales de Tetrazolio/química , Humanos
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