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1.
J Crohns Colitis ; 18(3): 446-461, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-37748021

RESUMO

BACKGROUND AND AIMS: Inflammatory bowel diseases (IBD) are characterized by mucosal inflammation and sequential fibrosis formation, but the exact role of the hyperactive NLRP3 inflammasome in these processes is unclear. Thus, we studied the expression and function of the NLRP3 inflammasome in the context of inflammation and fibrosis in IBD. METHODS: We analysed intestinal NLRP3 expression in mucosal immune cells and fibroblasts from IBD patients and NLRP3-associated gene expression via single-cell RNA sequencing and microarray analyses. Furthermore, cytokine secretion of NLRP3 inhibitor treated blood and mucosal cells, as well as proliferation, collagen production, and cell death of NLRP3 inhibitor treated intestinal fibroblasts from IBD patients were studied. RESULTS: We found increased NLRP3 expression in the inflamed mucosa of IBD patients and NLRP3 inhibition led to reduced IL-1ß and IL-18 production in blood cells and diminished the bioactive form of mucosal IL-1ß. Single cell analysis identified overlapping expression patterns of NLRP3 and IL-1ß in classically activated intestinal macrophages and we also detected NLRP3 expression in CD163+ macrophages. In addition, NLRP3 expression was also found in intestinal fibroblasts from IBD patients. Inhibition of NLRP3 led to reduced proliferation of intestinal fibroblasts, which was associated with a marked decrease in production of collagen type I and type VI in IBD patients. Moreover, NLRP3 inhibition in intestinal fibroblasts induced autophagy, a cellular process involved in collagen degradation. CONCLUSIONS: In the presented study, we demonstrate that inhibiting NLRP3 might pave the way for novel therapeutic approaches in IBD, especially to prevent the severe complication of intestinal fibrosis formation.


Assuntos
Doenças Inflamatórias Intestinais , Proteína 3 que Contém Domínio de Pirina da Família NLR , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Inflamassomos/metabolismo , Mucosa/metabolismo , Interleucina-1beta/metabolismo , Inflamação , Fibroblastos/metabolismo , Colágeno , Fibrose
2.
Bioorg Med Chem ; 24(16): 3636-42, 2016 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-27316542

RESUMO

Linking two tacrine molecules results in a tremendous increase of activity against Plasmodia in comparison to the monomer. This finding prompted the synthesis of a library of monomeric and dimeric tacrine derivatives in order to derive structure-activity relationships. The most active compounds towards chloroquine sensitive Plasmodium strain 3D7 and chloroquine resistant strain Dd2 show IC50 values in the nanomolar range of concentration, low cytotoxicity and target the cysteine protease falcipain-2, which is essential for parasite growth.


Assuntos
Antimaláricos/farmacologia , Tacrina/análogos & derivados , Tacrina/farmacologia , Animais , Antimaláricos/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Dimerização , Concentração Inibidora 50 , Plasmodium/efeitos dos fármacos , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade , Tacrina/química
3.
Cell Microbiol ; 13(6): 897-912, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21501358

RESUMO

Malaria parasites reside in human erythrocytes within a parasitophorous vacuole. The parasites are transmitted from the human to the mosquito by the uptake of intraerythrocytic gametocytes during a blood meal, which in the midgut become activated by external stimuli and subsequently egress from the enveloping erythrocyte. Gametocyte egress is a crucial step for the parasite to prepare for fertilization, but the molecular mechanisms of egress are not well understood. Via electron microscopy, we show that Plasmodium falciparum gametocytes exit the erythrocyte by an inside-out type of egress. The parasitophorous vacuole membrane (PVM) ruptures at multiple sites within less than a minute following activation, a process that requires a temperature drop and parasite contact with xanthurenic acid. PVM rupture can also be triggered by the ionophore nigericin and is sensitive to the cysteine protease inhibitor E-64d. Following PVM rupture the subpellicular membrane begins to disintegrate. This membrane is specific to malaria gametocytes, and disintegration is impaired by the aspartic protease inhibitor EPNP and the cysteine/serine protease inhibitor TLCK. Approximately 15 min post activation, the erythrocyte membrane ruptures at a single breaking point, which can be inhibited by inhibitors TLCK and TPCK. In all cases inhibitor treatment results in interrupted gametogenesis.


Assuntos
Culicidae/parasitologia , Eritrócitos/parasitologia , Plasmodium falciparum/crescimento & desenvolvimento , Animais , Compostos de Epóxi/metabolismo , Eritrócitos/ultraestrutura , Humanos , Membranas Intracelulares/ultraestrutura , Leucina/análogos & derivados , Leucina/metabolismo , Microscopia Eletrônica , Nigericina/metabolismo , Nitrofenóis/metabolismo , Plasmodium falciparum/ultraestrutura , Temperatura , Tosilina Clorometil Cetona/metabolismo , Vacúolos/parasitologia , Vacúolos/ultraestrutura , Xanturenatos/metabolismo
4.
Antimicrob Agents Chemother ; 55(4): 1338-48, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21245445

RESUMO

Ribosome-targeting antibiotics exert their antimalarial activity on the apicoplast of the malaria parasite, an organelle of prokaryote origin having essential metabolic functions. These antibiotics typically cause a delayed-death phenotype, which manifests in parasite killing during the second replication cycle following administration. As an exception, treatment with the antibiotic thiostrepton results in an immediate killing. We recently demonstrated that thiostrepton and its derivatives interfere with the eukaryotic proteasome, a multimeric protease complex that is important for the degradation of ubiquitinated proteins. Here, we report that the thiostrepton-based compounds are active against chloroquine-sensitive and -resistant Plasmodium falciparum, where they rapidly eliminate parasites before DNA replication. The minor parasite fraction that escapes the fast killing of the first replication cycle is arrested in the schizont stage of the following cycle, displaying a delayed-death phenotype. Thiostrepton further exhibits gametocytocidal activity by eliminating gametocytes, the sexual precursor cells that are crucial for parasite transmission to the mosquito. Compound treatment results in an accumulation of ubiquitinated proteins in the blood stages, indicating an effect on the parasite proteasome. In accordance with these findings, expression profiling revealed that the proteasome is present in the nucleus and cytoplasm of trophozoites, schizonts, and gametocytes. In conclusion, thiostrepton derivatives represent promising candidates for malaria therapy by dually acting on two independent targets, the parasite proteasome and the apicoplast, with the capacity to eliminate both intraerythrocytic asexual and transmission stages of the parasite.


Assuntos
Antimaláricos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/metabolismo , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Tioestreptona/farmacologia , Animais , Western Blotting , Cloroquina/farmacologia , Resistência a Medicamentos , Técnica Indireta de Fluorescência para Anticorpo , Células HeLa , Humanos , Microscopia Imunoeletrônica , Plasmodium falciparum/patogenicidade , Complexo de Endopeptidases do Proteassoma/metabolismo , Esquizontes/efeitos dos fármacos , Esquizontes/metabolismo , Trofozoítos/efeitos dos fármacos , Trofozoítos/metabolismo
5.
Cell Res ; 21(4): 683-96, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21173797

RESUMO

Physical contact is important for the interaction between animal cells, but it can represent a major challenge for protists like malaria parasites. Recently, novel filamentous cell-cell contacts have been identified in different types of eukaryotic cells and termed nanotubes due to their morphological appearance. Nanotubes represent small dynamic membranous extensions that consist of F-actin and are considered an ancient feature evolved by eukaryotic cells to establish contact for communication. We here describe similar tubular structures in the malaria pathogen Plasmodium falciparum, which emerge from the surfaces of the forming gametes upon gametocyte activation in the mosquito midgut. The filaments can exhibit a length of > 100 µm and contain the F-actin isoform actin 2. They actively form within a few minutes after gametocyte activation and persist until the zygote transforms into the ookinete. The filaments originate from the parasite plasma membrane, are close ended and express adhesion proteins on their surfaces that are typically found in gametes, like Pfs230, Pfs48/45 or Pfs25, but not the zygote surface protein Pfs28. We show that these tubular structures represent long-distance cell-to-cell connections between sexual stage parasites and demonstrate that they meet the characteristics of nanotubes. We propose that malaria parasites utilize these adhesive "nanotubes" in order to facilitate intercellular contact between gametes during reproduction in the mosquito midgut.


Assuntos
Comunicação Celular , Culicidae/parasitologia , Células Germinativas/metabolismo , Nanotubos/parasitologia , Plasmodium falciparum/fisiologia , Actinas , Animais , Adesão Celular , Moléculas de Adesão Celular , Sistema Digestório/metabolismo , Sistema Digestório/parasitologia , Técnica Indireta de Fluorescência para Anticorpo , Interações Hospedeiro-Parasita , Malária/parasitologia , Microscopia Eletrônica , Plasmodium falciparum/metabolismo , Isoformas de Proteínas , Proteínas de Protozoários/metabolismo , Proteínas de Protozoários/fisiologia , Reprodução
6.
Bioorg Med Chem ; 18(9): 2998-3003, 2010 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-20382538

RESUMO

The bisquaternary bisnaphthalimides are a versatile class of compounds being active against the malaria parasite Plasmodium falciparum in the lower nanomolar range of concentration combined with no cytotoxicity. The series of compounds is designed as choline analogues and interfering agents of the phosphatidylcholine biosynthesis. The qualitative analysis of the structure-activity relationships (SAR) revealed the importance of a long methylene middle chain of at least 8 methylene groups between the two bisquaternary naphthalimides or a monoquaternary naphthalimide consisting of a long alkyl chain attached to the positively charged nitrogen atom. Since the SARs are different from reported biscationic antimalarial drugs the mode of action remains to be elucidated.


Assuntos
Antimaláricos/farmacologia , Naftalimidas/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Animais , Linhagem Celular , Macrófagos/ultraestrutura , Estrutura Molecular , Plasmodium falciparum/ultraestrutura , Compostos de Amônio Quaternário/farmacologia , Relação Estrutura-Atividade
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