• Autophagy
• Chagas disease
• Immune response
• Leishmaniasis
• Malaria
• Toxoplasmosis

• Autophagy
• Humans
• Animals
• Host-Parasite Interactions
• Protozoan Infections/parasitology

• ATG
• LAP
• LC3
• autophagy
• intracellular microorganisms
• invading bacteria
• parasites
• viruses

• Dancing
• Immunity, Innate
• Autophagy

• 12 06/JOI2-Tl Secretaría de Investigación, Internacionales y Posgrado, Universidad Nacional de Cuyo
• SIIP M-012-T1 Secretaría de Investigación, Internacionales y Posgrado, Universidad Nacional de Cuyo
• SIIP2022-2024 06/J046-T1 Secretaría de Investigación, Internacionales y Posgrado, Universidad Nacional de Cuyo
• R383-2022-180 Lundbeck Foundation
• Aarhus Universitets Forskningsfond
• 754513 HORIZON EUROPE Marie Sklodowska-Curie Actions
• CRSII5_189952 SNSF Sinergia
• PICT 2018-04427 Fondo para la Investigación Científica y Tecnológica
• PICT 2019-01324 Fondo para la Investigación Científica y Tecnológica
• PICT 2019-01038 Fondo para la Investigación Científica y Tecnológica
• PICT 2020-00106 Fondo para la Investigación Científica y Tecnológica
• PICT2019-00640 Fondo para la Investigación Científica y Tecnológica
• 0066384 Novo Nordisk Fonden

• Trypanosoma cruzi
• drug delivery systems
• drug targeting
• nanotechnology
• neglected diseases

• Chagas Disease/drug therapy
• Humans
• Nitroimidazoles/therapeutic use
• Nitroimidazoles/chemistry
• Trypanocidal Agents/therapeutic use
• Trypanocidal Agents/pharmacology
• Trypanocidal Agents/chemistry
• Trypanosoma cruzi/drug effects
• Nanotechnology/methods
• Animals
• Drug Delivery Systems/methods
• Nanoparticles/chemistry
• Drug Carriers/chemistry

• 308382/2017-0, 436051/2018-4, 311209/2020-3. National Council for Scientific and Technological Development
• CODE 01 Coordenação de Aperfeicoamento de Pessoal de Nível Superior

The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a significant component of the innate immune system that plays a vital role in the development of various parasitic diseases. However, its role in hepatic alveolar echinococcosis (HAE) remains unclear.

To investigate the NLRP3 inflammasome and its mechanism of activation in HAE.

We assessed the expression of NLRP3, caspase-1, interleukin (IL)-1β, and IL-18 in the marginal zone and corresponding normal liver of 60 patients with HAE. A rat model of HAE was employed to investigate the role of the NLRP3 inflammasome in the marginal zone of HAE. Transwell experiments were conducted to investigate the effect of Echinococcus multilocularis (E. multilocularis) in stimulating Kupffer cells and hepatocytes. Furthermore, immunohistochemistry, Western blotting, and enzyme-linked immunosorbent assay were used to evaluate NLRP3, caspase-1, IL-1β, and IL-18 expression; flow cytometry was used to detect apoptosis and reactive oxygen species (ROS).

NLRP3 inflammasome activation was significantly associated with ROS. Inhibition of ROS production decreased NLRP3-caspase-1-IL-1β pathway activation and mitigated hepatocyte damage and inflammation.

E. multilocularis induces hepatocyte damage and inflammation by activating the ROS-mediated NLRP3-caspase-1-IL-1β pathway in Kupffer cells, indicating that ROS may serve as a potential target for the treatment of HAE.

• Hepatic alveolar echinococcosis
• Inflammasome
• Inflammation
• Kupffer cell
• NLR family pyrin domain-containing 3 protein
• Reactive oxygen species

• Animals
• Rats
• Inflammasomes/metabolism
• Reactive Oxygen Species/metabolism
• NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
• Interleukin-18
• NLR Proteins
• Echinococcosis, Hepatic
• Pyrin Domain
• Signal Transduction
• Inflammation/metabolism
• Caspase 1/metabolism
• Interleukin-1beta/metabolism

• Humans
• Giardiasis
• Enterocytes/metabolism
• Tight Junction Proteins/metabolism
• AMP-Activated Protein Kinases/metabolism
• Reactive Oxygen Species
• Nitric Oxide
• TOR Serine-Threonine Kinases/metabolism
• Autophagy

• National Natural Science Foundation of China

• Autophagy
• Biological cycle
• Leishmania sp.
• Plasmodium sp.
• Protists
• Toxoplasma gondii
• Trypanosoma brucei
• Trypanosoma cruzi

• R01 AI120607 NIAID NIH HHS
• R21 AI160610 NIAID NIH HHS

• A549
• Carissa macrocarpa
• HDAC6
• Leishmania major
• PDK3
• UPLC-ESI-MS/MS
• cytotoxicity
• molecular docking

Long after Trypanosoma cruzi infection, 40% of individuals develop a progressive chronic chagasic cardiomyopathy (CCC), with systolic dysfunction and arrhythmias. Since we previously showed IL-1β mediates the development of systolic dysfunction and cardiac arrhythmias in diabetes mellitus and cardiorenal syndrome, and IL-1β remains elevated in Chagas disease patients, here we tested the role of IL-1β in CCC using a mouse model. Mice deficient in IL-1R expression (Il-1r^−/−) survived acute T. cruzi infection with greater parasitemia than controls but did not lose weight as wild-type (WT) did. At the chronic stage, WT presented prolonged ventricular repolarization intervals (QJ), while Il-1r^−/− presented intervals like noninfected controls. Infected Il-1r^−/− and WT did not differ in stroke volume (SV), the incidence of cardiac arrhythmias on electrocardiography (EKG), whole heart action potential duration (APD), or the incidence of triggered activity after S1–S2 protocol, which is a measure of susceptibility to cardiac arrhythmias. We also treated chronically infected WT mice with an IL-1R antagonist, anakinra. Treatment shortened the QJ interval but did not improve the SV or the incidence of cardiac arrhythmias on EKG. Anakinra failed to reduce triggered activity following the electrical extra-stimulation protocol. In conclusion, the absence of functional IL-1β/IL-1R signaling did not prevent or reverse the decrease of SV or the incidence of cardiac arrhythmias induced by chronic T. cruzi infection, implying this is not a critical mechanism in generating or maintaining CCC. Since similar cardiac abnormalities were previously credited to IL-1β signaling, ruling out this mechanism is important to discourage further attempts of IL-1β blockade as a therapeutical measure.

• Mice
• Animals
• Trypanosoma cruzi/physiology
• Interleukin 1 Receptor Antagonist Protein/metabolism
• Mice, Inbred C57BL
• Chagas Disease
• Cardiomyopathies
• Arrhythmias, Cardiac/etiology

Giant pandas (Ailuropoda melanoleuca) are the obligate host of the parasitic roundworm Baylisascaris schroederi. The infection of giant pandas with B. schroederi is very common. At present, little is known about the mechanism of immune interaction between B. schroederi and the host. As an important component of innate immunity, the NOD-like receptor 3 (NLRP3) inflammasome plays an important role in host immune response and the occurrence and development of infectious diseases.

We analyzed the regulation of NLRP3 inflammasome activation in monocyte-derived macrophages (MDMs) by the recombinant B. schroederi migratory larvae cysteine protease inhibitor rBsCPI-1, knowing from a previous study that the CPI-1 is highly expressed in B. schroederi migratory larvae. We first determined the effects of rBsCPI-1 and excretory–secretory products of B. schroederi migratory larvae on cell proliferation using the CCK-8 and LDH release assays. We then analyzed NLRP3 inflammasome activation, pyroptosis and pro-inflammatory cytokine release by quantitative-PCR, western blotting and enzyme-linked immunosorbent assay. The signaling pathway of rBsCPI-1 to activate NLRP3 inflammasomes was analyzed in activation and inhibition experiments. Finally, the effects of rBsCPI-1 on inflammasome activation in mice immunized with rBsCPI-1 were analyzed.

The activation and inhibition experiments revealed that rBsCPI-1 induced inflammasome activation through the TLR4–ROS–NLRP3 signaling pathway, with reactive oxygen species (ROS) not only functioning as an activator of the NLRP3 inflammasome, but also an activation product of the NLRP3 inflammasome. rBsCPI-1 promoted the activation and assembly of the NLRP3 inflammasome, which further converted the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 into mature active forms. At the same time, caspase-1 cleaved gasdermin D to trigger cell pyroptosis. The results of animal immunization experiments further confirmed that rBsCPI-1 could induce the activation of the NLRP3 inflammasome.

rBsCPI-1 activates the inflammasome through the TLR4–ROS–NLRP3 signaling pathway and further induces the pyroptosis of MDMs and release of pro-inflammatory factors IL-1β and IL-18, thus promoting the occurrence and development of the inflammatory response in the host.

• Baylisascaris schroederi
• Cysteine protease inhibitors
• Inflammasome
• Pyroptosis
• ROS

• Animals
• Autophagy
• Chagas Disease
• Macrophages/metabolism
• Mice
• Triterpenes
• Trypanosoma cruzi/metabolism

• Agencia Nacional de Promoción Científica y Tecnológica

• Entamoba histolytica
• gasdermin
• innate immunity
• macrophage
• parasite

• Animals
• Caspase 1
• Cell Membrane
• Entamoeba histolytica
• Parasites
• Pyroptosis

• PJT-173551 CIHR
• PJT-162284 CIHR
• Canadian Institutes of Health Research

• autophagy
• cancer therapy
• molecular pathway
• quercetin
• therapeutic effects

• Aged
• Antioxidants
• Autophagy
• Humans
• Neoplasms/drug therapy
• Neoplasms/prevention & control
• Quercetin/pharmacology
• Signal Transduction

• Cellular infection
• Host cell signaling
• Immune response
• Protein kinases
• Trypanosoma cruzi

Angiostrongyliasis is induced by the nematode Angiostrongylus cantonensis and leads to eosinophilic meningitis and meningoencephalitis in humans. Excretory-secretory products (ESPs) are important investigation targets for studying the relationship between hosts and nematodes. These products assist worms in penetrating the blood-brain barrier and avoiding the host immune response. Autophagy is a catabolic process that is responsible for digesting cytoplasmic organelles, proteins, and lipids and removing them through lysosomes. This process is essential to cell survival and homeostasis during nutritional deficiency, cell injury and stress. In this study, we investigated autophagy induction upon treatment with the ESPs of the fifth-stage larvae (L5) of A. cantonensis and observed the relationship between autophagy and the Shh pathway. First, the results showed that A. cantonensis infection induced blood-brain barrier dysfunction and pathological changes in the brain. Moreover, A. cantonensis L5 ESPs stimulated autophagosome formation and the expression of autophagy molecules, such as LC3B, Beclin, and p62. The data showed that upon ESPs treatment, rapamycin elevated cell viability through the activation of the autophagy mechanism in astrocytes. Finally, we found that ESPs induced the activation of the Sonic hedgehog (Shh) signaling pathway and that the expression of autophagy molecules was increased through the Shh signaling pathway. Collectively, these results suggest that A. cantonensis L5 ESPs stimulate autophagy through the Shh signaling pathway and that autophagy has a protective effect in astrocytes.

In helminthes, Excretory-secretory products (ESPs) contains a wide range of molecules, including proteins, lipids, glycans, and nucleic acids, that assist in the penetration of host defensive barriers, reduction of oxidative stress, and avoid the host immune attack. It has been known as a key factor for parasite development, including feeding, invasion and molting. Therefore, ESPs is a valuable target for the investigation of the host-parasite relationships. However, only a few researches about the function of Angiostrongyliasis cantonensis ESPs have been verified to date. Angiostrongyliasis cantonensis, a blood-feeding nematode, and it is an important causative agent of eosinophilic meningitis and meningoencephalitis in human. Recent our studies have demonstrated that the A. cantonensis ESPs can induce oxidative stress, apoptosis, and immune response. In this study, we will use a mouse astrocytes as a model to investigate the signaling mechanisms of autophagy induction by ESPs treatment. First, the Microarray, Western blotting, and Transmission electron microscopy data demonstrated that A. cantonensis ESPs can induce autophagy generation in astrocytes. Next, ESPs-induced autophagy was activated via Sonic hedgehog (Shh) signaling, and it has a protective potential for astrocytes. These finding will provide new insights into the mechanisms and effects of the A. cantonensis ESPs.

• Angiostrongylus cantonensis/immunology
• Angiostrongylus cantonensis/metabolism
• Animals
• Astrocytes/cytology
• Astrocytes/parasitology
• Autophagy
• Blood-Brain Barrier/physiopathology
• Brain/parasitology
• Brain/pathology
• Hedgehog Proteins/metabolism
• Host-Parasite Interactions
• Larva/metabolism
• Mice
• Mice, Inbred BALB C
• Rats
• Rats, Sprague-Dawley
• Signal Transduction
• Snails

• National Science Council
• Chang Gung Memorial Hospital, Linkou
• China Medical University Research Grant

• Leishmania
• Plasmodium
• Toxoplasma
• Trypanosoma cruzi
• inflammasome
• parasite

Endothelial cell damage caused by oxidative stress is widely considered to be a triggering event in atherosclerosis (AS). However, the specific effect elicited by autophagy in endothelial cells undergoing oxidative stress remains controversial, especially during end-stage autophagy. The inhibition of end-stage autophagy has been reported to increase cell pyroptosis and contribute to endothelial damage. Several studies have shown that microRNA-103 is involved in end-stage autophagy; however, its specific mechanism of action is not yet characterized. In this study, we addressed the regulatory role of miR-103 in autophagy during oxidative stress of endothelial cells. Hydrogen peroxide (H₂O₂) treatment was used as an in vitro model of oxidative stress. MTS and ROS levels were measured to evaluate cell activity. qRT-PCR was used to detect the expression of miR-103. Autophagy was examined using western blot, immunofluorescence staining, and electron microscopy, while western blot analysis detected pyroptosis-related proteins. Results show that miR-103 expression decreased under oxidative stress. Further, miR-103 repressed transcription of Bcl-2/adenovirus E1B 19 kDa interacting protein (BNIP3). The oxidative stress caused by H₂O₂ caused cell damage from 2 hours (P < 0.05) and increased the level of intracellular reactive oxygen species (P < 0.05); at the same time, the damage could be further aggravated by the stimulation of bafA1 (P < 0.05). Under the stimulation of H₂O₂, the expression of miR-103 decreased (P < 0.05). However, high expression of miR-103 could reduce the accumulation of LC3II and P62 (P < 0.05) by inhibiting the downstream target gene Bcl-2/adenovirus E1B 19 kDa interacting protein (BNIP3), thus reducing the occurrence of cell pyroptosis (P < 0.05). This process could be blocked by end-stage autophagy inhibitor bafA1 (P < 0.05), which further indicated that miR-103 affected cell injury by autophagy. On the contrary, the low expression of miR-103 promoted the accumulation of autophagy protein and increased the occurrence of pyroptosis (P < 0.05). In conclusion, inhibition of miR-103 restrained end-stage of autophagy by regulating BNIP3, thus changing the occurrence of cell pyroptosis.

• Infection
• Inflammasome
• Inflammation
• Pathogen
• Pattern recognition receptors

• Animals
• Humans
• Immunity
• Infections/complications
• Infections/pathology
• Inflammasomes/genetics
• Inflammation/etiology
• Inflammation/pathology
• Receptors, Pattern Recognition/immunology

• IL-18
• PVAT
• endothelial cells
• mitochondria
• thoracic aorta