Profiling inflammatory response in lesions of cutaneous leishmaniasis patients using a non-invasive sampling method combined with a high-throughput protein detection assay

Taslimi, Yasaman; Agbajogu, Christopher; Brynjólfsson, Siggeir F.; Masoudzadeh, Nasrin; Mashayekhi, Vahid; Gharibzadeh, Safoora; Östensson, Malin; Nakka, Sravya Sowdamini; Mizbani, Amir; Rafati, Sima; Harandi, Ali M.

doi:10.1016/j.cyto.2020.155056

Cited by 15 publications

(7 citation statements)

References 44 publications

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“…The effects of atomoxetine on the synaptic, metabolism, and glial immunity protein panels were specific, as there were no significant effects on the vascular or myelination protein panels. We also assessed CSF inflammatory protein changes using an independent sensitive and specific PEA assay, 63 and found that atomoxetine significantly altered CSF levels of several other immunomodulatory proteins including CDCP1, 93,94 CD244, 95 and TNF superfamily members OPG and TWEAK. 96 Atomoxetine treatment was associated with reduced levels of the pro-inflammatory cytokines CDCP1, CD244, and TWEAK.…”

Section: (Which Was Not Certified By Peer Review)mentioning

confidence: 99%

A phase II study repurposing atomoxetine for neuroprotection in mild cognitive impairment

Levey

Qiu

Zhao

et al. 2022

Brain

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The locus coeruleus (LC) is the initial site of Alzheimer’s disease neuropathology, with hyperphosphorylated Tau appearing in early adulthood followed by neurodegeneration in dementia. LC dysfunction contributes to Alzheimer’s pathobiology in experimental models, which can be rescued by increasing norepinephrine (NE) transmission. To test NE augmentation as a potential disease-modifying therapy, we performed a biomarker-driven phase II trial of atomoxetine, a clinically-approved NE transporter inhibitor, in subjects with mild cognitive impairment due to Alzheimer’s disease. The design was a single-center, 12-month double-blind crossover trial. Thirty-nine participants with mild cognitive impairment (MCI) and biomarker evidence of Alzheimer’s disease were randomized to atomoxetine or placebo treatment. Assessments were collected at baseline, 6- (crossover) and 12-months (completer). Target engagement was assessed by CSF and plasma measures of NE and metabolites. Prespecified primary outcomes were CSF levels of IL1α and Thymus-Expressed Chemokine. Secondary/exploratory outcomes included clinical measures, CSF analyses of Aβ42, Tau, and pTau181, mass spectrometry proteomics, and immune-based targeted inflammation-related cytokines, as well as brain imaging with MRI and FDG-PET. Baseline demographic and clinical measures were similar across trial arms. Dropout rates were 5.1% for atomoxetine and 2.7% for placebo, with no significant differences in adverse events. Atomoxetine robustly increased plasma and CSF NE levels. IL-1α and Thymus-Expressed Chemokine were not measurable in most samples. There were no significant treatment effects on cognition and clinical outcomes, as expected given the short trial duration. Atomoxetine was associated with a significant reduction in CSF Tau and pTau181 compared to placebo, but not associated with change in Aβ42. Atomoxetine treatment also significantly altered CSF abundances of protein panels linked to brain pathophysiologies, including synaptic, metabolism, and glial immunity, as well as inflammation-related CDCP1, CD244, TWEAK, and OPG proteins. Treatment was also associated with significantly increased BDNF and reduced triglycerides in plasma. Resting state fMRI showed significantly increased inter-network connectivity due to atomoxetine between the insula and the hippocampus. FDG-PET showed atomoxetine-associated increased uptake in hippocampus, parahippocampal gyrus, middle temporal pole, inferior temporal gyrus, and fusiform gyrus, with carry-over effects six months after treatment. In summary, atomoxetine treatment was safe, well tolerated, and achieved target engagement in prodromal Alzheimer’s disease. Atomoxetine significantly reduced CSF Tau and pTau, normalized CSF protein biomarker panels linked to synaptic function, brain metabolism, and glial immunity, and increased brain activity and metabolism in key temporal lobe circuits. Further study of atomoxetine is warranted for repurposing the drug to slow Alzheimer’s disease progression.

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Section: (Which Was Not Certified By Peer Review)mentioning

confidence: 99%

A phase II study repurposing atomoxetine for neuroprotection in mild cognitive impairment

Levey

Qiu

Zhao

et al. 2022

Brain

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“…In addition, Leishmania strains induced significant amounts of IL‐8 and stimulated the production of IL‐1β, TNF‐α and TGF‐β by human neutrophils 34 . A significantly higher expression of pro‐inflammatory cytokines including IL‐8 was shown in the lesions of ACL patients compared with normal skin 35 and in the lesions of ZCL patients compared with sporadic CL lesions caused by L infantum 36 . IL‐8 has been suggested as an immune marker for evaluation of CL progression, since the serum levels of IL‐8 were high before treatment and decreased after treatment of ACL patients 37 .…”

Section: Discussionmentioning

confidence: 97%

Differential inflammatory responses associated with Leishmania major and L tropica in culture

Darzi

Davoudian

Rostami

2021

Parasite Immunology

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Background: Anthroponotic cutaneous leishmaniasis (ACL) due to Leishmania tropica and zoonotic CL (ZCL) due to L major have different clinical and epidemiological features. Objectives: To determine whether pro-inflammatory cytokines are involved in diverse pathogenicity of Leishmania species causing CL. Patients/Methods: The capacity of L major/L tropica to modulate expression of IL-1β, IL-8 (CXCL8), IFNγ, TNFα and MCP-1 (CCL2) in peripheral blood mononuclear cells (PBMCs) and monocyte-derived macrophages (MDMs) was evaluated by real-time RT-PCR technique.Results: PBMCs from both ZCL and ACL cases expressed significantly higher IFNγ (P < .001) and TNFα (P < .05) compared with healthy controls (HC). PBMCs from ACL patients expressed significantly higher IL-1β and IL-8 compared with ZCL patients and HC when stimulated with live L major or L tropica promastigotes (P < .001).After 4 and 10 hours, L major-infected MDMs expressed significantly higher IFNγ (P < .05), and after 10 hours, L tropica-infected MDMs expressed significantly higher IL-1β, IFNγ and IL-8 compared with noninfected cells (P < .05). Conclusions:This study shows differential parasite-mediated stimulations of the inflammatory response with L major vs L tropica ex vivo. Pro-inflammatory cytokines particularly IL-8 (CXCL8) and IL-1β might contribute in diverse clinical features of CL such as longer duration of lesion persistence in ACL patients.

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“…ST1A1, like STAMBP, is down-regulated during late pregnancy in women with postpartum depression ( Bränn et al, 2017 ) and is associated with an increased risk of esophageal squamous cell carcinoma ( Aversa et al, 2020 ). Furthermore, changes in ST1A1 expression may also cause inflammation in the skin lesions of patients with cutaneous leishmaniasis ( Taslimi et al, 2020 ) and predict short-term mortality in patients with acute myocardial infarction ( Schmitz et al, 2022 ). SIRT2 is the only NAD-dependent deacetylase primarily localized in the cytoplasm, which plays an important regulatory role in biological processes such as neural cell differentiation and survival, mitotic regulation, genomic integrity, cell differentiation, cell homeostasis, aging, infection, inflammation, oxidative stress, and autophagy ( Wang et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Olink proteomics profiling platform reveals non-invasive inflammatory related protein biomarkers in autism spectrum disorder

Bao

Chen

et al. 2023

Front. Mol. Neurosci.

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BackgroundOwing to the lack of valid biomarkers, the diagnosis of autism spectrum disorder (ASD) diagnosis relies solely on the behavioral phenotypes of children. Several researchers have suggested an association between ASD and inflammation; however, the complex relationship between the two is unelucidated to date. Therefore, the current study aims to comprehensively identify novel circulating ASD inflammatory biomarkers.MethodsOlink proteomics was applied to compare the plasma inflammation-related protein changes in a group of the healthy children (HC, n = 33) and another with ASD (n = 31). The areas under the receiver operating characteristic curves (AUCs) of the differentially expressed proteins (DEPs) were calculated. The functional analysis of the DEPs was performed using Gene Ontology and Kyoto Encyclopedia Genes and Genomes. Pearson correlation tests were used employed to analyze the correlation between the DEPs and clinical features.ResultsA total of 13 DEPs were significantly up-regulated in the ASD group compared with the HC group. The four proteins, namely, STAMBP, ST1A1, SIRT2, and MMP-10 demonstrated good diagnostic accuracy with the corresponding AUCs (95% confidence interval, CI) of 0.7218 (0.5946–0.8489), 0.7107 (0.5827–0.8387), 0.7016 (0.5713–0.8319), and 0.7006 (0.568–0.8332). Each panel of STAMBP and any other differential protein demonstrated a better classification performance [AUC values from 0.7147 (0.5858–0.8436, STAMBP/AXIN1) to 0.7681 (0.6496–0.8867, STAMBP/MMP-10)]. These DEP profiles were enriched in immune and inflammatory response pathways, including TNF and NOD-like receptor signaling pathways. The interaction between STAMBP and SIRT2 (R = 0.97, p = 8.52 × 10−39) was found to be the most significant. In addition, several DEPs related to clinical features in patients with ASD, particularly AXIN1 (R = 0.36, p = 0.006), SIRT2 (R = 0.34, p = 0.010) and STAMBP (R = 0.34, p = 0.010), were positively correlated with age and parity, indicating that older age and higher parity may be the inflammation-related clinical factors in ASD.ConclusionInflammation plays a crucial role in ASD, and the up-regulated inflammatory proteins may serve as potential early diagnostic biomarkers for ASD.

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Profiling inflammatory response in lesions of cutaneous leishmaniasis patients using a non-invasive sampling method combined with a high-throughput protein detection assay

Cited by 15 publications

References 44 publications

A phase II study repurposing atomoxetine for neuroprotection in mild cognitive impairment

A phase II study repurposing atomoxetine for neuroprotection in mild cognitive impairment

Differential inflammatory responses associated with Leishmania major and L tropica in culture

Olink proteomics profiling platform reveals non-invasive inflammatory related protein biomarkers in autism spectrum disorder

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