Novel Potent Imidazo[1,2-a]pyridine-N-Glycinyl-Hydrazone Inhibitors of TNF-α Production: In Vitro and In Vivo Studies

Lipopolysaccharydes (LPS) are responsible for the intestinal inflammatory reaction, as they may disrupt tight junctions and induce cytokines (CKs) secretion. Osthole has a wide spectrum of pharmacological effects, thus its anti-inflammatory potential in the LPS-treated Caco-2 cell line as well as in Caco-2/THP-1 and Caco-2/macrophages co-cultures was investigated. In brief, Caco-2 cells and co-cultures were incubated with LPS to induce an inflammatory reaction, after which osthole (150–450 ng/mL) was applied to reduce this effect. After 24 h, the level of secreted CKs and changes in gene expression were examined. LPS significantly increased the levels of IL-1β, -6, -8, and TNF-α, while osthole reduced this effect in a concentration-dependent manner, with the most significant decrease when a 450 ng/mL dose was applied (p < 0.0001). A similar trend was observed in changes in gene expression, with the significant osthole efficiency at a concentration of 450 ng/μL for IL1R1 and COX-2 (p < 0.01) and 300 ng/μL for NF-κB (p < 0.001). Osthole increased Caco-2 monolayer permeability, thus if it would ever be considered as a potential drug for minimizing intestinal inflammatory symptoms, its safety should be confirmed in extended in vitro and in vivo studies.

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Differential modulation of complement factor H and C3 expression by TNF-α in the rat. In vitro and in vivo studies

Molecular Immunology ◽

10.1016/0161-5890(92)90137-m ◽

1992 ◽

Vol 29 (7-8) ◽

pp. 983-988 ◽

Cited By ~ 5

Author(s):

Nathalie Julen ◽

Christian Davrinche ◽

Denyse Ozanne ◽

Jean-Pierre Lebreton ◽

Marc Fontaine ◽

...

Keyword(s):

Factor H ◽

Complement Factor H ◽

In Vivo Studies ◽

Complement Factor ◽

Differential Modulation ◽

Tnf Α

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Genetic Predisposition of the Interleukin-6 Response to Inflammation: Implications for a Variety of Major Diseases?

Clinical Chemistry ◽

10.1373/clinchem.2004.037531 ◽

2004 ◽

Vol 50 (11) ◽

pp. 2136-2140 ◽

Cited By ~ 140

Author(s):

Marie Bennermo ◽

Claes Held ◽

Sten Stemme ◽

Carl-Göran Ericsson ◽

Angela Silveira ◽

...

Keyword(s):

Interleukin 6 ◽

Promoter Region ◽

Insulin Dependent Diabetes Mellitus ◽

Juvenile Chronic Arthritis ◽

In Vivo Studies ◽

Dependent Diabetes Mellitus ◽

Tnf Α

Abstract Background: A single-nucleotide polymorphism (SNP) in the promoter region of the interleukin-6 (IL-6) gene at position −174 (G>C) has been reported to be associated with a variety of major diseases, such as Alzheimer disease, atherosclerosis, and cardiovascular disease, cancer, non-insulin-dependent diabetes mellitus, osteoporosis, sepsis, and systemic-onset juvenile chronic arthritis. However, authors of previous in vitro and in vivo studies have reported conflicting results regarding the functionality of this polymorphism. We therefore aimed to clarify the role of the −174 SNP for the induction of IL-6 in vivo. Methods: We vaccinated 20 and 18 healthy individuals homozygous for the −174 C and G alleles, respectively, with 1 mL of Salmonella typhii vaccine. IL-1β, IL-6, and tumor necrosis factor-α (TNF-α) were measured in the blood at baseline and up to 24 h after vaccination. Results: Individuals with the G genotype had significantly higher plasma IL-6 values at 6, 8, and 10 h after vaccination than did individuals with the C genotype (P <0.005). There were no differences between the two genotypes regarding serum concentrations of IL-1β and TNF-α before or after vaccination. Conclusions: The −174 G>C SNP in the promoter region of the IL-6 gene is functional in vivo with an increased inflammatory response associated with the G allele. Considering the central role of IL-6 in a variety of major diseases, the present finding might be of major relevance.

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Phylloseptin-1 is Leishmanicidal for Amastigotes of Leishmania amazonensis Inside Infected Macrophages

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph17134856 ◽

2020 ◽

Vol 17 (13) ◽

pp. 4856

Author(s):

Selma A. S. Kückelhaus ◽

Daniela Sant’Ana de Aquino ◽

Tatiana K. Borges ◽

Daniel C. Moreira ◽

Luciana de Magalhães Leite ◽

...

Keyword(s):

Hydrogen Peroxide ◽

Leishmania Amazonensis ◽

In Vivo Studies ◽

Public Health Issue ◽

Neglected Diseases ◽

No Production ◽

Tnf Α ◽

Production Of Hydrogen

Leishmania protozoans are the causal agents of neglected diseases that represent an important public health issue worldwide. The growing occurrence of drug-resistant strains of Leishmania and severe side effects of available treatments represent an important challenge for the leishmaniases treatment. We have previously reported the leishmanicidal activity of phylloseptin-1 (PSN-1), a peptide found in the skin secretion of Phyllomedusa azurea (=Pithecopus azureus), against Leishmania amazonensis promastigotes. However, its impact on the amastigote form of L. amazonensis and its impact on infected macrophages are unknown. In this work, we evaluated the effects of PSN-1 on amastigotes of L. amazonensis inside macrophages infected in vitro. We assessed the production of hydrogen peroxide and nitric oxide, as well as the levels of inflammatory and immunomodulatory markers (TGF-β, TNF-α and IL-12), in infected and non-infected macrophages treated with PSN-1. Treatment with PSN-1 decreased the number of infected cells and the number of ingested amastigotes per cell when compared with the untreated cells. At 32 µM (64 µg/mL), PSN-1 reduced hydrogen peroxide levels in both infected and uninfected macrophages, whereas it had little effect on NO production or TGF-β release. The effect of PSN-1 on IL-12 and TNF-α secretion depended on its concentration, but, in general, their levels tended to increase as PSN-1 concentration increased. Further in vitro and in vivo studies are needed to clarify the mechanisms of action of PSN-1 and its interaction with the immune system aiming to develop pharmacological applications.

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In Silico, in Vitro and in Vivo Investigation of a Newly Synthesized Ionic Compound As Anti-Alzheimer Multi-Target Dual AChE/BuChE Inhibitor Possessing Neuro-Protective Effects Against Aβ Induced Neurotoxicity in PC12 Cells and Alzheimer Rat Model

10.21203/rs.3.rs-230581/v1 ◽

2021 ◽

Author(s):

Hosna Karami ◽

somaieh soltani ◽

Gerhard Wolber ◽

Saeed Sadigh-Eteghad ◽

Roghaye Nikbakht ◽

...

Keyword(s):

Pc12 Cells ◽

Quaternary Ammonium ◽

Aqueous Solubility ◽

In Vivo Studies ◽

Protective Effects ◽

Rat Models ◽

Tnf Α ◽

Neuro Inflammation

Abstract Multi-target anti Alzheimer’s disease (AD) compounds are promising leads for the development of AD modifying agents. Ionic compounds containing quaternary ammonium moiety were synthesized and their multi-targeted anti-AD effects were examined in the current study. Compound 5g possessed suitable aqueous solubility and cell toxicity. It also showed non-competitive dual hAChE/hBuChE inhibition activity. Compound 5g reversed the Aβ-treated PC12 cells’ morphology alteration and reduced PC12 cells’ death. Compound 5g possessed anti-oxidative stress activity through anti-oxidant, anti-ROS production and anti-lipid peroxidation mechanisms. It also reduced the expression of IL-1β and TNF-α genes. Furthermore, compound 5g LDH inhibition, reduction of neuro-inflammation and prevention of autophagy-apoptosis were approved by the results of in vitro studies. Compound 5g delivery to brain was confirmed by in vivo studies. Administration of compound 5g to Aβ-induced AD rat models improved their cognition function and spatial memory learning behavior. TNF-α and NFkB down-regulated in compound 5g treated AD rats’ hippocamp. Besides, compound 5g reversed the up-regulation of AChE in Aβ treated rats’ hippocamp. Molecular modeling studies confirmed the interaction of compound 5g with both steric and catalytic sites of ChE enzymes. The newly synthesized quaternary ammonium containing derivative (compound 5g) possessed multi-target anti-AD efficacy based on in vitro and in vivo studies and its efficacy in AD rat models were approved by behavioral and molecular investigations.

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Photosynthetically Controlled Spirulina, but Not Solar Spirulina, Inhibits TNF-α Secretion: Potential Implications for COVID-19-Related Cytokine Storm Therapy

Marine Biotechnology ◽

10.1007/s10126-021-10020-z ◽

2021 ◽

Vol 23 (1) ◽

pp. 149-155

Author(s):

Asaf Tzachor ◽

Or Rozen ◽

Soliman Khatib ◽

Sophie Jensen ◽

Dorit Avni

Keyword(s):

Therapeutic Potential ◽

Human Subjects ◽

Arthrospira Platensis ◽

In Vivo Studies ◽

Cytokine Storm ◽

Blue Green Algae ◽

Tnf Α ◽

Novel Coronavirus

AbstractAn array of infections, including the novel coronavirus (SARS-CoV-2), trigger macrophage activation syndrome (MAS) and subsequently hypercytokinemia, commonly referred to as a cytokine storm (CS). It is postulated that CS is mainly responsible for critical COVID-19 cases, including acute respiratory distress syndrome (ARDS). Recognizing the therapeutic potential of Spirulina blue-green algae (Arthrospira platensis), in this in vitro stimulation study, LPS-activated macrophages and monocytes were treated with aqueous extracts of Spirulina, cultivated in either natural or controlled light conditions. We report that an extract of photosynthetically controlled Spirulina (LED Spirulina), at a concentration of 0.1 µg/mL, decreases macrophage and monocyte-induced TNF-α secretion levels by over 70% and 40%, respectively. We propose prompt in vivo studies in animal models and human subjects to determine the putative effectiveness of a natural, algae-based treatment for viral CS and ARDS, and explore the potential of a novel anti-TNF-α therapy. Graphical abstract

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Vitamin D3 Controls TLR4- and TLR2-Mediated Inflammatory Responses of Endometrial Cells

Gynecologic and Obstetric Investigation ◽

10.1159/000513590 ◽

2021 ◽

pp. 1-10

Author(s):

Alireza Ghanavatinejad ◽

Nesa Rashidi ◽

Mahroo Mirahmadian ◽

Simin Rezania ◽

Mahdokht Mosalaei ◽

...

Keyword(s):

Reproductive Tract ◽

Inflammatory Responses ◽

Female Reproductive Tract ◽

In Vivo Studies ◽

Endometrial Stromal Cells ◽

Endometrial Cells ◽

Tnf Α ◽

Tract Infections

Objectives: Vitamin D has potent immunoregulatory features and modulates innate and adaptive immune responses. There is a significant association between intrauterine infection-associated inflammatory responses and pregnancy complications such as abortion and preterm labor. Here, we investigated how 1,25 (OH)2 D3 could modulate inflammatory responses of endometrial cells. Design: This is an in vitro experimental study. Endometrial stromal cells (ESCs) and whole endometrial cells (WECs) were collected from 15 apparently normal women, and the immunomodulatory effects of 1,25 (OH)2 D3 on lipopolysaccharide (LPS)- or lipoteichoic acid (LTA)-treated ESCs and WECs were investigated. Participants/Materials, Setting, and Methods: Women with no history of abortion, infertility, endometriosis, or sign of vaginal infection were enrolled in this study. Endometrial samples were collected by gynecologists using a Pipelle pipette in the proliferative phase of the menstrual cycle. WECs and ESCs were collected and treated with either LPS or LTA. The levels of IL-6, IL-8, and TNF-α in culture supernatants were quantified using the ELISA technique. TLR2, TLR4, and MyD88 expressions were assessed by RT-qPCR. TLR4 expression at the protein level was studied by the Western blot technique. Results: 1,25 Dihydroxycholecalciferol (1,25 (OH)2 D3) significantly reduced TNF-α production in LPS-activated ESCs and TNF-α and IL-6 production by LTA-stimulated WECs. In contrast, 1,25 (OH)2 D3 pretreatment increased the production of IL-8 by LPS- and LTA-stimulated endometrial cells. 1,25 (OH)2 D3 pretreatment markedly reduced LPS-induced TLR4 protein expression by ESCs. LPS treatment of ESCs significantly induced MyD88 gene expression. This effect was reversed when these cells were pretreated with 1,25 (OH)2 D3 before stimulation with LPS. Limitations: Because of the small size of samples, doing experiments all together on some samples was not feasible. Confirmation of the results obtained here needs well-designed in vivo studies. Conclusions: 1,25 (OH)2 D3 is an immunomodulatory molecule essential for maintaining endometrial immune homeostasis by controlling potentially harmful inflammatory responses associated with female reproductive tract infections.

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Can mesenchymal stem cells pretreated with platelet-rich plasma modulate tissue remodeling in a rat with burned skin?

Biochemistry and Cell Biology ◽

10.1139/bcb-2016-0224 ◽

2017 ◽

Vol 95 (5) ◽

pp. 537-548 ◽

Cited By ~ 9

Author(s):

Hanan Hosni Ahmed ◽

Laila Ahmed Rashed ◽

Sohair Mahfouz ◽

Rania Elsayed Hussein ◽

Marwa Alkaffas ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Transforming Growth Factor ◽

Burn Injury ◽

Platelet Rich Plasma ◽

In Vivo Studies ◽

Control Group ◽

Tnf Α

Our aim was to study the effect of platelet-rich plasma (PRP) on the proliferation of bone-marrow-derived mesenchymal stem cells (BM-MSCs) and to investigate their roles in the healing of experimental burn injury and the possible mechanism of action. Our work was divided into in-vitro and in-vivo studies. The in-vitro study included untreated MSCs and MSCs treated with PRP. Levels of TGF-β and cell proliferation were assessed. In the in-vivo study, 72 rats were distributed equally among 6 groups: control, burn, burn with MSCs, burn with PRP, burn with both MSCs and PRP, and burn with MSCs pretreated with PRP. On the 7th and 20th day after injury, the serum levels of transforming growth factor beta (TGF-β) and tumor necrosis factor alpha (TNF-α), as well as interleukin-10 (IL-10) levels in skin tissue were measured by ELISA; histopathology and gene expression of MMP-1, TIMP-2, Ang-1, Ang-2, and vimentin by real-time PCR were performed in all groups. In vitro: proliferation of MSCs and TGF-β increased in the PRP-treated group compared with the control group. In vivo: Ang-1, Ang-2, and vimentin were upregulated, whereas MMP-1 and TIMP-2 were downregulated. TGF-β and IL-10 were increased, whereas TNF-α was decreased in all treated groups with more significance in MSCs and PRP on day 20. Histopathology of burn skin was improved in all treated groups, particularly in MSCs pretreated with PRP 20 days post-burn.

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Tert-butyl-(4-hydroxy-3-((3-(2-methylpiperidin-yl)propyl)carbamoyl)phenyl)carbamate Has Moderated Protective Activity in Astrocytes Stimulated with Amyloid Beta 1-42 and in a Scopolamine Model

Molecules ◽

10.3390/molecules25215009 ◽

2020 ◽

Vol 25 (21) ◽

pp. 5009

Author(s):

Raúl Horacio Camarillo-López ◽

Maricarmen Hernández Rodríguez ◽

Mónica Adriana Torres-Ramos ◽

Ivonne Maciel Arciniega-Martínez ◽

Iohanan Daniel García-Marín ◽

...

Keyword(s):

Amyloid Beta ◽

Acetylcholinesterase Inhibitor ◽

In Vitro Studies ◽

In Vivo Studies ◽

In Vivo Model ◽

Tert Butyl ◽

Tnf Α ◽

Aβ Aggregation

Alzheimer’s disease (AD) is a neurodegenerative disease with no cure nowadays; there is no treatment either to prevent or to stop its progression. In vitro studies suggested that tert-butyl-(4-hydroxy-3-((3-(2-methylpiperidin-yl)propyl)carbamoyl)phenyl) carbamate named the M4 compound can act as both β-secretase and an acetylcholinesterase inhibitor, preventing the amyloid beta peptide (Aβ) aggregation and the formation of fibrils (fAβ) from Aβ1-42. This work first aimed to assess in in vitro studies to see whether the death of astrocyte cells promoted by Aβ1-42 could be prevented. Second, our work investigated the ability of the M4 compound to inhibit amyloidogenesis using an in vivo model after scopolamine administration. The results showed that M4 possesses a moderate protective effect in astrocytes against Aβ1-42 due to a reduction in the TNF-α and free radicals observed in cell cultures. In the in vivo studies, however, no significant effect of M4 was observed in comparison with a galantamine model employed in rats, in which case this outcome was attributed to the bioavailability of M4 in the brain of the rats.

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