scholarly journals Synthetic glycolipid-based TLR4 antagonists negatively regulate TRIF-dependent TLR4 signalling in human macrophages

2021 ◽  
Vol 27 (3) ◽  
pp. 275-284
Author(s):  
Charys Palmer ◽  
Fabio A Facchini ◽  
Richard PO Jones ◽  
Frank Neumann ◽  
Francesco Peri ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Functional Activity ◽  
Inflammatory Diseases ◽  
Pharmacological Intervention ◽  
Pharmacological Interventions ◽  
Human Macrophages ◽  
Therapeutic Uses ◽  
Inflammatory Signalling ◽  
Dependent Pathway ◽  
Tlr4 Antagonist

TLRs, including TLR4, play a crucial role in inflammatory-based diseases, and TLR4 has been identified as a therapeutic target for pharmacological intervention. In previous studies, we investigated the potential of FP7, a novel synthetic glycolipid active as a TLR4 antagonist, to inhibit haematopoietic and non-haematopoietic MyD88-dependent TLR4 pro-inflammatory signalling. The main aim of this study was to investigate the action of FP7 and its derivative FP12 on MyD88-independent TLR4 signalling in THP-1 derived macrophages. Western blotting, Ab array and ELISA approaches were used to explore the effect of FP7 and FP12 on TRIF-dependent TLR4 functional activity in response to LPS and other endogenous TLR4 ligands in THP-1 macrophages. A different kinetic in the inhibition of endotoxin-driven TBK1, IRF3 and STAT1 phosphorylation was observed using different LPS chemotypes. Following activation of TLR4 by LPS, data revealed that FP7 and FP12 inhibited TBK1, IRF3 and STAT1 phosphorylation which was associated with down-regulation IFN-β and IP-10. Specific blockage of the IFN type one receptor showed that these novel molecules inhibited TRIF-dependent TLR4 signalling via IFN-β pathways. These results add novel information on the mechanism of action of monosaccharide FP derivatives. The inhibition of the TRIF-dependent pathway in human macrophages suggests potential therapeutic uses for these novel TLR4 antagonists in pharmacological interventions on inflammatory diseases.

scholarly journals The synthetic glycolipid-based TLR4 antagonist FP7 negatively regulates in vitro and in vivo haematopoietic and non-haematopoietic vascular TLR4 signalling

2018 ◽  
Vol 24 (7) ◽  
pp. 411-421 ◽  
Author(s):  
Charys Palmer ◽  
Francesco Peri ◽  
Frank Neumann ◽  
Feroz Ahmad ◽  
David S. Leake ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Inflammatory Diseases ◽  
Sterile Inflammation ◽  
Pharmacological Intervention ◽  
In Vivo Models ◽  
Tlr4 Activation ◽  
Inflammatory Signalling ◽  
Tlr4 Antagonist

TLRs, including TLR4, have been shown to play a crucial role in cardiovascular inflammatory-based diseases. The main goal of this study was to determine the potential of FP7, a synthetic glycolipid active as a TLR4 antagonist, to modulate haematopoietic and non-haematopoietic vascular TLR4 pro-inflammatory signalling. HUVEC, human THP-1 monocytes, THP-1-derived macrophages, mouse RAW-264.7 macrophages and Angiotensin II-infused apolipoprotein E-deficient mice were in vitro and in vivo models, respectively. Western blotting, Ab array and ELISA approaches were used to explore the effect of FP7 on TLR4 functional activity in response to bacterial LPS ( in vitro) and endogenous ligands of sterile inflammation ( in vitro and in vivo). Following activation of TLR4, in vitro and in vivo data revealed that FP7 inhibited p38 MAPK and p65 NF-kB phosphorylation associated with down-regulation of a number of TLR4-dependent pro-inflammatory proteins. In addition to inhibition of LPS-induced TLR4 signalling, FP7 negatively regulated TLR4 activation in response to ligands of sterile inflammation (hydroperoxide-rich oxidised LDL, in vitro and Angiotensin II infusion, in vivo). These results demonstrate the ability of FP7 to negatively regulate in vitro and in vivo haematopoietic and non-haematopoietic vascular TLR4 signalling both in humans and mice, suggesting the potential therapeutic use of this TLR4 antagonist for pharmacological intervention of vascular inflammatory diseases.

Novel Pharmacotherapeutics for Stress-Related Disorders

2019 ◽  
pp. 642-672
Author(s):  
Jamie E. Mondello ◽  
Jenny E. Pak ◽  
Dennis F. Lovelock ◽  
Terrence Deak
Keyword(s):  
Mental Health Problems ◽  
Drug Efficacy ◽  
Careful Consideration ◽  
Pharmacological Intervention ◽  
Pharmacological Interventions ◽  
Diverse Range ◽  
Disease States ◽  
Efficacy Trials ◽  
Participant Selection ◽  
The Relationship

Most mental health problems associated with psychological distress originate with activation of centrally regulated stress pathways, yet a diverse range of central nervous system and somatic disease states can be influenced by exposure to severe or unrelenting stress. The goal of this chapter is to provide a conceptual framework to guide the development of pharmacological intervention strategies. We propose that careful consideration of the relationship between the timing of stressful life experiences, pharmacological intervention, and the ultimate expression of disease symptomatology is critical for the development of pharmacological interventions to treat stress-related disorders. We review a range of physiological systems that are known to be activated by stress, offering potentially new targets for drug development efforts, and argue that participant selection is a key predictor of drug efficacy trials. In doing so, we point toward inflammatory signaling pathways as a potential final common mediator of multiple stress-related disease states.

scholarly journals Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models

2021 ◽  
Vol 22 (4) ◽  
pp. 1514 ◽  
Author(s):  
Akihiro Yachie
Keyword(s):  
Oxidative Stress ◽  
Animal Models ◽  
Heme Oxygenase ◽  
Inflammatory Diseases ◽  
Cell Types ◽  
Pharmacological Intervention ◽  
Heme Oxygenase 1 ◽  
Inflammatory Reactions

Since Yachie et al. reported the first description of human heme oxygenase (HO)-1 deficiency more than 20 years ago, few additional human cases have been reported in the literature. A detailed analysis of the first human case of HO-1 deficiency revealed that HO-1 is involved in the protection of multiple tissues and organs from oxidative stress and excessive inflammatory reactions, through the release of multiple molecules with anti-oxidative stress and anti-inflammatory functions. HO-1 production is induced in vivo within selected cell types, including renal tubular epithelium, hepatic Kupffer cells, vascular endothelium, and monocytes/macrophages, suggesting that HO-1 plays critical roles in these cells. In vivo and in vitro studies have indicated that impaired HO-1 production results in progressive monocyte dysfunction, unregulated macrophage activation and endothelial cell dysfunction, leading to catastrophic systemic inflammatory response syndrome. Data from reported human cases of HO-1 deficiency and numerous studies using animal models suggest that HO-1 plays critical roles in various clinical settings involving excessive oxidative stress and inflammation. In this regard, therapy to induce HO-1 production by pharmacological intervention represents a promising novel strategy to control inflammatory diseases.

Pharmacologic activities of phytosteroids in inflammatory diseases: Mechanism of action and therapeutic potentials

2021 ◽  
Author(s):  
Rishab Marahatha ◽  
Kabita Gyawali ◽  
Kabita Sharma ◽  
Narayan Gyawali ◽  
Parbati Tandan ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Inflammatory Diseases

scholarly journals Techniques to Study Inflammasome Activation and Inhibition by Small Molecules

Molecules ◽  
2021 ◽  
Vol 26 (6) ◽  
pp. 1704
Author(s):  
Diego Angosto-Bazarra ◽  
Cristina Molina-López ◽  
Alejandro Peñín-Franch ◽  
Laura Hurtado-Navarro ◽  
Pablo Pelegrín
Keyword(s):  
Inflammatory Response ◽  
Small Molecules ◽  
Mechanism Of Action ◽  
Inflammatory Diseases ◽  
Inflammasome Activation ◽  
Chronic Inflammatory Diseases ◽  
Anti Inflammatory ◽  
Inhibitory Molecules ◽  
Inflammasome Inhibitors

Inflammasomes are immune cytosolic oligomers involved in the initiation and progression of multiple pathologies and diseases. The tight regulation of these immune sensors is necessary to control an optimal inflammatory response and recover organism homeostasis. Prolonged activation of inflammasomes result in the development of chronic inflammatory diseases, and the use of small drug-like inhibitory molecules are emerging as promising anti-inflammatory therapies. Different aspects have to be taken in consideration when designing inflammasome inhibitors. This review summarizes the different techniques that can be used to study the mechanism of action of potential inflammasome inhibitory molecules.

scholarly journals TNFa alter cholesterol metabolism in human macrophages via PKC-theta-dependent pathway

2013 ◽  
Vol 14 (1) ◽  
pp. 20 ◽  
Author(s):  
A Zhi Sha Ma ◽  
Qian Zhang ◽  
Zhi Yuan Song
Keyword(s):  
Cholesterol Metabolism ◽  
Human Macrophages ◽  
Dependent Pathway

scholarly journals Quality of care indicators for schizophrenia: determinants of observed variations among Italian Departments of Mental Health. Results from the ETAS DSM study

2016 ◽  
Vol 26 (3) ◽  
pp. 299-313 ◽  
Author(s):  
G. Fantini ◽  
G. Tibaldi ◽  
P. Rucci ◽  
D. Gibertoni ◽  
M. Vezzoli ◽  
...  
Keyword(s):  
Mental Health ◽  
Quality Of Care ◽  
Health Care Professionals ◽  
Treatment Guidelines ◽  
Psychosocial Rehabilitation ◽  
Metabolic Effects ◽  
Administrative Databases ◽  
Pharmacological Intervention ◽  
Pharmacological Interventions

Aims.The primary aim of this study is to analyse the conformance of usual care patterns for persons with schizophrenia to treatment guidelines in three Italian Departments of Mental Health (DMHs). The secondary aim is to examine possible organisational and structural reasons accounting for variations among DMHs.Methods.Within the framework of the Evaluation of Treatment Appropriateness in Schizophrenia (ETAS) project, 20 consensus quality of care indicators were developed. Ten concerned pharmacological treatment and ten encompassed general care and psychosocial rehabilitation interventions. Indicators were calculated using data from a stratified random sample of 458 patients treated at three DMHs located in North-Eastern, North-Western and Southern Italy. Patients’ data were collected by combining information from medical charts and from a survey carried out by the health care professionals in charge of the patients. Data on the structural and organisational characteristics of the DMHs were retrieved from administrative databases. For each indicator, the number and percentage of appropriate interventions with and without moderators were calculated. Appropriateness was defined as the percentage of eligible patients receiving an intervention conformant with guidelines. Moderators, i.e., reasons justifying a discrepancy between the interventions actually provided and that recommended by guidelines were recorded. Indicators based on a sufficient number of eligible patients were further explored in a statistical analysis to compare the performance of the DMHs.Results.In the overall sample, the percentage of inappropriate interventions ranged from 11.1 to 59.3% for non-pharmacological interventions and from 5.9 to 66.8% for pharmacological interventions. Comparisons among DMHs revealed significant variability in appropriateness for the indicators ‘prevention and monitoring of metabolic effects’, ‘psychiatric visits’, ‘psychosocial rehabilitation’, ‘family involvement’ and ‘work’. After adjusting the patient's gender, age and functioning, only the indicators ‘Prevention and monitoring of metabolic effects’, ‘psychiatric visits’ and ‘work’ continued to differ significantly among DMHs. The percentage of patients receiving appropriate integrated care (at least one appropriate non-pharmacological intervention and one pharmacological intervention) was significantly different among the three DMHs and lower than expected.Conclusions.Our results underscore discrepancies among Italian DMHs in indicators that explore key aspects of care of patients with schizophrenia. The use of quality indicators and improved guideline adherence can address suboptimal clinical outcomes, and has the potential to reduce practice variations and narrow the gap between optimal and routine care.

Propeptides as modulators of functional activity of proteases

2010 ◽  
Vol 1 (3-4) ◽  
pp. 305-322 ◽  
Author(s):  
Ilya V. Demidyuk ◽  
Andrey V. Shubin ◽  
Eugene V. Gasanov ◽  
Sergey V. Kostrov
Keyword(s):  
Mechanism Of Action ◽  
Functional Activity ◽  
Protein Function ◽  
Living Organism ◽  
Biological Properties ◽  
Biological Mechanism ◽  
Structural Elements ◽  
Specific Mechanism ◽  
Catalytic Domains ◽  
Cognate Protein

AbstractMost proteases are synthesized in the cell as precursor-containing propeptides. These structural elements can determine the folding of the cognate protein, function as an inhibitor/activator peptide, mediate enzyme sorting, and mediate the protease interaction with other molecules and supramolecular structures. The data presented in this review demonstrate modulatory activity of propeptides irrespective of the specific mechanism of action. Changes in propeptide structure, sometimes minor, can crucially alter protein function in the living organism. Modulatory activity coupled with high variation allows us to consider propeptides as specific evolutionary modules that can transform biological properties of proteases without significant changes in the highly conserved catalytic domains. As the considered properties of propeptides are not unique to proteases, propeptide-mediated evolution seems to be a universal biological mechanism.

scholarly journals Effectiveness of Pharmacological Intervention Among Men with Infertility: A Systematic Review and Network Meta-Analysis

2021 ◽  
Vol 12 ◽  
Author(s):  
Muhammad Nabeel Shahid ◽  
Tahir Mehmood Khan ◽  
Chin Fen Neoh ◽  
Qi Ying Lean ◽  
Allah Bukhsh ◽  
...  
Keyword(s):  
Male Infertility ◽  
Meta Analysis ◽  
Clomiphene Citrate ◽  
Random Effect ◽  
Random Effect Model ◽  
Sperm Concentration ◽  
Pharmacological Intervention ◽  
Total Testosterone ◽  
Pharmacological Interventions ◽  
Testosterone Undecanoate

Background. Infertility is an emerging health issue for men. Comparative efficacy of different pharmacological interventions on male infertility is not clear. The aim of this review is to investigate the efficacy of various pharmacological interventions among men with idiopathic male infertility. All randomized control trials evaluating the effectuality of interventions on male infertility were included for network meta-analysis (NMA) from inception to 31 April 2020, systematically performed using STATA through the random effect model. The protocol was registered at PROSPERO (CRD42020152891).Results. The outcomes of interest were semen and hormonal parameters. Treatment effects (p < 0.05) were estimated through WMD at the confidence interval of 95%. Upon applying exclusion criteria, n=28 RCTs were found eligible for NMA. Results from NMA indicated that consumption of supplements increases sperm concentration levels [6.26, 95% CI 3.32, 9.21] in comparison to SERMs [4.97, 95% CI 1.61, 8.32], hormones [4.14, 95% CI 1.83, 6.46], and vitamins [0.15, 95% CI −20.86, 21.15)] with placebo, whereas the use of SERMs increased percentage sperm motility [6.69, 95% CI 2.38, 10.99] in comparison to supplements [6.46, 95% CI 2.57, 10.06], hormones [3.47, 95% CI 0.40, 6.54], and vitamins [−1.24, 95% CI −11.84, 9.43] with placebo. Consumption of hormones increased the sperm morphology [3.71, 95% CI, 1.34, 6.07] in contrast to supplements [2.22, 95% CI 0.12, 4.55], SERMs [2.21, 95% CI −0.78, 5.20], and vitamins [0.51, 95% CI −3.60, 4.62] with placebo. Supplements boosted the total testosterone levels [2.70, 95% CI 1.34, 4.07] in comparison to SERMs [1.83, 95% CI 1.16, 2.50], hormones [0.40, 95% CI −0.49, 1.29], and vitamins [−0.70, 95% CI −6.71, 5.31] with placebo. SERMs increase the serum FSH levels [3.63, 95% CI 1.48, 5.79] better than hormones [1.29, 95% CI −0.79, 3.36], vitamins [0.03, 95% CI −2.69, 2.76], and supplements [−4.45, 95% CI −7.15, −1.76] in comparison with placebo.Conclusion. This review establishes that all interventions had a significantly positive effect on male infertility. Statistically significant increased sperm parameters were noted in combinations of zinc sulfate (220 mg BID), clomiphene citrate (50 mg BID), and testosterone undecanoate and CoQ10; tamoxifen citrate and FSH were shown to improve the hormonal profile in infertile males.

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