Binding Mode Exploration of B1 Receptor Antagonists’ by the Use of Molecular Dynamics and Docking Simulation—How Different Target Engagement Can Determine Different Biological Effects

Gemei, Marica; Talarico, Carmine; Brandolini, Laura; Manelfi, Candida; Za, Lorena; Bovolenta, Silvia; Liberati, Caterina; Vecchio, Luigi Del; Russo, Roberto; Cerchia, Carmen; Allegretti, Marcello; Beccari, Andrea R.

doi:10.3390/ijms21207677

Cited by 4 publications

(3 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2A, B). Measurement of bipedal balance using weight-bearing asymmetry [39] and von Frey test using the dynamic plantar tactile device [40] were performed on all surviving animals on Day-7, 0, 7, 21, 35, and 49. All animals were euthanized on Day 54.…”

Section: Animalsmentioning

confidence: 99%

Cell-free fat extract attenuates osteoarthritis via chondrocytes regeneration and macrophages immunomodulation

et al. 2022

View full text Add to dashboard Cite

Background The prevalence of osteoarthritis (OA) is increasing, yet clinically effective and economical treatments are unavailable. We have previously proposed a cell-free fat extract (CEFFE) containing multiple cytokines, which possessed antiapoptotic, anti-oxidative, and proliferation promotion functions, as a “cell-free” strategy. In this study, we aimed to evaluate the therapeutic effect of CEFFE in vivo and in vitro. Methods In vivo study, sodium iodoacetate-induced OA rats were treated with CEFFE by intra-articular injections for 8 weeks. Behavioral experiments were performed every two weeks. Histological analyses, anti-type II collagen, and toluidine staining provided structural evaluation. Macrophage infiltration was assessed by anti-CD68 and anti-CD206 staining. In vitro study, the effect of CEFFE on macrophage polarization and secretory factors was evaluated by flow cytometry, immunofluorescence, and quantitative reverse-transcription polymerase chain reaction (qRT-PCR). The effect of CEFFE on cartilage regeneration was accessed by cell counting kit-8 assay and qRT-PCR. The generation of reactive oxygen species (ROS) and levels of ROS-related enzymes were investigated by qRT-PCR and western blotting. Results In rat models with sodium iodoacetate (MIA)-induced OA, CEFFE increased claw retraction pressure while decreasing bipedal pressure in a dose-dependent manner. Moreover, CEFFE promoted cartilage structure restoration and increased the proportion of CD206+ macrophages in the synovium. In vitro, CEFFE decreased the proportion of CD86+ cells and reduced the expression of pro-inflammatory factors in LPS + IFN-γ induced Raw 264.7. In addition, CEFFE decreased the expression of interleukin-6 and ADAMTs-5 and promoted the expression of SOX-9 in mouse primary chondrocytes. Besides, CEFFE reduced the intracellular levels of reactive oxygen species in both in vitro models through regulating ROS-related enzymes. Conclusions CEFFE inhibits the progression of OA by promoting cartilage regeneration and limiting low-grade joint inflammation. Graphical abstract

show abstract

Section: Animalsmentioning

confidence: 99%

Cell-free fat extract attenuates osteoarthritis via chondrocytes regeneration and macrophages immunomodulation

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Measurement of bipedal balance using weight-bearing asymmetry [39] and von Frey test using the dynamic plantar tactile device [40] were performed on all surviving animals before modeling, one week after modelling, and one week after each administration.…”

Section: Preparation Of Ceffementioning

confidence: 99%

Cell-Free Fat Extract Attenuate Osteoarthritis via Chondrocytes Regeneration and Macrophages Immunomodulation

Jia¹,

Kang²,

Cai³

et al. 2022

Preprint

View full text Add to dashboard Cite

Background: The prevalence of osteoarthritis (OA) is increasing, yet clinically effective and economical treatments are unavailable. We have previously proposed a cell-free fat extract (CEFFE) containing multiple cytokines, which possessed anti-apoptotic, anti-oxidative, and proliferation promotion functions, as a “cell-free” strategy. In this study, we aimed to evaluate the therapeutic effect of CEFFE in vivo and in vitro . Methods: In vivo study, sodium iodoacetate-induced OA rats were treated with CEFFE by intra-articular injections for 8 weeks. Behavioral experiments were performed every two weeks. Histological analyses, anti-type II collagen, and toluidine staining provided structural evaluation. Macrophage infiltration was assessed by anti-CD68 and anti-CD206 staining. In vitro study, the effect of CEFFE on macrophage polarization and secretory factors was evaluated by flow cytometry, immunofluorescence, and quantitative reverse-transcription polymerase chain reaction (qRT-PCR). The effect of CEFFE on cartilage regeneration was accessed by cell counting kit-8 assay and qRT-PCR. The generation of reactive oxygen species (ROS) and levels of ROS-related enzymes were investigated by qRT-PCR and western blotting. Results: In rat models with sodium iodoacetate (MIA)-induced OA, CEFFE increased claw retraction pressure while decreasing bipedal pressure in a dose-depend manner. Moreover, CEFFE promoted cartilage structure restoration and increased the proportion of CD206 + macrophages in the synovium. In vitro , CEFFE decreased the proportion of CD86 + cells and reduced the expression of pro-inflammatory factors in LPS + IFN-γ induced Raw 264.7. In addition, CEFFE decreased the expression of interleukin-6 and ADAMTs-5 and promoted the expression of SOX-9 in mouse primary chondrocytes. Besides, CEFFE reduced the intracellular levels of reactive oxygen species in both in vitro models through regulating ROS-related enzymes. Conclusions: CEFFE inhibits the progression of OA by promoting cartilage regeneration and limiting low-grade joint inflammation.

show abstract

“…As illustrated in Figure 1, bradykinin possesses vasorelaxant and natriuretic activity, where it inhibits sodium reabsorption via NO and prostacyclin (PGI2)-coupled BKB2R and provokes pain (25,47,49,62,65). In contrast, [des-Arg9]-BK induces pain probably due to its proinflammatory, coagulation and proliferative actions along enhanced vascular permeability and edema formation, mediated by BKB1R (24,29,37,50,62). However, [des-Arg9]-BK also has low affinity to the BKB2R in some tissues, likely explaining how selective BKB2R blocker (icatibant) may exert antiinflammatory pulmonary effects in patients with ARDS (57).…”

Section: Introductionmentioning

confidence: 99%

Kinins and chymase: the forgotten components of the renin-angiotensin system and their implications in COVID-19 disease

Abassi

Skorecki

Hamo-Giladi

et al. 2021

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

The unique clinical features of COVID-19 disease present a formidable challenge in the understanding of its pathogenesis. Within a very short time, our knowledge regarding basic physiologic pathways that participate in SARS CoV-2 invasion and subsequent organ damage have been dramatically expanded. In particular, we now better understand the complexity of the renin-angiotensin-aldosterone system (RAAS) and the important role of angiotensin converting enzyme (ACE)-2 in viral binding. Furthermore, the critical role of its major product, angiotensin (Ang) 1-7, in maintaining microcirculatory balance and in the control of activated pro-inflammatory and pro-coagulant pathways, generated in this disease, have been clarified. The kalikrein-bradykinin (BK) system and chymase are intensively interwoven with RAAS through many pathways with complex reciprocal interactions. Yet, so far, very little attention has been paid to a possible role of these physiologic pathways in the pathogenesis of COVID-19 disease, even though BK and chymase exert many physiologic changes characteristic to this disorder. Herein we outline the current knowledge regarding the reciprocal interactions of RAAS, BK and chymase that are probably turned-on in COVID-19 disease and participate in its clinical features. Interventions affecting these systems, such as the inhibition of chymase or blocking BKB1R/BKB2R might be explored as potential novel therapeutic strategies in this devastating disorder.

show abstract

Binding Mode Exploration of B1 Receptor Antagonists’ by the Use of Molecular Dynamics and Docking Simulation—How Different Target Engagement Can Determine Different Biological Effects

Cited by 4 publications

References 53 publications

Cell-free fat extract attenuates osteoarthritis via chondrocytes regeneration and macrophages immunomodulation

Cell-free fat extract attenuates osteoarthritis via chondrocytes regeneration and macrophages immunomodulation

Cell-Free Fat Extract Attenuate Osteoarthritis via Chondrocytes Regeneration and Macrophages Immunomodulation

Kinins and chymase: the forgotten components of the renin-angiotensin system and their implications in COVID-19 disease

Contact Info

Product

Resources

About