scholarly journals Integrated computational and in vivo models reveal Key Insights into Macrophage Be-havior during bone healing

2021 ◽  
Author(s):  
Etienne Baratchart ◽  
Chen Hao Lo ◽  
Conor Lynch ◽  
David Basanta
Keyword(s):  
Bone Healing ◽  
Osteoclast Differentiation ◽  
Mathematical Framework ◽  
In Vivo Models ◽  
Inflammatory Monocytes ◽  
Injury Data ◽  
Bone Injury ◽  
Anti Inflammatory ◽  
Inflammatory Macrophages

Myeloid-derived monocyte and macrophages are key cells in the bone that contribute to remod-eling and injury repair. However, their temporal polarization status and control of bone-resorbing osteoclasts and bone-forming osteoblasts responses is largely unknown. In this study, we fo-cused on two aspects of monocyte/macrophage dynamics and polarization states over time: 1) the injury-triggered pro- and anti-inflammatory monocytes/macrophages temporal profiles, 2) the contributions of pro- versus anti-inflammatory monocytes/macrophages in coordinating healing response. Bone healing is a complex multicellular dynamic process. While traditional in vitro and in vivo experimentation may capture the behavior of select populations with high resolution, they cannot simultaneously track the behavior of multiple populations. To address this, we have used an integrated a coupled ordinary differential equations (ODEs)-based framework describing mul-tiple cellular species to in vivo bone injury data in order to identify and test various hypotheses regarding bone cell populations dynamics. Our approach allowed us to infer several biological insights including, but not limited to,: 1) anti-inflammatory macrophages are key for early osteo-clast inhibition and pro-inflammatory macrophage suppression, 2) pro-inflammatory macrophag-es are involved in osteoclast bone resorptive activity, whereas osteoblasts promote osteoclast differentiation, 3) Pro-inflammatory monocytes/macrophages rise during two expansion waves, which can be explained by the anti-inflammatory macrophages-mediated inhibition phase be-tween the two waves. In addition, we further tested the robustness of the mathematical model by comparing simulation results to an independent experimental dataset. Taken together, this novel comprehensive mathematical framework allowed us to identify biological mechanisms that best recapitulate bone injury data and that explain the coupled cellular population dynamics involved in the process. Furthermore, our hypothesis testing methodology could be used in other contexts to decipher mechanisms in complex multicellular processes.

scholarly journals Impact of Janus Kinase Inhibition with Tofacitinib on Fundamental Processes of Bone Healing

2020 ◽  
Vol 21 (3) ◽  
pp. 865 ◽  
Author(s):  
Timo Gaber ◽  
Antonia Clara Katharina Brinkman ◽  
Justyna Pienczikowski ◽  
Karoline Diesing ◽  
Alexandra Damerau ◽  
...  
Keyword(s):  
Fracture Healing ◽  
Bone Healing ◽  
Positive Impact ◽  
Healing Process ◽  
Osteoclast Differentiation ◽  
Janus Kinase ◽  
Inflammatory Microenvironment ◽  
Positive Effects ◽  
Anti Inflammatory

Both inflammatory diseases like rheumatoid arthritis (RA) and anti-inflammatory treatment of RA with glucocorticoids (GCs) or non-steroidal anti-inflammatory drugs (NSAIDs) negatively influence bone metabolism and fracture healing. Janus kinase (JAK) inhibition with tofacitinib has been demonstrated to act as a potent anti-inflammatory therapeutic agent in the treatment of RA, but its impact on the fundamental processes of bone regeneration is currently controversially discussed and at least in part elusive. Therefore, in this study, we aimed to examine the effects of tofacitinib on processes of bone healing focusing on recruitment of human mesenchymal stromal cells (hMSCs) into the inflammatory microenvironment of the fracture gap, chondrogenesis, osteogenesis and osteoclastogenesis. We performed our analyses under conditions of reduced oxygen availability in order to mimic the in vivo situation of the fracture gap most optimal. We demonstrate that tofacitinib dose-dependently promotes the recruitment of hMSCs under hypoxia but inhibits recruitment of hMSCs under normoxia. With regard to the chondrogenic differentiation of hMSCs, we demonstrate that tofacitinib does not inhibit survival at therapeutically relevant doses of 10–100 nM. Moreover, tofacitinib dose-dependently enhances osteogenic differentiation of hMSCs and reduces osteoclast differentiation and activity. We conclude from our data that tofacitinib may influence bone healing by promotion of hMSC recruitment into the hypoxic microenvironment of the fracture gap but does not interfere with the cartilaginous phase of the soft callus phase of fracture healing process. We assume that tofacitinib may promote bone formation and reduce bone resorption, which could in part explain the positive impact of tofacitinib on bone erosions in RA. Thus, we hypothesize that it will be unnecessary to stop this medication in case of fracture and suggest that positive effects on osteoporosis are likely.

A Review on Opuntia Species and its Chemistry, Pharmacognosy, Pharmacology and Bioapplications

2020 ◽  
Vol 16 (8) ◽  
pp. 1227-1244
Author(s):  
Dharmendra Kumar ◽  
Pramod K. Sharma
Keyword(s):  
Human Consumption ◽  
In Vivo Models ◽  
Sugar Amino Acids ◽  
Opuntia Species ◽  
Therapeutic Uses ◽  
Anti Inflammatory ◽  
Online Library ◽  
Different Parts

Background:: Opuntia species, locally known as prickly pear was used for various purposes as food, medicine, beverage, source of dye and animal food. Many studies have revealed its pharmacology activity from time to time. This review is a collection of chemistry, pharmacognosy, pharmacology and bioapplications of the cactus family. Methods: Many sources were used to collect information about Opuntia species such as Pub med, Google scholar, Agris, science direct, Embase, Merk index, Wiley online library, books and other reliable sources. This review contains studies from 1812 to 2019. Results: The plants from the cactus family offer various pharmacological active compounds including phenolic compounds, carotenoids, betalains, vitamins, steroids, sugar, amino acids, minerals and fibers. These bioactive compounds serve various pharmacological activities such as anticancer, antiviral, anti-diabetic, Neuroprotective, anti-inflammatory, antioxidant, Hepatoprotective, antibacterial, antiulcer and alcohol hangover. According to various studies, Opuntia species offer many bioapplications such as fodder for animal, soil erosion, prevention, human consumption and waste water decontamination. Finally, different parts of plants are used in various formulations that offer many biotechnology applications. Conclusion: Different parts of Opuntia plant (fruits, seeds, flowers and cladodes) are used in various health problems which include wound healing, anti-inflammatory and urinary tract infection from ancient times. Nowadays, researches have extended several pharmacological and therapeutic uses of Opuntia species as discussed in this review. Many in-vitro and in-vivo models are also discussed in this review as the proofs of research findings. Various research gaps have been observed in current studies that require attention in the future.

scholarly journals Anti-Inflammatory Potential of Daturaolone from Datura innoxia Mill.: In Silico, In Vitro and In Vivo Studies

2021 ◽  
Vol 14 (12) ◽  
pp. 1248
Author(s):  
Muhammad Waleed Baig ◽  
Humaira Fatima ◽  
Nosheen Akhtar ◽  
Hidayat Hussain ◽  
Mohammad K. Okla ◽  
...  
Keyword(s):  
In Silico ◽  
Therapeutic Potential ◽  
In Vivo Studies ◽  
Metabolic Reaction ◽  
Datura Innoxia ◽  
In Vivo Models ◽  
Immobility Time ◽  
Anti Inflammatory

Exploration of leads with therapeutic potential in inflammatory disorders is worth pursuing. In line with this, the isolated natural compound daturaolone from Datura innoxia Mill. was evaluated for its anti-inflammatory potential using in silico, in vitro and in vivo models. Daturaolone follows Lipinski’s drug-likeliness rule with a score of 0.33. Absorption, distribution, metabolism, excretion and toxicity prediction show strong plasma protein binding; gastrointestinal absorption (Caco-2 cells permeability = 34.6 nm/s); no blood–brain barrier penetration; CYP1A2, CYP2C19 and CYP3A4 metabolism; a major metabolic reaction, being aliphatic hydroxylation; no hERG inhibition; and non-carcinogenicity. Predicted molecular targets were mainly inflammatory mediators. Molecular docking depicted H-bonding interaction with nuclear factor kappa beta subunit (NF-κB), cyclooxygenase-2, 5-lipoxygenase, phospholipase A2, serotonin transporter, dopamine receptor D1 and 5-hydroxy tryptamine. Its cytotoxicity (IC50) value in normal lymphocytes was >20 µg/mL as compared to cancer cells (Huh7.5; 17.32 ± 1.43 µg/mL). Daturaolone significantly inhibited NF-κB and nitric oxide production with IC50 values of 1.2 ± 0.8 and 4.51 ± 0.92 µg/mL, respectively. It significantly reduced inflammatory paw edema (81.73 ± 3.16%), heat-induced pain (89.47 ± 9.01% antinociception) and stress-induced depression (68 ± 9.22 s immobility time in tail suspension test). This work suggests a possible anti-inflammatory role of daturaolone; however, detailed mechanistic studies are still necessary to corroborate and extrapolate the findings.

scholarly journals Extracellular vesicles from human cardiovascular progenitors trigger a reparative immune response in infarcted hearts

2020 ◽  
Author(s):  
Bruna Lima Correa ◽  
Nadia El Harane ◽  
Ingrid Gomez ◽  
Hocine Rachid Hocine ◽  
José Vilar ◽  
...  
Keyword(s):  
Immune Response ◽  
Extracellular Vesicles ◽  
Inflammatory Cytokines ◽  
Nk Cell ◽  
Inflammatory Monocytes ◽  
Ifn Γ ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

Abstract Aims The cardioprotective effects of human induced pluripotent stem cell-derived cardiovascular progenitor cells (CPC) are largely mediated by the paracrine release of extracellular vesicles (EV). We aimed to assess the immunological behaviour of EV-CPC, which is a prerequisite for their clinical translation. Methods and results Flow cytometry demonstrated that EV-CPC expressed very low levels of immune relevant molecules including HLA Class I, CD80, CD274 (PD-L1), and CD275 (ICOS-L); and moderate levels of ligands of the natural killer (NK) cell activating receptor, NKG2D. In mixed lymphocyte reactions, EV-CPC neither induced nor modulated adaptive allogeneic T cell immune responses. They also failed to induce NK cell degranulation, even at high concentrations. These in vitro effects were confirmed in vivo as repeated injections of EV-CPC did not stimulate production of immunoglobulins or affect the interferon (IFN)-γ responses from primed splenocytes. In a mouse model of chronic heart failure, intra-myocardial injections of EV-CPC, 3 weeks after myocardial infarction, decreased both the number of cardiac pro-inflammatory Ly6Chigh monocytes and circulating levels of pro-inflammatory cytokines (IL-1α, TNF-α, and IFN-γ). In a model of acute infarction, direct cardiac injection of EV-CPC 2 days after infarction reduced pro-inflammatory macrophages, Ly6Chigh monocytes, and neutrophils in heart tissue as compared to controls. EV-CPC also reduced levels of pro-inflammatory cytokines IL-1α, IL-2, and IL-6, and increased levels of the anti-inflammatory cytokine IL-10. These effects on human macrophages and monocytes were reproduced in vitro; EV-CPC reduced the number of pro-inflammatory monocytes and M1 macrophages, while increasing the number of anti-inflammatory M2 macrophages. Conclusions EV-CPC do not trigger an immune response either in in vitro human allogeneic models or in immunocompetent animal models. The capacity for orienting the response of monocyte/macrophages towards resolution of inflammation strengthens the clinical attractiveness of EV-CPC as an acellular therapy for cardiac repair.

scholarly journals Anti-Inflammatory Activity of A Polyphenolic Extract from Arabidopsis thaliana in In Vitro and In Vivo Models of Alzheimer’s Disease

2019 ◽  
Vol 20 (3) ◽  
pp. 708 ◽  
Author(s):  
Roberto Mattioli ◽  
Antonio Francioso ◽  
Maria d’Erme ◽  
Maurizio Trovato ◽  
Patrizia Mancini ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Arabidopsis Thaliana ◽  
Heme Oxygenase 1 ◽  
Neuroprotective Effects ◽  
In Vivo Models ◽  
Polyphenolic Extract ◽  
Anti Inflammatory ◽  
The Impact

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and the primary form of dementia in the elderly. One of the main features of AD is the increase in amyloid-beta (Aβ) peptide production and aggregation, leading to oxidative stress, neuroinflammation and neurodegeneration. Polyphenols are well known for their antioxidant, anti-inflammatory and neuroprotective effects and have been proposed as possible therapeutic agents against AD. Here, we investigated the effects of a polyphenolic extract of Arabidopsis thaliana (a plant belonging to the Brassicaceae family) on inflammatory response induced by Aβ. BV2 murine microglia cells treated with both Aβ25–35 peptide and extract showed a lower pro-inflammatory (IL-6, IL-1β, TNF-α) and a higher anti-inflammatory (IL-4, IL-10, IL-13) cytokine production compared to cells treated with Aβ only. The activation of the Nrf2-antioxidant response element signaling pathway in treated cells resulted in the upregulation of heme oxygenase-1 mRNA and in an increase of NAD(P)H:quinone oxidoreductase 1 activity. To establish whether the extract is also effective against Aβ-induced neurotoxicity in vivo, we evaluated its effect on the impaired climbing ability of AD Drosophila flies expressing human Aβ1–42. Arabidopsis extract significantly restored the locomotor activity of these flies, thus confirming its neuroprotective effects also in vivo. These results point to a protective effect of the Arabidopsis extract in AD, and prompt its use as a model in studying the impact of complex mixtures derived from plant-based food on neurodegenerative diseases.

The anti-inflammatory vasostatin-2 attenuates atherosclerosis in ApoE-/- mice and inhibits monocyte/macrophage recruitment

2017 ◽  
Vol 117 (02) ◽  
pp. 401-414 ◽  
Author(s):  
Weixin Xiong ◽  
Xiaoqun Wang ◽  
Daopeng Dai ◽  
Bao Zhang ◽  
Lin Lu ◽  
...  
Keyword(s):  
Chromogranin A ◽  
Mesenteric Arteries ◽  
Adhesion Assay ◽  
Aortic Sinus ◽  
Necrosis Factor Alpha ◽  
Macrophage Recruitment ◽  
Inflammatory Monocytes ◽  
Anti Inflammatory

SummaryWe showed previously that reduced level of vasostatin-2 (VS-2) correlates to the presence and severity of coronary artery disease. In this study, we aimed to figure out the role of chromogranin A (CGA) derived VS-2 in the development of atherosclerosis and monocyte/macrophage recruitment. Apolipoprotein E-deficient (ApoE-/-) mice fed a high-fat diet exhibited attenuated lesion size by 65 % and 41 % in En face and aortic root Oil red O staining, MOMA-2 positive area by 64 %, respectively, in VS-2 treatment group compared with PBS group. Proinflammatory cytokines tumour necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1) were all remarkably reduced in aortic tissues after VS-2 treatment. Mechanistically, in adhesion assay using intravital microscopy in vivo, VS-2 suppressed the number of leukocytes adhering to the wall of apoE-/- mice mesenteric arteries. In chemotactic assay, flow cytometry analysis of peritoneal lavage exudate from C57BL/6 mice showed VS-2 significantly decreased the recruiment number of inflammatory monocytes/macrophages in a thioglycollate-induced peritonitis model. Furthermore, fewer fluorescent latex beads labelled Ly-6Chi monocytes accumulated in aortic sinus lesions of apoE-/- mice after VS-2 treatment. In addition, according to the microarray of human monocyte/macrophage, we found VS-2 stimulation caused a dose-dependent decrease of Rac1 expression and inactivation of Pak1 in mice primary monocytes as well as THP-1 cells and inhibited MCP-1/CCL-5 induced transmigration in vitro. In conclusion, the Chromogranin A-derived VS-2 attenuates atherosclerosis in apoE-/- mice and, in addition to its anti-inflammatory property, also acts as an inhibitor in monocyte/macrophage recruitment.Supplementary Material to this article is available online at www.thrombosis-online.com.

Anti-inflammatory, anti-proliferative and anti-atherosclerotic effects of quercetin in human in vitro and in vivo models

2011 ◽  
Vol 218 (1) ◽  
pp. 44-52 ◽  
Author(s):  
Robert Kleemann ◽  
Lars Verschuren ◽  
Martine Morrison ◽  
Susanne Zadelaar ◽  
Marjan J. van Erk ◽  
...  
Keyword(s):  
In Vivo Models ◽  
Anti Inflammatory

Probiotic yeast Kluyveromyces marxianus CIDCA 8154 shows anti-inflammatory and anti-oxidative stress properties in in vivo models

2016 ◽  
Vol 7 (1) ◽  
pp. 83-93 ◽  
Author(s):  
D.E. Romanin ◽  
S. Llopis ◽  
S. Genovés ◽  
P. Martorell ◽  
V.D. Ramón ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Kluyveromyces Marxianus ◽  
Intestinal Inflammation ◽  
In Vivo Models ◽  
Benzene Sulfonic Acid ◽  
Bowel Diseases ◽  
Probiotic Yeast ◽  
Anti Inflammatory

Inflammatory bowel diseases (IBDs) are complex affections with increasing incidence worldwide. Multiple factors are involved in the development and maintenance of the symptoms including enhanced oxidative stress in intestinal mucosa. The conventional therapeutic approaches for IBDs are based on the use anti-inflammatory drugs with important collateral effects and partial efficacy. In the present work we tested the anti-inflammatory capacity of Kluyveromyces marxianus CIDCA 8154 in different models. In vitro, we showed that the pretreatment of epithelial cells with the yeast reduce the levels of intracellular reactive oxygen species. Furthermore, in a murine model of trinitro benzene sulfonic acid-induced colitis, yeast-treated animals showed a reduced histopathological score (P<0.05) and lower levels of circulating interleukin 6 (P<0.05). The capacity to modulate oxidative stress in vivo was assessed using a Caenorhabditis elegans model. The yeast was able to protect the nematodes from oxidative stress by modulating the SKN-1 transcription factor trough the DAF-2 pathway. These results indicate that K. marxianus CIDCA 8154 could control the intestinal inflammation and cellular oxidative stress. Deciphering the mechanisms of action of different probiotics might be useful for the rational formulation of polymicrobial products containing microorganisms targeting different anti-inflammatory pathways.

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