Background
The resolution of inflammation is an active process mediated by specialized lipid mediators called lipoxins and resolvins. Periodontal ligament fibroblasts (PDLFs) play a significant role ...in periodontal regeneration. The purpose of the current study was to determine the impact of resolvin D1 (RvD1) on human PDLF cell wound healing and proliferation, receptor expression (G‐protein‐coupled receptor 32 GPR32 and formyl peptide receptor 2 ALX/FPR2), and cytokine expression and release.
Methods
PDLFs were stimulated with interleukin‐1β (IL‐1β) (500 pg/ml) with and without RvD1 (100 nM). RvD1 receptor expression was determined by quantitative real‐time polymerase chain reaction (qPCR), immunofluorescence microscopy, and fluorescence‐activated cell sorting. Wound closure was measured by a scratch assay, and proliferation was determined by bromodeoxyuridine incorporation. Interleukin‐6 (IL‐6), interleukin‐8 (IL‐8), monocyte chemoattractant protein‐1, cyclooxygenase‐2, matrix metalloproteinases‐1, ‐2, and ‐3 (MMP‐1, ‐2, and ‐3), tissue inhibitors of metalloproteinases‐1 and ‐2 (TIMP‐1 and ‐2), prostaglandin E2, and osteoprotegerin (OPG) gene expression and production were measured using qPCR and Western blotting, multiplex immunoassay, and enzyme‐linked immunosorbent assay.
Results
PDLF expressed GPR32 and ALX/FPR2. RvD1 reversed IL‐1β‐induced inhibition of wound healing and proliferation of PDLF. IL‐1β also induced the production of proinflammatory cytokines and MMPs. This effect was reversed by RvD1. RvD1 reversed IL‐1β‒induced inhibition of TIMP‐1, TIMP‐2, and OPG.
Conclusion
The data suggested that RvD1 has a pro‐wound healing, proliferative, and anti‐inflammatory impact on the PDLF that favors periodontal regeneration.
The study aimed to investigate the role of RvD1 in acute and prolonged sterile inflammation and bone remodeling. A mouse model of sterile inflammation that involves bone resorption was used to ...examine endogenous RvD1 kinetics during inflammation. Application of exogenous RvD1 significantly inhibited bone remodeling
via
osteoclast reduction, alongside an anti-inflammatory secretome shift, increased macrophages recruitment and reduction of T-cytotoxic cells.
In vitro
and
in vivo
, RvD1 led to significant reduction in RANK expression which reduce osteoclastogenesis in a dose-dependent manner. Taken together, the data shows a dual role for RvD1, as a potent immunoresolvent agent alongside an osteoresolvent role, showing a potential therapeutic agent in bone resorption associated inflammatory conditions.
Graphical figure: Lipid mediators and enzymes involved in inflammation and resolution.
Arachidonic acid, docosahexaenoic acid and eicosapentaenoic acid are the main precursors of lipid metabolites ...involved in inflammation. 5-lipoxygenase (5-LOX) is the most critical enzyme in the production of 15-Hydroxyeicosatetraenoic acid (15-HPETE) which that the precursor of the leukotrienes (LTs) responsible for the formation and maintenance of proinflammatory response. LTs are very potent chemotactic molecules and increase proinflammatory cytokine production from immune cells and the production of reactive oxygen species and phagocytosis. For the resolution of inflammation, lipoxins (LXs) and resolvins (Rvs) are synthesized from the same lipid precursors by enzymes cyclooxygenase-2 (Cox-2), P450, 5-LOX, 12-LOX, and 15-LOX. However, these metabolites antagonize the proinflammatory effect of LTs.
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•Rheumatoid arthritis is a chronic disease in which pro-inflammatory and anti-inflammatory balance is impaired.•Lipoxin A4, Resolvin D1 and Resolvin E1 are lipid metabolites with strong immunomodulatory effects.•Patients with rheumatoid arthritis have lower Lipoxin A4, Resolvin D1 and Resolvin E1 levels compared to healthy individuals.•These low levels are independent of disease activities of patients with rheumatoid arthritis.
Rheumatoid arthritis (RA) is a disease in which joint inflammation is at the forefront but the whole body is affected, and prevention of inflammation is the main treatment approach. Lipoxins (LXs) and resolvins (Rvs) are critical molecules in the resolution of inflammation. In this study, we aimed to investigate the role of LXs and Rvs in the RA pathogenesis. To this end, we measured the LXA 4, RvD 1, RvE 1 levels, and inflammatory cytokines and chemokines IL-6, IL-8, IL-10, IL-17a, IL-22 and MCP-1 in patients with RA and healthy individuals. We found that the LXA4, RvD1, RvE1 levels of the active RA cases were significantly lower than in remission RA and healthy individuals, but the levels of inflammatory cytokines and chemokines were significantly higher. The decreases in LXs and Rvs were independent of disease activity, suggesting that there might be an impairment of LX and Rvs synthesis or catabolism in patients with RA.
Pulmonary hypertension (PH) is a life-threatening disease characterized by pulmonary vascular remodeling. Endothelial-to-mesenchymal transition (EndMT) is an important manifestation and mechanism of ...pulmonary vascular remodeling. Resolvin D1 (RvD1) is an endogenous lipid mediator promoting the resolution of inflammation. However, the role of RvD1 on EndMT in PH remains unknown. Here, we aimed to investigate the effect and mechanisms of RvD1 on the treatment of PH. We showed that RvD1 and its receptor FPR2 expression were markedly decreased in PH patients and both chronic hypoxia-induced PH (CH-PH) and sugen 5416/hypoxia-induced PH (SuHx-PH) mice models. RvD1 treatment decreased right ventricular systolic pressure (RVSP) and alleviated right ventricular function, and reduced pulmonary vascular remodeling and collagen deposition in the perivascular of both two PH mice models. Then, RvD1 inhibited EndMT in both the lungs of PH mice models and primary cultured human umbilical vein endothelial cells (HUVECs) treated with TGF-β and IL-1β. Moreover, RvD1 inhibited EndMT by downregulating Smad2/3 phosphorylation in vivo and in vitro via FPR2. In conclusion, our date suggest that RvD1/FPR2 axis prevent experimental PH by inhibiting endothelial-mensenchymal-transition and may be a therapeutic target for PH.
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•The RvD1/FPR2 axis is downregulated in patients and mice with pulmonary hypertension.•Post-treatment with RvD1 attenuated right ventricular systolic pressure and right ventricular dysfunction in pulmonary hypertensive mice.•RvD1 improved pulmonary vascular remodeling in pulmonary hypertensive mice.•RvD1 inhibited endothelial-to-mesenchymal via downregulating Smad2/3 phosphorylation in vivo and vitro.
OBJECTIVE:To evaluate the potential changes in the plasma levels of resolvin D1 (RvD1) in patients with trauma and hemorrhage. Having found that trauma results in a profound reduction in plasma RvD1 ...in patients, we have then investigated the effects of RvD1 on the organ injury and dysfunction associated with hemorrhagic shock (HS) in the rat.
BACKGROUND:HS is a common cause of death in trauma due to excessive systemic inflammation and multiple organ failure. RvD1 is a member of the resolvin family of pro-resolution mediators.
METHODS:Blood samples were drawn from critically injured patients (n = 27, ACITII-prospective observational cohort study) within 2 hours of injury for targeted liquid chromatography tandem mass spectrometry. HS rats (removal of blood to reduce arterial pressure to 30 ± 2 mm Hg, 90 minutes, followed by resuscitation) were treated with RvD1 (0.3 or 1 μg/kg intravenous (i.v.)) or vehicle (n = 7). Parameters of organ injury and dysfunction were determined.
RESULTS:Plasma levels of RvD1 (mg/dL) were reduced in patients with trauma+HS (0.17 ± 0.08) when compared with healthy volunteers (0.76 ± 0.25) and trauma patients (0.62 ± 0.20). In rats with HS, RvD1 attenuated the kidney dysfunction, liver injury, and tissue ischemia. RvD1 also reduced activation of the nuclear factor (NF)-κB pathway and reduced the expression of pro-inflammatory proteins such as inducible nitric oxide synthase, tumor necrosis factor-α, interleukin-1β, and interleukin-6.
CONCLUSION:Plasma RvD1 is reduced in patients with trauma-HS. In rats with HS, administration of synthetic RvD1 on resuscitation attenuated the multiple organ failure associated with HS by a mechanism that involves inhibition of the activation of NF-κB.
To study whether resolvin D1 (RvD1), a metabolite of docosahexaenoic acid (DHA), prevents NA-STZ-induced type 2 diabetes mellitus (type 2 DM) in vivo and if so, what could be the mechanism of this ...action.
Single intra-peritoneal (i.p) injection of NA-STZ (175 mg/kg body weight of NA and 65 mg/kg of STZ) was injected simultaneously with RvD1 (60 ng/animal) (injected for 5 consecutive days) to Wistar rats. The effect of RvD1 on plasma glucose levels and apoptotic (Bcl2/Bax) and inflammatory (NF-κB/iNOS) protein expression, plasma lipoxin A4 and BDNF (brain-derived neurotrophic factor) were studied. Protein expressions of PI3k-Akt-mTOR pathway along with histopathological studies of brain were also evaluated.
NA-STZ-induced type 2 DM rats showed hyperglycemia, enhanced plasma IL-6/TNF-α (p ≤0.01), reduced plasma BDNF (p ≤0.01) and LXA4 (p ≤0.01) levels and low BDNF in pancreatic, hepatic and brain tissues (p <0.001), which were restored to near normal (p ≤0.01) in RvD1 treated group. RvD1 increased insulin sensitivity by suppressing inflammation (NF-κB/iNOS) (p ≤0.01) and decreasing apoptosis (Bcl2/Bax) and restoring BDNF and LXA4 levels to near normal. RvD1 treatment increased phosphorylation of Akt (Ser473), and subsequent activation (phosphorylation) of downstream signaling molecules of PI3K and mTOR indicating that RvD1 acts through PI3K/Akt/mTOR axis.
RvD1 is effective in preventing NA-STZ-induced type 2 DM in vivo by suppressing oxidative damage, enhancing the production of anti-inflammatory LXA4 and enhancing neuronal cell survival by augmenting the production of BDNF. Thus, RvD1 may be of benefit not only in preventing diabetes mellitus but also diabetes associated Alzheimer's disease and memory loss.
BACKGROUND AND PURPOSE Transient receptor potential ion channel vanilloid 3 (TRPV3) is expressed in skin keratinocytes and plays an important role in thermal and chemical nociceptions in the ...periphery. The presence of TRPV3 inhibitors would improve our understanding of TRPV3 function and help to develop receptor‐specific analgesics. However, little is known about physiological substances that specifically inhibit TRPV3 activity. Here, we investigated whether 17(R)‐resolvin D1 (17R‐RvD1), a naturally occurring pro‐resolving lipid specifically affects TRPV3 activity.
EXPERIMENTAL APPROACH We examined the effect of 17R‐RvD1 on sensory TRP channels using Ca2+ imaging and whole cell electrophysiology experiments in a HEK cell heterologous expression system, cultured sensory neurons and keratinocytes. We also examined changes in sensory TRP agonist‐specific acute licking/flicking or flinching behaviours and mechanical and thermal pain behaviours using Hargreaves, Randall‐Selitto and von Frey assay systems in the absence and presence of inflammation.
KEY RESULTS We showed that 17R‐RvD1 specifically suppresses TRPV3‐mediated activity at nanomolar and micromolar concentrations. The voltage‐dependence of TRPV3 activation by camphor was shifted rightwards by 17R‐RvD1, which indicates its inhibitory mechanism is as a result of a shift in voltage‐dependence. Consistently, TRPV3‐specific acute pain behaviours were attenuated by locally injected 17R‐RvD1. Moreover, the administration of 17R‐RvD1 significantly reversed the thermal hypersensitivity that occurs during an inflammatory response. Knockdown of epidermal TRPV3 blunted these antinociceptive effects of 17R‐RvD1.
CONCLUSIONS AND IMPLICATIONS 17R‐RvD1 is a novel natural inhibitory substance specific for TRPV3. The results of our behavioural studies suggest that 17R‐RvD1 has acute analgesic potential via TRPV3‐specific mechanisms.
After the initiation of inflammation, a series of processes start to resolve the inflammation. A group of endogenous lipid mediators, namely specialized pro‐resolving lipid mediators is at the top ...list of inflammation resolution. Resolvin D1 (RvD1), is one of the lipid mediators with significant anti‐inflammatory properties. It is produced from docosahexaenoic acid (omega‐3 polyunsaturated fatty acid) in the body. In this article, we aimed to review the most recent findings concerning the pharmacological effects of RvD1 in the central nervous system with a focus on major neurological diseases and dysfunctions. A literature review of the past studies demonstrated that RvD1 plasma level changes during mania, depression, and Parkinson's disease. Furthermore, RVD1 and its epimer, aspirin‐triggered RvD1 (AT‐RvD1), have significant therapeutic effects on experimental models of ischemic and traumatic brain injuries, memory dysfunction, pain, depression, amyotrophic lateral sclerosis, and Alzheimer's and Parkinson's diseases. Interestingly, the beneficial effects of RvD1 and AT‐RvD1 were mostly induced at nanomolar and micromolar concentrations implying the significant potency of these lipid mediators in treating diseases with inflammation.
•Lipoxygenase (LOX) enzymes are upregulated in first trimester sporadic miscarriage tissues.•Both dNK and macrophage cells can affect the uterine inflammatory milieu by synthesizing pro-resolving ...lipid mediators.•Higher production of LOX may reflect inflammatory imbalance through the production of anti-inflammatory lipid mediators.•Pro-resolving mediators lipoxin A4 and resolvin D1 suppress decidualization in primary and immortalized ESCs.
A pivotal event in uterine receptivity and human reproduction is the differentiation of endometrial stromal cells into decidual cells, known as decidualization. Decidualization is interlinked with its inflammatory environment. Our study aimed to investigate the presence and role of pro-resolving lipid mediators in first trimester maternal tissue. We assessed the levels of LXA4 and RvD1, along with their metabolic LOX enzymes, in elective (control) and sporadic miscarriage samples. We investigated the effects of LXA4 and RvD1 on decidualization using primary endometrial stromal cells and the immortalized endometrial stromal St-T1b cell line. The upregulation of 12- and 15-LOX expression was observed in pregnancy tissue after sporadic miscarriage, suggesting an inflammatory imbalance. Furthermore, incubation with these lipid mediators led to a decrease in decidualization biomarkers PRL and IGFBP-1, accompanied by morphological changes indicative of aberrant differentiation. The expression of LOX enzymes in decidual natural killer cells suggests their involvement in regulating the inflammatory surroundings and the extent of decidualization.
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