International Journal of

Molecular Sciences

Review
Roles of Resolvins in Chronic Inflammatory Response
Chang Liu 1,2 , Dancai Fan 3 , Qian Lei 1,3 , Aiping Lu 1,4,5, * and Xiaojuan He 3, *

1 Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases,
School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
2 National TCM Key Laboratory of Serum Pharmacochemistry, Laboratory of Metabolomics, Department of
Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Harbin 150040, China
3 Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences,
Beijing 100700, China
4 Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine, Institute of Arthritis
Research, Shanghai Academy of Chinese Medical Sciences, Shanghai 200052, China
5 Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research,
Guangzhou 510120, China
* Correspondence: aipinglu@hkbu.edu.hk (A.L.); hxj19@126.com (X.H.)

Abstract: An inflammatory response is beneficial to the organism, while an excessive uncontrolled

inflammatory response can lead to the nonspecific killing of tissue cells. Therefore, promoting
the resolution of inflammation is an important mechanism for protecting an organism suffering
from chronic inflammatory diseases. Resolvins are a series of endogenous lipid mediums and
have the functions of inhibiting a leukocyte infiltration, increasing macrophagocyte phagocytosis,
regulating cytokines, and alleviating inflammatory pain. By promoting the inflammation resolution,
resolvins play an irreplaceable role throughout the pathological process of some joint inflammation,
neuroinflammation, vascular inflammation, and tissue inflammation. Although a large number of
experiments have been conducted to study different subtypes of resolvins in different directions, the
differences in the action targets between the different subtypes are rarely compared. Hence, this paper
reviews the generation of resolvins, the characteristics of resolvins, and the actions of resolvins under
a chronic inflammatory response and clinical translation of resolvins for the treatment of chronic
Citation: Liu, C.; Fan, D.; Lei, Q.; inflammatory diseases.
Lu, A.; He, X. Roles of Resolvins in
Chronic Inflammatory Response. Int. Keywords: resolvins; chronic inflammation response; characteristics; mechanism; clinical translation
J. Mol. Sci. 2022, 23, 14883. https://
doi.org/10.3390/ijms232314883

Academic Editor: Alain Couvineau

1. Introduction
Received: 18 October 2022
The inflammatory response is the defense response of the body’s normal tissue to a
Accepted: 18 November 2022
Published: 28 November 2022
damage factor such as a pathogen invasion [1]. Under normal circumstances, the inflam-
matory response is beneficial for the organism, but a chronic inflammatory response can
Publisher’s Note: MDPI stays neutral result when a disorder of an inflammation resolution causes an excessive uncontrolled
with regard to jurisdictional claims in inflammatory response [2,3]. A chronic inflammatory response is dominated by hyper-
published maps and institutional affil-
plasia, usually with lymphocyte and a plasma cell infiltration as the main pathological
iations.
manifestation [4]. A chronic inflammatory disease is a chronic inflammatory response
which is caused by an abnormal immune response and environmental factors including
rheumatoid arthritis, atherosclerosis, diabetes, nervous system diseases, etc., which se-
Copyright: © 2022 by the authors.
riously threaten human health [5]. Therefore, an excessive inflammatory response must
Licensee MDPI, Basel, Switzerland.
be resolved to prevent the onset of chronic inflammatory diseases and the restoration of
This article is an open access article
the homeostasis of organisms [6–8]. The inflammatory resolution phase is characterized
distributed under the terms and by the ceasing of a neutrophil infiltration, the recession of proinflammatory cytokines,
conditions of the Creative Commons and the elimination of fragments and foreign matters in the inflammatory response by
Attribution (CC BY) license (https:// efferocytosis [9,10]. Resolvins, acting as an "agonist", are metabolites of omega-3 fatty acids
creativecommons.org/licenses/by/ and together with martins, protectins, and lipoxins, they are collectively referred to as
4.0/). "special pro-decomposition mediators" (SPMs). The generation of resolvins begins with the

Int. J. Mol. Sci. 2022, 23, 14883. https://doi.org/10.3390/ijms232314883 https://www.mdpi.com/journal/ijms

Int. J. Mol. Sci. 2022, 23, 14883 2 of 16

peak period of inflammation and resolvins also promote an inflammation resolution better
than its lipid precursors at concentrations as low as one which is nanomolar [11,12].
Resolvins such as the E series from eicosapentaenoic acid (EPA), D series from docosa-
hexaenoic acid (DHA), and T series from docosapentaenoic acid (DPA) are synthesized
from essential omega-3 fatty acids by corresponding enzymes such as epoxidase and lipoxi-
dase [13,14]. Omega-3 fatty acid has been proved to be effective in treating COVID-19 [15],
cardiovascular diseases [16], cognitive impairment [17], rheumatoid arthritis [18], and
other complex diseases through an immune regulation. The actions of resolvins in the
inflammatory response mainly include reducing the PMN inflammatory infiltration [19–22],
decreasing inflammatory factors [23–28], improving inflammatory pain and preventing
a central sensitization [29]. The basic characteristics and biological effects of common
resolvins have been demonstrated. Since earlier studies were conducted on individual
subtypes of resolvins, using a different experimental design, a comparison of the results
is possible. Therefore, this paper reviews the possible effect of resolvins on promoting
an inflammation resolution under chronic inflammatory response state and explores their
clinical use to resolve inflammation.

2. Production and Characteristics of Resolvins

Resolvins are the products of omega-3 polyunsaturated fatty acids DHA, EPA, and
DPA metabolic catalyzed by lipoxygenases (LOXs), cytochrome P450s (CYP450s), and
cyclooxygenases (COXs) [30,31]. The D-series resolvins have been synthesized from RvD1
to RvD6, and the E series have been synthesized from RvE1 to RvE4 and 18S-RvE1. The T
series of resolvins have also been discovered and synthesized from RvT1 to RvT4 [32].
As shown in Figure 1, there are two routes for the synthesis of D series resolvins. One
route is that exogenous DHA stored in cell membranes is catalyzed by 15-lipoxygenase
(15-LOX) into 17S-H (p) DHA [33]. On the one hand, 17S-H (p) DHA is further converted
into 7(8)-epoxide intermediates by 15-LOX and becomes RvD1 and RvD2 by the related
enzymes [34,35]. RvD1 and RvD2 were first detected in human cord blood using LC-
MS/MS [36]. On the other hand, 4-(5)-epoxide intermediates are generated through 5-LOX,
and RvD3-RvD6 are generated under the action of enzymes [37,38]. RvD1 to RvD6 belong
to the 17S-D series of resolvins. RvD3 and RvD4 have been detected in human bone marrow
cells based on metabololipidomics [39,40]. Through the method of untargeted lipidomics,
RvD5 in a synovial fluid gathered from rheumatoid arthritis patients was also detected [41].
Another synthetic route is the conversion of DHA to 17R-H(p)DHA by acetylated-COX-2
(acCOX-2), which is then catalyzed to the 17R-D series of resolvins by LOXs. Although
the 17R-D series of resolvins are initially named aspirin-triggered resolvins D (AT-RvDs)
as their biosynthesis is initiated by aspirin, recent research shows that the COX-2 can be
acetylated by other agents in vivo, so these resolvins are named 17R resolvins D according
to the IUPAC nomenclature of the stereocenters [42,43]. These resolvins have the same
effects of promoting an inflammation resolution as the 17S-D series resolvins in vivo [44].
The biosynthesis of E-series resolvins normally occurs under the action of endothelial
cells and leukocytes, and EPA is converted to 18R-H(p)EPE by ASACOX-II. With the
help of 5-LOX, 18R-H(p)EPE enters the cell directly and is converted into 5S-peroxy-18R-
hydroxy-EPE [45]. In the end, the 5(S),6-epoxy intermediate is converted to RvE1 [46].
At the same time, the complete stereochemical structure of RvE1 was determined to be
5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-EPA [47]. However, RvE2 is produced after the
hydrolysis of the 5(S),6-epoxy intermediate, and RvE3 is generated after 18R-H(p)EPE is
catalyzed by 12/15-LOX [48]. By 15-LOX, EPA is converted to 15S-H(p)EPE and further
converted to 15S-hydroxy-5S-HpEPE, the precursor of RvE4 with the help of 15-LOX or
5-LOX [49]. In addition, another synthetic pathway for E-series resolvins is the conversion
of EPA to 18R-H(p)EPE and 17,18-epoxyeicosatetraenoic acid(17,18-EEP) by cytochrome
P450 oxidase [50].
Int. J. Mol. Sci. 2022, 23, 14883 3 of 16

Figure 1. The generation of D series resolvins, E series resolvins, and T series resolvins.

The T series of resolvins are derived from DPA via endothelial cyclooxygenase-2 (COX-
2). The first precursor during the production of T series resolvins is 13(R)-hydroperoxy-
docosapentaenoic acid and it is converted to 13(R)-hydroxy-docosapentaenoic acid after a
reduction [51]. When converted to 7-hydroperoxy-13(R)-hydroxy-docosapentaenoic acid,
RvT4 is obtained from the reduction in the hydroperoxy group after the transcellular
trafficking to the neutrophils [52]. The enzymatic lipoxygenase reaction occurs during
the transition to RvT1, and an allylic epoxide intermediate is formed in the process of
the conversion to RvT2 and RvT3 [53]. T series resolvins are either generated in healthy
subjects or are converted from DPA after statin therapy [4,54]. The complete stereochemical
structure of resolvins is shown in Table 1.
Int. J. Mol. Sci. 2022, 23, 14883 4 of 16

Table 1. The complete stereochemical structure and related abbreviation of resolvins.

Name Structure Abbreviation

Resolvin D1 7S, 8R, 17S-trihydroxy-docosa-4Z, 9E, 11E, 13Z, 15E, 19Z-hexanoic acid RvD1
Resolvin D2 7S, 16R, 17S-trihydroxy-docosa-4Z, 8E, 10Z, 12E, 14E, 19Z-hexanoic acid RvD2
Resolvin D3 4S, 11R, 17S-trihydroxy-docosa-5Z, 7E, 9E, 13Z, 15E, 19Z-hexanoic acid RvD3
Resolvin D4 4S, 5R, 17S-trihydroxy-docosa-6E, 8E,10Z, 13Z, 15E, 19Z-hexanoic acid RvD4
Resolvin D5 7S, 17S-dihydroxy-docosa-4Z, 8E, 10Z, 13Z, 15E, 19Z-hexanoic acid RvD5
Resolvin D6 4S, 17S-trihydroxy-docosa-5E, 7Z, 10Z, 13Z, 15E, 19Z-hexanoic acid RvD6
17R-Resolvin D1 7S, 8R, 17R-trihydroxy-docosa-4Z, 9E, 11E, 13Z, 15E, 19Z-hexanoic acid 17R-RvD1
17R-Resolvin D2 7S, 16R, 17R-trihydroxy-docosa-4Z, 8E, 10Z, 12E, 14E, 19Z-hexanoic acid 17R-RvD2
17R-Resolvin D3 4S, 11R, 17R-trihydroxy-docosa-5Z, 7E, 9E, 13Z, 15E, 19Z-hexanoic acid 17R-RvD3
17R-Resolvin D4 4S, 5R, 17R-trihydroxy-docosa-6E, 8E,10Z, 13Z, 15E, 19Z-hexanoic acid 17R-RvD4
17R-Resolvin D5 7S, 17R-dihydroxy-docosa-4Z, 8E, 10Z, 13Z, 15E, 19Z-hexanoic acid 17R-RvD5
17R-Resolvin D6 4S, 17R-trihydroxy-docosa-5E, 7Z, 10Z, 13Z, 15E, 19Z-hexanoic acid 17R-RvD6
Resolvin E1 5S, 12R, 18R-trihydroxy-eicosa-6Z, 8E, 10E, 14Z, 16E-pentaenoic acid RvE1
18S-Resolvin E1 5S, 12R, 18S-trihydroxy-eicosa-6Z, 8E, 10E, 14Z, 16E-pentaenoic acid 18S-RvE1
Resolvin E2 5S, 18R-dihydroxy-eicosa-6E, 8Z, 11Z, 14Z, 16E-pentaenoic acid RvE2
Resolvin E3 17R, 18R-dihydroxy-eicosa-5Z, 8Z, 11Z, 13E,15E-pentaenoic acid RvE3
Resolvin E4 5S, 15S-dihydroxy-eicosa-6E, 8Z, 11Z, 13E, 17Z-pentaenoic acid RvE4
Resolvin T1 7S,13R,20S-trihydroxy-8E,10Z,14E,16Z,18E-docosapentaenoicacid RvT1
Resolvin T2 7S,12R,13S-trihydroxy-8Z,10E,14E,16Z,19Z-docosapentaenoic acid RvT2
Resolvin T3 7S,8R,13S-trihydroxy-9E,11E,14E,16Z,19Z-docosapentaenoic acid RvT3
Resolvin T4 7S,13R-dihydroxy-8E,10Z,14E,16Z,19Z-docosapentaenoic acid RvT4
Int. J. Mol. Sci. 2022, 23, 14883 5 of 16

3. Resolvins Receptors
RvD1, 17R-RvD1, RvD3, 17R-RvD3, RvD5, RvE1, and 18S-RvE1 can combine with the
G protein-coupled receptor (GPR32) expressed in monocyte-macrophages, lymphocytes,
endothelial cells, and vascular smooth muscle cells, while GPR18/DRV2 is a novel discov-
ered receptor of RvD2 expressed in macrophages, neutrophils, and monocytes [55,56]. In
addition, RvD1, 17R-RvD1, and RvD3 can also combine with the G protein-coupled formyl
peptide receptor 2 (ALX/FPR2) to produce anti-inflammatory effects [57–59]. Leukotriene
B4 receptor 1 (BLT1) expressed in lymphocytes and leukocytes and ChemR23 expressed
in NK cells, macrophages, epithelial cells, and dendritic cells have been proven to be the
receptors of RvE1, 18S-RvE1, and RvE2 through target screening [60,61]. The actions of
RvD4 in the phagocytosis of human leukocytes have been suggested to be related to Gs
protein and the responding G protein-coupled receptors [39]. The resolvin receptors are cell
specific and organ specific and have been shown to be affected by disease and homeostatic
states. However, the corresponding receptors of the characterized RvD6, RvE3, and T series
of resolvins have not yet been identified, and relevant studies are still needed to explore
these receptors [62].

4. Effects of Resolvins on Target Cells in Chronic Inflammatory Response

The cellular targets of resolvins depend on the unique receptor repertoire of the differ-
ent cells. Different resolvin subtypes also have common target cells, while the mechanisms
of their actions on the same cell have obvious differences, as shown in Figure 2.

Figure 2. Different actions of resolvins on several target cells.

4.1. Effects on Neutrophils

Neutrophils constitute the cell’s first line of immune defense. Activated neutrophils
may release neutrophil extracellular traps (NETs) during a distinct form of cell death,
which promote inflammation. RvE1 regulates CD18 in neutrophils, downregulates the
phosphorylation of AKT and MAPK, and inhibits a superoxide production and migration
Int. J. Mol. Sci. 2022, 23, 14883 6 of 16

between epithelial and endothelial cells [63,64]. RvD1 stops neutrophil chemotaxis, inhibits
a neutrophil migration, and downregulates the actin aggregation and the expression of
adhesion molecules via miR-21 and miR-155 [65]. 17R-RvD1 decreases the expression of
p-selection and its ligand CD24 in neutrophils, while RvD2 decreases CD62L shedding in
human neutrophils [66]. Bacterial and viral infections trigger an uncontrolled inflammation
upon contact with excess NETs and clearance obstacles of NETs. The newly found T series
resolvins dose- and time-dependently reduce NETs in human neutrophils and restricted
neutrophil infiltration and NETs in a murine Staphylococcus aureus infection [67].

4.2. Effects on Macrophages

Macrophages produce a large number of inflammatory cytokines during autoinflam-
matory diseases that cause a cascade of release of inflammatory mediators and are therefore
regarded as inflammatory triggers [68]. Macrophages are critical for restoring homeostasis,
and their function contributes to the pathological development of fibrosis, atherosclerosis,
cancer, and other chronic diseases in the event of a persistent injury or failure to resolve in-
flammation [69]. RvE1, RvD1, RvD2, RvD3, and RvD5 can all act on macrophages, but their
effects are exerted in different ways. RvE1 reduces the expression of the HO-1 and NADPH
oxidase subunit p47Phox, while RvD1 induces the transition from M1 macrophages to M2
macrophages [70,71]. RvD2 regulates the transcription factor IRF4, while RvD3 and RvD5
enhance efferocytosis and phagocytosis of M2 macrophages [34,55]. Monocytes are the
precursors of macrophages, and the functions of RvE1 on monocytes are to decrease the
shedding of L-selectin and the expression of integrin CD18, while RvD1 decreases CD11b,
CD68, and GR-1 [72]. RvD1 and RvD2 regulate a macrophage polarization through multiple
targets, while the activation of the PKA pathway is necessary [73,74]. RvD1 can regulate
miR-208a and miR-219 in macrophages to target regulating IL-10 and 5-lipoxygenase [58,75].
RvT2 in the T series stimulates the clearance of NETs by macrophages through increas-
ing intracellular cyclic adenosine phosphate and phospho-AMP-activated protein kinase
(AMPK) in both human and mouse cells [67].

4.3. Effects on Lymphocytes

Lymphocytes are the smallest leukocytes and include T cells, B cells, and natural killer
(NK) cells. A lymphocyte infiltration is a key step in the tissue damage caused by a chronic
inflammatory response in which lymphocytes migrate abnormally into nonlymphoid
tissues [76]. B cells are the target cells of RvD1, which reduces their production of IgE,
while RvD2 protects against an alveolar bone loss by decreasing CD4+ T cells [77,78]. RvD5
has been assessed to significantly inhibit the Th17 cells’ differentiation and proliferation,
and RvD1 controls downstream miR-30e-5p to increase Treg and reduce the differentiation
of Th17 to repair the imbalance in the Treg/Th17 ratio [79,80]. RvE1 not only inhibits the
proliferation of Th17 but it also affects Th17s secretion of IL-17 and increases the expression
of CCR-5 [81]. In addition, RvE1 facilitates the cell migration of NK to remove eosinophilic
granulocytes and apoptotic PMNs by CMKLR1, and RvD1 also reduces the secretion of
TNF-α and IL-6 in acinous cells by upregulating NF-κB [82–84].

4.4. Effects on Astrocytes

Astrocytes are the most widely distributed cells in the brain and dynamically regulate
a neural and synaptic plasticity, the blood-brain barrier (BBB) homeostasis, and the trans-
mission of signals [85] that are closely related to inflammation and Alzheimer’s disease [86].
Astrocytes promote and maintain a microglial activation, leading to a chronic inflammatory
response, in addition to regulating the activity of oligodendrocytes and cells of the adaptive
immune system and controlling an infiltration of the central nervous system [87,88]. RvD1
can activate the ALX4/FPR2 receptor in astrocytes and induce higher levels of mitochon-
drial phagocytosis to eliminate damaged mitochondria [89]. Another study showed that
RvD1 impaired a neuronal cell death through miR-146b and miR-219a-1–3p to enhance
functional recovery [26]. 17R-RvD1 has effects on the neuronal dysfunction by impairing
Int. J. Mol. Sci. 2022, 23, 14883 7 of 16

and downregulating the neuronal plasticity [90]. It can not only decrease the release of
TNF in LPS and IFN-γ-stimulated astrocytes, but also reduce the TNF-induced activation
of ERK1/2 [91]. Zhang et al. showed that GPR18 was expressed in astrocytes, and the acti-
vation of RvD2-GPR18 mediated an anti-nociceptive effect by regulating the Akt/GSK-3β
signal pathway in a radicular pain rat model [92].

4.5. Effects on Endothelial Cells

Endothelial cells, which are found at the inner wall of the blood vessels, are the
target of RvD1, RvD2, and RvE1. The junction of interendothelial adhesion molecules
forms the endothelial cell barrier that regulates the vascular permeability and leukocyte
extravasation. An increased or prolonged leukocyte recruitment leads to the increased
expression of interendothelial adhesion molecules during the chronic inflammatory re-
sponse [93]. RvD2 regulates the production of NO and the expression of adhesion receptors
in endothelial cells [94]. RvD1 activates the ENaC and Na+ -K+ -ATP axes by regulating
the ALX/cAMP/PI3K signaling pathways and effectively blocks the interaction between
endothelial cells and monocytes as well as the inactivation of SHP2 and PP2A [95]. In
addition, RvD1 upregulates the expression of ZO-1, occludin, and tight junction proteins
to protect against the impairment of the endothelial barrier function through the IκBα
pathway [96]. RvE1 has been demonstrated to attenuate an endothelial senescence by
reducing not only the expression of the pro-IL-1β proteins pP65 and NLRP3 but also the
generation of the NLRP3 inflammasome complexes [97].

4.6. Effects on Cancer Cells

The steps of chronic inflammation-induced cancer syndrome include a cell transfor-
mation, promotion, survival, proliferation, invasion, angiogenesis, and metastasis [98].
Resolvins specifically inhibit the cancer progression stimulated by cell fragments through
a reprogramming of macrophages to enhance the clearance of fragments, and counter
regulating cytokines or chemokines released by human macrophages [74,99]. In addition,
resolvins can stimulate the antineoplastic activity of neutrophils [100]. Resolvins also
inhibit the differentiation of cancer-associated fibroblasts in a hepatocellular carcinoma
and pancreatic cancer [101,102]. Besides affecting the function of immune cells in a tumor
microenvironment, resolvins can also directly act on tumor cells. When acting on A549
lung cancer cells, RvD1 and RvD2 inhibit the epithelial–mesenchymal transition (EMT)
by reducing the phosphorylation of PI3K to downregulate the expression of N-cadherin
and ZEB1 and modulate the macrophage polarization to inhibit cancer growth [74,103,104].
RvD1 inhibits the secretion of a cartilage oligomeric matrix protein (COMP) by targeting
FPR1/ROS/ROXM1 signaling, thereby impeding the cancer stem-like properties and EMT
of hepatocellular carcinoma cells [101]. Moreover, increasing the expression of monocyte
chemoattractant protein-1 (MCP-1), stimulating PMNs reprogramming, and promoting
a protective PMN-dependent recruitment are potential ways that RvD1 inhibits tumor
growth [100]. RvE1 and RvD1 reduce the activity of NF-κB/AP-1 to prevent the transition
from a liver injury and hepatitis to liver cancer [105]. The anticancer actions of resolvins,
mainly including RvD1, RvD2, and RvE1, are achieved with the receptor-dependent promo-
tion of a tumor debris clearance and the inhibition of tumor cell growth mediated by cells
in the tumor stroma [99]. However, 17R-RvD1 inhibits EMT by reducing the expression of
mTOR, Pkm2, and Nrf2 to downregulate E-cadherin and vimentin [20].

5. Mechanism and Clinical Translation of Resolvins for Chronic Inflammatory

Diseases Treatment
Due to the fact that the receptors of resolvins are located on different target cells, tissues,
and organs, different resolvins have different effects on different diseases. Increasing
evidence and research have been provided to clarify the relationship between resolvins and
the chronic inflammatory response as well as chronic inflammatory diseases. Therefore,
resolvins have been gradually applied in clinical practice based on their mechanism.
Int. J. Mol. Sci. 2022, 23, 14883 8 of 16

5.1. Effects on Pain

Research on heat pain sensitivity and osteoarthritis pain in 250 healthy volunteers
and 62 volunteers affected with knee osteoarthritis was performed to measure endogenous
17-HDHA, RvD1-3, RvD5, and RvE1 by LC-MS. The study concluded that the level of 17-
HDHA was closely related to increasing heat pain thresholds, and its effect on the sensitivity
of the heat pain and osteoarthritis pain was based on the level of DHA [106]. A mouse model
of postoperative pain induced by a tibial bone fracture (fPOP) was used to show that RvD1
and RvD5 could reduce mechanical allodynia and cold allodynia and that RvD1 inhibited
mechanical hyperalgesia by regulating CGPR [107]. Further research indicated that RvD1
increased a cell-selective polarization by regulating the NK-κB nuclear translocation and
M2-type polarization in microglial cells, thereby reducing the neuropathic pain [108]. RvD2
alleviated hyperalgesia in cystitis rats by activating GPR18 and inhibiting TRPV1, and
RvD5 exhibited sex differences in the modulation of pain and inhibited neuropathic pain
only in male mice [109,110]. The ERK signaling pathway is a common target regulated
by RvD1 and RvE1, while RvD1 significantly alleviates neuropathic pain by inhibiting
the Nod-like receptor protein 3 (NLRP3) inflammasome in the ERK signaling pathway,
and RvE1 alters the mechanical allodynia by inhibiting the ERK phosphorylation in spinal
dorsal horn neurons [111,112]. RvD1 and RvE1 have analgesic effects on bone cancer pain,
and RvD1 can additionally promote the upregulation of endocannabinoids through CB2
receptors, so RvD1 has a stronger analgesic effect on bone cancer than RvE1 [113].

5.2. Effects on Atherosclerosis

Fat-fed Ldlr−/− mice were administered RvD1 to test whether SPMs, especially
RvD1, were related to facilitating efferocytosis in atherosclerosis and suppressing plaque
necrosis by a targeted a mass spectrometry platform. Finally, the research confirmed that
RvD1 had the ability to promote a plaque stability by accelerating lesional efferocytosis
and decreasing lesion oxidative stress and necrosis [114]. To examine whether RvE1 could
reduce atherosclerosis, a mouse model of ApoE*3 Leiden mice fed a hypercholesterolaemic
diet was used, and the RvE1 effects of protecting against atherosclerosis and decreasing
a lesional inflammation had been demonstrated to involve regulating the expression of
immune responses and inflammatory genes in arteries without changing the serum amyloid
A and plasma cholesterol [115]. The proliferation and migration of vascular smooth muscle
cells (VSMCs) is a significant feature of the atherosclerotic lesions. Research shows that
RvE1 can block the migration of the human great saphenous vein mesangial cells stimulated
by a platelet-derived growth factor and reduce the phosphorylation of the platelet-derived
growth factor receptor-β to control the formation of atherosclerosis [116]. RvE1 inhibits
the contractions of both the human pulmonary artery (HPA) and rat thoracic aorta (RTA),
while RvD1 and RvD2 only control the contractions of the RTA. These results indicate
that resolvins provide useful novel therapeutics and have the characteristic of increasing
the activity of thromboxane contractile for pulmonary arterial hypertension [11]. Viola
et al. have demonstrated that the delivery of RvD2 and Maresin 1 induces macrophages to
transform into the repair phenotype and stimulate the collagen synthesis of smooth muscle
cells [117]. Elajami et al. tested the endogenous SPMs profiles of six patients suffering from
stable coronary artery disease (CAD) through targeted metabololipidomics, and the results
showed that the absence of RvE1, RvD1, RvD2, RvD3, and RvD5 appeared in CAD patients.
After a treatment with Lovaza (one capsule contains 840 mg of EPA and DHA), 17R-RvD3
and RvD6 were increased in patients with CAD, and the result also showed that SPMs
could promote a macrophage phagocytosis in blood clots [118,119]. In addition, RvD1 was
able to reduce M1-type macrophages in patients with ApoEε3/ε3 but increased M1-type
macrophages in patients with ApoEε3/ε4 [17]. Resolvins, as natural receptor agonists
mainly associated with the stability of plaques and a lack of proatherogenic side effects,
have a great potential as a new therapy for CAD [120]. Patients with Chagas disease always
develop chronic myocarditis when the infection is untreated. 17R-RvD1 modulates a local
and systemic inflammation in mouse cardiac tissue chronically infected with parasites,
Int. J. Mol. Sci. 2022, 23, 14883 9 of 16

reduces cellular infiltration, and reduces cardiac hypertrophy and fibrosis in the early
chronic phase of the disease, providing a strategy for improving drug therapy [121].

5.3. Effects on Diabetes

In conjunction with the interactions among adipocytes, macrophages, and other im-
mune cells infiltrating the adipose tissue, adipose tissue produces an inflammatory re-
sponse, which in turn contributes to the development of type 2 diabetes mellitus (T2DM)
by leading to an insulin resistance [122]. Research was performed with twenty-four T2DM
patients randomized to a three-period crossover study including drinking red wine for
4 weeks or the equivalent volumes of water or dealcoholized red wine to measure the
effects of red wine on plasma SPMs of T2DM patients and the difference between patients
and healthy volunteers. Red wine did not appear to differentially affect any SPMs, and
the SPM levels in T2DM patients were higher than those in healthy volunteers. This re-
search proves that increasing the SPM level is a homeostatic response to counter ongoing
inflammation [123]. In addition, by researching dorsal root ganglion (DRG) neurons in a
T2DM mouse model fed with a high-fat diet for 8 weeks and administered daily injections
of RvD1, the results showed that RvD1 could promote the growth of DRG neurites and
indicated that neuropathy, such as the slow nerve conduction caused by T2DM, could be
reversed by RvD1 [124]. The results showed that a supplementation with polyunsaturated
fatty acids could be an effective therapy for diabetic neuropathy. The most recent research
showed that the MAPK-NF-κB signaling pathway was the target of RvD1 for fungal growth
and the inflammatory response against Aspergillus fumigatus keratitis in diabetes [125].
RvD5 prevents the elevation of IL-1β in the hippocampus and prefrontal cortex of type
1 diabetes mellitus rats, thereby intervening in behaviors related to depression and anxiety.
RvE3 plays a role in glucose homeostasis by activating PI3K and Akt phosphorylation to
enhance the adipocyte uptake of glucose [126].

5.4. Effects on Anti-Depression and Wound Healing

Different resolvin subtypes also play the same role through different mechanisms. In
terms of anti-depression, RvD1 plays an anti-depression role through the transmission of
glutamic acid or PI3K/AKT signaling, while RvD2 can also act on MEK/ERK [127]. The
activation of mTORC1 signaling is the key anti-depressive role of RvD1, RvD2, RvE1, RvE2,
and RvE3 [25,128–132]. In addition, RvD2 promotes the healing of periapical bone lesions
and the regeneration of pulp-like tissue by enhancing the expression of dentin matrix acidic
phosphoprotein 1 (DMP1) and the phosphorylation of STAT3 [133]. To promote wound
healing, the effect of RvE1 is obviously better than that of RvD2, while the effect of RvD1 is
weaker than that of RvD2 [134]. Resolvin D6-isomer (RvD6si) contributes to the functional
recovery and wound healing of corneal tissue by restoring an innervation after injury [135].

5.5. Effects on Rheumatoid Arthritis

Rheumatoid arthritis (RA) is characterized by chronic inflammation and progressive
joint destruction. The levels of RvD1 and RvE1 in patients with RA had been measured
and were significantly lower than those in healthy individuals and patients in remission
of RA [136]. RvD1 restrains the expression of TRAP, cathepsin K, TNF-α, IL-1 β, IFN-γ,
and PGE2 to inhibit the differentiation and activation of osteoclasts [137]. The mech-
anism of RvD1 against RA had been further elucidated in a collagen-induced arthritis
(CIA) mouse model; that is, RvD1 alleviated the progression of RA by inhibiting CTGF
via the upregulation of miRNA-146a-5p [138]. Research has indicated that the level of
RvD3 was reduced in delayed-resolving arthritis mice and RA patients and RvD3 could
reduce joint leukocytes [40]. Furthermore, an SKG arthritic mouse model was used to
explore the actions of RvD5, and the results showed that RvD5 weakened the osteoclast
differentiation to interfere with the genesis of osteoclasts involved in the pathogenesis of
RA [79]. Another research indicated that GPR101 was the top candidate receptor for RvD5
to display antiarthritic action by regulating neutrophil and macrophage responses [139].
Int. J. Mol. Sci. 2022, 23, 14883 10 of 16

RvE1 inhibits bone resorption and osteoclastogenesis through suppressing the expression
of the transcription factors nuclear factor of activated T cells c1 (NFATc1) and c-fos [140].

5.6. Application of Resolvins in the Treatment of Pre-Diseases

A clinical study aimed to evaluate the SPM levels in offspring supplied with fatty acids
during pregnancy and at 12 years of age. This was the first time that RvE1, RvE2, RvE3,
RvD1, 17R-RvD1, and RvD2 had been identified in human cord blood. A supplementation
with n-3 fatty acids in pregnancy can significantly increase SPM precursors and DHA-
derived 17-HDHA at birth but not at 12 years [36]. The application of the accumulative
score relies on the gene expression related to the generation, metabolism, and signaling
of D series resolvins to comparatively analyze the relationship between the resolution of
inflammation and tumorigenesis. As a result, a higher RvD score distinguishes patients with
an improved resolution of inflammation who can benefit from an anticancer treatment [141].
Regardless of the method of directly supplementing exogenous resolvins or increasing
endogenous resolvins, resolvins have certain effects on the resolution of inflammation and
the maintenance of homeostasis in vivo. Numerous animal and clinical experiments have
provided the basis for the development of new anti-inflammatory drugs and the treatment
of chronic diseases caused by inflammation.

6. Further Perspectives
Resolvins are a series of endogenous lipid mediators with a positive effect on inflam-
mation resolution, and their origin and chemical structure have been confirmed for many
years. Studies of receptors have reported a few receptors for resolvins; however, the recep-
tors of the T-series resolvins RvD6 and RvE3 are not clear, so a further study of resolvin
receptors can provide new evidence and directions for us to resolve inflammation. Many
human and animal experiments have also substantiated that resolvins can reduce the joint
pain and stiffness of RA, reduce vessel inflammation in coronary heart disease, promote
plaque stability, and improve the metabolic parameters and complications of diabetes.
The mechanism of action of the resolvins in the process of an inflammation resolution is
complex, and the existing evidence is only the tip of the iceberg. A large number of studies
still need to be confirmed and explained.
In inflammatory diseases, there are naturally expressed resolvins in many organs.
However, as its biosynthetic precursor omega-3 polyunsaturated fatty acid cannot be
synthesized by the human body itself, the resolvins obtained from the body are very limited.
As resolvins are endogenous lipid mediators and are sensitive to light, heat, and oxidation,
synthesis costs are very high in vitro and production supplies are limited, so it is difficult
to perform a large-scale production and new drug industry chain formation. According
to systems’ biology theory and methods, resolvins can be regarded as the breakthrough
point in the search for related correlative proteins and signaling pathways to elucidate the
mechanism of anti-inflammatory prescriptions and drugs. The cross-analysis of multiple
layers and multi-omics may be a way to provide a basis for new anti-inflammatory drugs
research to discover novel drugs with fewer side effects and significant therapeutic effects
on chronic inflammatory diseases as soon as possible.

7. Conclusions
With the development of detection techniques and a deeper understanding of the
chronic inflammatory response, the study of resolvins will no longer be limited to simple
individual subtypes of resolvins. Hence, this paper reviews not only the production process
and characteristics of resolvins but also possible mechanisms by the subtypes of resolvins
in a chronic inflammatory response and explores their clinical use to resolve inflammation.

Author Contributions: C.L. wrote the manuscript. D.F. and Q.L. participated in the writing. A.L.
and X.H. conceptualized the idea and revised the manuscript. All authors have read and agreed to
the published version of the manuscript.
Int. J. Mol. Sci. 2022, 23, 14883 11 of 16

Funding: This paper is supported by National Science Foundation of China (No. 81873053), the
Fundamental Research Funds for the Central Public Welfare Research Institutes (No. Z0736), and the
2020 Guangdong Provincial Science and Technology Innovation Strategy Special Fund (Guangdong-
Hong Kong-Macau Joint Lab, No: 2020B1212030006).
Conflicts of Interest: The authors declare that the research was conducted in the absence of any
commercial or financial relationships that could be construed as a potential conflict of interest.

References
1. Sochocka, M.; Diniz, B.S.; Leszek, J. Inflammatory Response in the CNS: Friend or Foe? Mol. Neurobiol. 2017, 54, 8071–8089.
[CrossRef] [PubMed]
2. Balta, M.G.; Loos, B.G.; Nicu, E.A. Emerging Concepts in the Resolution of Periodontal Inflammation: A Role for Resolvin E1.
Front. Immunol. 2017, 8, 1682. [CrossRef] [PubMed]
3. Kazemi, S.; Shirzad, H.; Rafieian-Kopaei, M. Recent Findings in Molecular Basis of Inflammation and Anti-inflammatory Plants.
Curr. Pharm. Des. 2018, 24, 1551–1562. [CrossRef] [PubMed]
4. Serhan, C.N.; Levy, B.D. Resolvins in inflammation: Emergence of the pro-resolving superfamily of mediators. J. Clin. Investig.
2018, 128, 2657–2669. [CrossRef] [PubMed]
5. Abdolmaleki, F.; Kovanen, P.T.; Mardani, R.; Gheibi-Hayat, S.M.; Bo, S.; Sahebkar, A. Resolvins: Emerging Players in Autoimmune
and Inflammatory Diseases. Clin. Rev. Allergy Immunol. 2020, 58, 82–91. [CrossRef] [PubMed]
6. Fredman, G.; Serhan, C.N. Specialized proresolving mediator targets for RvE1 and RvD1 in peripheral blood and mechanisms of
resolution. Biochem. J. 2011, 437, 185–197. [CrossRef]
7. Lorente-Cebrian, S.; Costa, A.G.; Navas-Carretero, S.; Zabala, M.; Laiglesia, L.M.; Martinez, J.A.; Moreno-Aliaga, M.J. An update
on the role of omega-3 fatty acids on inflammatory and degenerative diseases. J. Physiol. Biochem. 2015, 71, 341–349. [CrossRef]
8. Chen, L.; Deng, H.; Cui, H.; Fang, J.; Zuo, Z.; Deng, J.; Li, Y.; Wang, X.; Zhao, L. Inflammatory responses and inflammation-
associated diseases in organs. Oncotarget 2018, 9, 7204–7218. [CrossRef]
9. Blaudez, F.; Ivanovski, S.; Fournier, B.; Vaquette, C. The utilisation of resolvins in medicine and tissue engineering. Acta Biomater.
2022, 140, 116–135. [CrossRef]
10. Kourtzelis, I.; Li, X.; Mitroulis, I.; Grosser, D.; Kajikawa, T.; Wang, B.; Grzybek, M.; von Renesse, J.; Czogalla, A.; Troullinaki, M.; et al.
DEL-1 promotes macrophage efferocytosis and clearance of inflammation. Nat. Immunol. 2019, 20, 40–49. [CrossRef]
11. Jannaway, M.; Torrens, C.; Warner, J.A.; Sampson, A.P. Resolvin E1, resolvin D1 and resolvin D2 inhibit constriction of rat
thoracic aorta and human pulmonary artery induced by the thromboxane mimetic U46619. Br. J. Pharmacol. 2018, 175, 1100–1108.
[CrossRef]
12. Dangi, B.; Obeng, M.; Nauroth, J.M.; Chung, G.; Bailey-Hall, E.; Hallenbeck, T.; Arterburn, L.M. Metabolism and biological
production of resolvins derived from docosapentaenoic acid (DPAn-6). Biochem. Pharmacol. 2010, 79, 251–260. [CrossRef]
13. Chiurchiu, V.; Leuti, A.; Maccarrone, M. Bioactive Lipids and Chronic Inflammation: Managing the Fire Within. Front. Immunol.
2018, 9, 38. [CrossRef]
14. Hong, S.; Lu, Y. Omega-3 fatty acid-derived resolvins and protectins in inflammation resolution and leukocyte functions: Targeting
novel lipid mediator pathways in mitigation of acute kidney injury. Front. Immunol. 2013, 4, 13. [CrossRef]
15. Arnardottir, H.; Pawelzik, S.C.; Sarajlic, P.; Quaranta, A.; Kolmert, J.; Religa, D.; Wheelock, C.E.; Back, M. Immunomodulation by
intravenous omega-3 fatty acid treatment in older subjects hospitalized for COVID-19: A single-blind randomized controlled trial.
Clin. Transl. Med. 2022, 12, e895. [CrossRef]
16. Myhre, P.L.; Kalstad, A.A.; Tveit, S.H.; Laake, K.; Schmidt, E.B.; Smith, P.; Nilsen, D.W.; Tveit, A.; Solheim, S.; Arnesen, H.; et al.
Changes in eicosapentaenoic acid and docosahexaenoic acid and risk of cardiovascular events and atrial fibrillation: A secondary
analysis of the OMEMI trial. J. Intern. Med. 2022, 291, 637–647. [CrossRef]
17. Famenini, S.; Rigali, E.A.; Olivera-Perez, H.M.; Dang, J.; Chang, M.T.; Halder, R.; Rao, R.V.; Pellegrini, M.; Porter, V.;
Bredesen, D.; et al. Increased intermediate M1-M2 macrophage polarization and improved cognition in mild cognitive impairment
patients on omega-3 supplementation. FASEB J. 2017, 31, 148–160. [CrossRef]
18. Proudman, S.M.; Cleland, L.G.; Metcalf, R.G.; Sullivan, T.R.; Spargo, L.D.; James, M.J. Plasma n-3 fatty acids and clinical outcomes
in recent-onset rheumatoid arthritis. Br. J. Nutr. 2015, 114, 885–890. [CrossRef]
19. Gerlach, B.D.; Marinello, M.; Heinz, J.; Rymut, N.; Sansbury, B.E.; Riley, C.O.; Sadhu, S.; Hosseini, Z.; Kojima, Y.; Tang, D.D.; et al.
Resolvin D1 promotes the targeting and clearance of necroptotic cells. Cell Death Differ. 2020, 27, 525–539. [CrossRef]
20. Liu, Y.; Yuan, X.; Li, W.; Cao, Q.; Shu, Y. Aspirin-triggered resolvin D1 inhibits TGF-beta1-induced EMT through the inhibition
of the mTOR pathway by reducing the expression of PKM2 and is closely linked to oxidative stress. Int. J. Mol. Med. 2016, 38,
1235–1242. [CrossRef]
21. Hasturk, H.; Abdallah, R.; Kantarci, A.; Nguyen, D.; Giordano, N.; Hamilton, J.; Van Dyke, T.E. Resolvin E1 (RvE1) Attenuates
Atherosclerotic Plaque Formation in Diet and Inflammation-Induced Atherogenesis. Arterioscler. Thromb. Vasc. Biol. 2015, 35,
1123–1133. [CrossRef] [PubMed]
22. El Kebir, D.; Gjorstrup, P.; Filep, J.G. Resolvin E1 promotes phagocytosis-induced neutrophil apoptosis and accelerates resolution
of pulmonary inflammation. Proc. Natl. Acad. Sci. USA 2012, 109, 14983–14988. [CrossRef] [PubMed]
Int. J. Mol. Sci. 2022, 23, 14883 12 of 16

23. Zhong, X.; Lee, H.N.; Surh, Y.J. RvD1 inhibits TNF alpha-induced c-Myc expression in normal intestinal epithelial cells and
destabilizes hyper-expressed c-Myc in colon cancer cells. Biochem. Biophys. Res. Commun. 2018, 496, 316–323. [CrossRef] [PubMed]
24. Xu, J.T.; Duan, X.R.; Hu, F.; Poorun, D.; Liu, X.X.; Wang, X.; Zhang, S.; Gan, L.; He, M.W.; Zhu, K.; et al. Resolvin D1 attenuates
imiquimod-induced mice psoriasiform dermatitis through MAPKs and NF-kappa B pathways. J. Dermatol. Sci. 2018, 89, 127–135.
[CrossRef] [PubMed]
25. Deyama, S.; Shimoda, K.; Suzuki, H.; Ishikawa, Y.; Ishimura, K.; Fukuda, H.; Hitora-Imamura, N.; Ide, S.; Satoh, M.; Kaneda, K.;
et al. Resolvin E1/E2 ameliorate lipopolysaccharide-induced depression-like behaviors via ChemR23. Psychopharmacology 2018,
235, 329–336. [CrossRef] [PubMed]
26. Bisicchia, E.; Sasso, V.; Catanzaro, G.; Leuti, A.; Besharat, Z.M.; Chiacchiarini, M.; Molinari, M.; Ferretti, E.; Viscomi, M.T.;
Chiurchiu, V. Resolvin D1 Halts Remote Neuroinflammation and Improves Functional Recovery after Focal Brain Damage Via
ALX/FPR2 Receptor-Regulated MicroRNAs. Mol. Neurobiol. 2018, 55, 6894–6905. [CrossRef]
27. Easley, J.T.; Nelson, J.W.; Mellas, R.E.; Sommakia, S.; Wu, C.; Trump, B.; Baker, O.J. Aspirin-Triggered Resolvin D1 Versus
Dexamethasone in the Treatment of Sjogren’s Syndrome-Like NOD/ShiLtJ Mice—A Pilot Study. J. Rheum. Dis. Treat. 2015, 4, 27.
[CrossRef]
28. Hsiao, H.M.; Thatcher, T.H.; Levy, E.P.; Fulton, R.A.; Owens, K.M.; Phipps, R.P.; Sime, P.J. Resolvin D1 Attenuates Polyinosinic-
Polycytidylic Acid-Induced Inflammatory Signaling in Human Airway Epithelial Cells via TAK1. J. Immunol. 2014, 193, 4980–4987.
[CrossRef]
29. Ji, R.R.; Xu, Z.Z.; Strichartz, G.; Serhan, C.N. Emerging roles of resolvins in the resolution of inflammation and pain. Trends
Neurosci. 2011, 34, 599–609. [CrossRef]
30. Serhan, C.N.; Libreros, S.; Nshimiyimana, R. E-series resolvin metabolome, biosynthesis and critical role of stereochemistry of
specialized pro-resolving mediators (SPMs) in inflammation-resolution: Preparing SPMs for long COVID-19, human clinical
trials, and targeted precision nutrition. Semin. Immunol. 2022, 101597. [CrossRef]
31. Zheng, Y.Y.; Liu, D.X.; Shi, X.X.; Xu, N.; Li, R.G. Efficacy of vitamin D2 on severe diabetic peripheral neuropathy of type 2 diabetes
mellitus: A multicenter random double-blind, placebo-controlled trial. Diabetes-Metab. Res. Rev. 2017, 33, 1–2.
32. Dalli, J.; Colas, R.A.; Serhan, C.N. Novel n-3 immunoresolvents: Structures and actions. Sci. Rep. 2013, 3, 1940. [CrossRef]
33. Hellmann, J.; Sansbury, B.E.; Wong, B.; Li, X.F.; Singh, M.; Nuutila, K.; Chiang, N.; Eriksson, E.; Serhan, C.N.; Spite, M.
Biosynthesis of D-Series Resolvins in Skin Provides Insights into their Role in Tissue Repair. J. Investig. Dermatol. 2018, 138,
2051–2060. [CrossRef]
34. Werz, O.; Gerstmeier, J.; Libreros, S.; De la Rosa, X.; Werner, M.; Norris, P.C.; Chiang, N.; Serhan, C.N. Human macrophages
differentially produce specific resolvin or leukotriene signals that depend on bacterial pathogenicity. Nat. Commun. 2018, 9, 59.
[CrossRef]
35. Chatterjee, A.; Komshian, S.; Sansbury, B.E.; Wu, B.; Mottola, G.; Chen, M.; Spite, M.; Conte, M.S. Biosynthesis of proresolving
lipid mediators by vascular cells and tissues. FASEB J. 2017, 31, 3393–3402. [CrossRef]
36. See, V.H.L.; Mas, E.; Prescott, S.L.; Beilin, L.J.; Burrows, S.; Barden, A.E.; Huang, R.C.; Mori, T.A. Effects of prenatal n-3 fatty acid
supplementation on offspring resolvins at birth and 12 years of age: A double-blind, randomised controlled clinical trial. Br. J.
Nutr. 2017, 118, 971–980. [CrossRef]
37. Ogawa, N.; Sugiyama, T.; Morita, M.; Suganuma, Y.; Kobayashi, Y. Total Synthesis of Resolvin D5. J. Org. Chem. 2017, 82,
2032–2039. [CrossRef]
38. Hernandez, J.P.; Chiurchiu, V.; Perruche, S.; You, S. Regulation of T-Cell Immune Responses by Pro-Resolving Lipid Mediators.
Front. Immunol. 2021, 12, 768133. [CrossRef]
39. Winkler, J.W.; Libreros, S.; De La Rosa, X.; Sansbury, B.E.; Norris, P.C.; Chiang, N.; Fichtner, D.; Keyes, G.S.; Wourms, N.; Spite, M.; et al.
Frontline Science: Structural insights into Resolvin D4 actions and further metabolites via a new total organic synthesis and
validation. J. Leukoc. Biol. 2018, 103, 995–1010. [CrossRef]
40. Arnardottir, H.H.; Dalli, J.; Norling, L.V.; Colas, R.A.; Perretti, M.; Serhan, C.N. Resolvin D3 Is Dysregulated in Arthritis and
Reduces Arthritic Inflammation. J. Immunol. 2016, 197, 2362–2368. [CrossRef]
41. Giera, M.; Ioan-Facsinay, A.; Fau-Toes, R.; Toes, R.; Fau-Gao, F.; Gao, F.; Fau-Dalli, J.; Dalli, J.; Fau-Deelder, A.M.; Deelder, A.; et al.
Lipid and lipid mediator profiling of human synovial fluid in rheumatoid arthritis patients by means of LC-MS/MS. Biochim.
Biophys. Acta 2012, 1821, 1415–1424. [CrossRef] [PubMed]
42. Zarghi, A.; Rao, P.N.; Knaus, E.E. Design and synthesis of new rofecoxib analogs as selective cyclooxygenase-2 (COX-2) inhibitors:
Replacement of the methanesulfonyl pharmacophore by a N-acetylsulfonamido bioisostere. J. Pharm. Pharm. Sci. Publ. Can. Soc.
Pharm. Sci. Soc. Can. Sci. Pharm. 2007, 10, 159–167.
43. Tang, H.; Liu, Y.; Yan, C.; Petasis, N.A.; Serhan, C.N.; Gao, H. Protective actions of aspirin-triggered (17R) resolvin D1 and
its analogue, 17R-hydroxy-19-para-fluorophenoxy-resolvin D1 methyl ester, in C5a-dependent IgG immune complex-induced
inflammation and lung injury. J. Immunol. 2014, 193, 3769–3778. [CrossRef] [PubMed]
44. Lima-Garcia, J.F.; Dutra, R.C.; Silva, K.D.; Motta, E.M.; Campos, M.M.; Calixto, J.B. The precursor of resolvin D series and
aspirin-triggered resolvin D1 display anti-hyperalgesic properties in adjuvant-induced arthritis in rats. Br. J. Pharmacol. 2011, 164,
278–293. [CrossRef]
Int. J. Mol. Sci. 2022, 23, 14883 13 of 16

45. Weylandt, K.H.; Chiu, C.-Y.; Gomolka, B.; Waechter, S.F.; Wiedenmann, B.; Wiedenmann, B. Omega-3 fatty acids and their lipid
mediators: Towards an understanding of resolvin and protectin formation. Prostaglandins Other Lipid Mediat. 2012, 97, 73–82.
[CrossRef]
46. Oh, S.F.; Vickery, T.W.; Serhan, C.N. Chiral lipidomics of E-series resolvins: Aspirin and the biosynthesis of novel mediators.
Biochim. Biophys. Acta-Mol. Cell Biol. Lipids 2011, 1811, 737–747. [CrossRef]
47. Artiach, G.; Carracedo, M.; Plunde, O.; Wheelock, C.E.; Thul, S.; Sjövall, P.; Franco-Cereceda, A.; Laguna-Fernandez, A.;
Arnardottir, H.; Bäck, M. Omega-3 Polyunsaturated Fatty Acids Decrease Aortic Valve Disease Through the Resolvin E1 and
ChemR23 Axis. Circulation 2020, 142, 776–789. [CrossRef]
48. Unno, Y.; Sato, Y.; Fukuda, H.; Ishimura, K.; Ikeda, H.; Watanabe, M.; Tansho-Nagakawa, S.; Ubagai, T.; Shuto, S.; Ono, Y. Resolvin
E1, but not resolvins E2 and E3, promotes fMLF-induced ROS generation in human neutrophils. FEBS Lett. 2018, 592, 2706–2715.
[CrossRef]
49. Libreros, S.; Shay, A.E.; Nshimiyimana, R.; Fichtner, D.; Martin, M.J.; Wourms, N.; Serhan, C.N. A New E-Series Resolvin: RvE4
Stereochemistry and Function in Efferocytosis of Inflammation-Resolution. Front. Immunol. 2020, 11, 631319. [CrossRef]
50. Serhan, C.N. Pro-resolving lipid mediators are leads for resolution physiology. Nature 2014, 510, 92–101. [CrossRef]
51. Primdahl, K.G.; Aursnes, M.; Walker, M.E.; Colas, R.A.; Serhan, C.N.; Dalli, J.; Hansen, T.V.; Vik, A. Synthesis of 13(R)-Hydroxy-
7Z,10Z,13R,14E,16Z,19Z Docosapentaenoic Acid (13R-HDPA) and Its Biosynthetic Conversion to the 13-Series Resolvins. J. Nat.
Prod. 2016, 79, 2693–2702. [CrossRef]
52. Rodriguez, A.R.; Spur, B.W. First total syntheses of the pro-resolving lipid mediators 7(S),13(R),20(S)-Resolvin T1 and 7(S),13(R)-
Resolvin T4. Tetrahedron Lett. 2020, 61, 151473. [CrossRef]
53. Rodriguez, A.R.; Spur, B.W. First total synthesis of the pro-resolving lipid mediator 7(S),12(R),13(S)-Resolvin T2 and its 13(R)-
epimer. Tetrahedron Lett. 2020, 61, 151857. [CrossRef]
54. Dalli, J.; Chiang, N.; Serhan, C.N. Elucidation of novel 13-series resolvins that increase with atorvastatin and clear infections. Nat.
Med. 2015, 21, 1071–1075. [CrossRef]
55. Dalli, J.; Winkler, J.W.; Colas, R.A.; Arnardottir, H.; Cheng, C.-Y.C.; Chiang, N.; Petasis, N.A.; Serhan, C.N. Resolvin D3 and
aspirin-triggered resolvin D3 are potent immunoresolvents. Chem. Biol. 2013, 20, 188–201. [CrossRef]
56. Chiang, N.; Fredman, G.; Backhed, F.; Oh, S.F.; Vickery, T.; Schmidt, B.A.; Serhan, C.N. Infection regulates pro-resolving mediators
that lower antibiotic requirements. Nature 2012, 484, 524–528. [CrossRef]
57. Dos Santos, H.T.; Nam, K.; Maslow, F.; Trump, B.; Baker, O.J. Specialized pro-resolving receptors are expressed in salivary glands
with Sjogren’s syndrome. Ann. Diagn. Pathol. 2022, 56, 151865. [CrossRef]
58. Krishnamoorthy, S.; Recchiuti, A.; Chiang, N.; Fredman, G.; Serhan, C.N. Resolvin D1 Receptor Stereoselectivity and Regulation
of Inflammation and Proresolving MicroRNAs. Am. J. Pathol. 2012, 180, 2018–2027. [CrossRef]
59. Lee, S.H.; Tonello, R.; Im, S.T.; Jeon, H.; Park, J.; Ford, Z.; Davidson, S.; Kim, Y.H.; Park, C.K.; Berta, T. Resolvin D3 controls mouse
and human TRPV1-positive neurons and preclinical progression of psoriasis. Theranostics 2020, 10, 12111–12126. [CrossRef]
60. Oh, S.F.; Dona, M.; Fredman, G.; Krishnamoorthy, S.; Irimia, D.; Serhan, C.N. Resolvin E2 Formation and Impact in Inflammation
Resolution. J. Immunol. 2012, 188, 4527–4534. [CrossRef]
61. Oh, S.F.; Pillai, P.S.; Recchiuti, A.; Yang, R.; Serhan, C.N. Pro-resolving actions and stereoselective biosynthesis of 18S E-series
resolvins in human leukocytes and murine inflammation. J. Clin. Investig. 2011, 121, 569–581. [CrossRef] [PubMed]
62. Chiang, N.; Serhan, C.N. Structural elucidation and physiologic functions of specialized pro-resolving mediators and their
receptors. Mol. Asp. Med. 2017, 58, 114–129. [CrossRef] [PubMed]
63. Barnig, C.; Frossard, N.; Levy, B.D. Towards targeting resolution pathways of airway inflammation in asthma. Pharmacol. Ther.
2018, 186, 98–113. [CrossRef] [PubMed]
64. Herrera, B.S.; Hasturk, H.; Kantarci, A.; Freire, M.O.; Nguyen, O.; Kansal, S.; Van Dyke, T.E. Impact of Resolvin E1 on Murine
Neutrophil Phagocytosis in Type 2 Diabetes. Infect. Immun. 2015, 83, 792–801. [CrossRef]
65. Codagnone, M.; Cianci, E.; Lamolinara, A.; Mari, V.C.; Nespoli, A.; Isopi, E.; Mattoscio, D.; Arita, M.; Bragonzi, A.; Iezzi, M.; et al.
Resolvin D1 enhances the resolution of lung inflammation caused by long-term Pseudomonas aeruginosa infection. Mucosal
Immunol. 2018, 11, 35–49. [CrossRef] [PubMed]
66. Duvall, M.G.; Levy, B.D. DHA- and EPA-derived resolvins, protectins, and maresins in airway inflammation. Eur. J. Pharmacol.
2016, 785, 144–155. [CrossRef]
67. Chiang, N.; Sakuma, M.; Rodriguez, A.R.; Spur, B.W.; Irimia, D.; Serhan, C.N. Resolvin T-series reduce neutrophil extracellular
traps. Blood 2022, 139, 1222–1233. [CrossRef]
68. Hamidzadeh, K.; Christensen, S.M.; Dalby, E.; Chandrasekaran, P.; Mosser, D.M. Macrophages and the Recovery from Acute and
Chronic Inflammation. Annu. Rev. Physiol. 2017, 79, 567–592. [CrossRef]
69. Oishi, Y.; Manabe, I. Macrophages in inflammation, repair and regeneration. Int. Immunol. 2018, 30, 511–528. [CrossRef]
70. Lopez-Vicario, C.; Rius, B.; Alcaraz-Quiles, J.; Garcia-Alonso, V.; Lopategi, A.; Titos, E.; Claria, J. Pro-resolving mediators
produced from EPA and DHA: Overview of the pathways involved and their mechanisms in metabolic syndrome and related
liver diseases. Eur. J. Pharmacol. 2016, 785, 133–143. [CrossRef]
71. Takamiya, R.; Fukunaga, K.; Arita, M.; Miyata, J.; Seki, H.; Minematsu, N.; Suematsu, M.; Asano, K. Resolvin E1 maintains
macrophage function under cigarette smoke-induced oxidative stress. FEBS Open Bio 2012, 2, 328–333. [CrossRef]
Int. J. Mol. Sci. 2022, 23, 14883 14 of 16

72. Dona, M.; Fredman, G.; Schwab, J.M.; Chiang, N.; Arita, M.; Goodarzi, A.; Cheng, G.; von Andrian, U.H.; Serhan, C.N. Resolvin
E1, an EPA-derived mediator in whole blood, selectively counterregulates leukocytes and platelets. Blood 2008, 112, 848–855.
[CrossRef]
73. Hosseini, Z.; Marinello, M.; Decker, C.; Sansbury, B.E.; Sadhu, S.; Gerlach, B.D.; Bossardi Ramos, R.; Adam, A.P.; Spite, M.;
Fredman, G. Resolvin D1 Enhances Necroptotic Cell Clearance Through Promoting Macrophage Fatty Acid Oxidation and
Oxidative Phosphorylation. Arterioscler. Thromb. Vasc. Biol. 2021, 41, 1062–1075. [CrossRef]
74. Shan, K.; Feng, N.; Cui, J.; Wang, S.; Qu, H.; Fu, G.; Li, J.; Chen, H.; Wang, X.; Wang, R.; et al. Resolvin D1 and D2 inhibit tumour
growth and inflammation via modulating macrophage polarization. J. Cell. Mol. Med. 2020, 24, 8045–8056. [CrossRef]
75. Recchiuti, A.; Krishnamoorthy, S.; Fredman, G.; Chiang, N.; Serhan, C.N. MicroRNAs in resolution of acute inflammation:
Identification of novel resolvin D1-miRNA circuits. FASEB J. 2011, 25, 544–560. [CrossRef]
76. Sakai, Y.; Kobayashi, M. Lymphocyte ‘homing’ and chronic inflammation. Pathol. Int. 2015, 65, 344–354. [CrossRef]
77. Kim, N.; Ramon, S.; Thatcher, T.H.; Woeller, C.F.; Sime, P.J.; Phipps, R.P. Specialized proresolving mediators (SPMs) inhibit human
B-cell IgE production. Eur. J. Immunol. 2016, 46, 81–91. [CrossRef]
78. Mizraji, G.; Heyman, O.; Van Dyke, T.E.; Wilensky, A. Resolvin D2 Restrains Th1 Immunity and Prevents Alveolar Bone Loss in
Murine Periodontitis. Front. Immunol. 2018, 9, 785. [CrossRef]
79. Yamada, H.; Saegusa, J.; Sendo, S.; Ueda, Y.; Okano, T.; Shinohara, M.; Morinobu, A. Effect of resolvin D5 on T cell differentiation
and osteoclastogenesis analyzed by lipid mediator profiling in the experimental arthritis. Sci. Rep. 2021, 11, 17312. [CrossRef]
80. Cheng, T.; Ding, S.; Liu, S.; Li, X.; Tang, X.; Sun, L. Resolvin D1 Improves the Treg/Th17 Imbalance in Systemic Lupus
Erythematosus Through miR-30e-5p. Front. Immunol. 2021, 12, 668760. [CrossRef]
81. Oner, F.; Alvarez, C.; Yaghmoor, W.; Stephens, D.; Hasturk, H.; Firatli, E.; Kantarci, A. Resolvin E1 Regulates Th17 Function and T
Cell Activation. Front. Immunol. 2021, 12, 637983. [CrossRef] [PubMed]
82. Miyata, J.; Arita, M. Role of omega-3 fatty acids and their metabolites in asthma and allergic diseases. Allergol. Int. 2015, 64, 27–34.
[CrossRef] [PubMed]
83. Lee, H.N.; Kundu, J.K.; Cha, Y.N.; Surh, Y.J. Resolvin D1 stimulates efferocytosis through p50/p50-mediated suppression of
tumor necrosis factor-alpha expression. J. Cell Sci. 2013, 126, 4037–4047. [CrossRef] [PubMed]
84. Haworth, O.; Cernadas, M.; Levy, B.D. NK cells are effectors for resolvin E1 in the timely resolution of allergic airway inflammation.
J. Immunol. 2011, 186, 6129–6135. [CrossRef]
85. Newcombe, E.A.; Camats-Perna, J.; Silva, M.L.; Valmas, N.; Huat, T.J.; Medeiros, R. Inflammation: The link between comorbidities,
genetics, and Alzheimer’s disease. J. Neuroinflamm. 2018, 15, 276. [CrossRef]
86. Tiberi, M.; Chiurchiu, V. Specialized Pro-resolving Lipid Mediators and Glial Cells: Emerging Candidates for Brain Homeostasis
and Repair. Front. Cell. Neurosci. 2021, 15, 673549. [CrossRef]
87. Rueda-Carrasco, J.; Martin-Bermejo, M.J.; Pereyra, G.; Mateo, M.I.; Borroto, A.; Brosseron, F.; Kummer, M.P.; Schwartz, S.;
López-Atalaya, J.P.; Alarcon, B.; et al. SFRP1 modulates astrocyte-to-microglia crosstalk in acute and chronic neuroinflammation.
EMBO Rep. 2021, 22, e51696. [CrossRef]
88. Joseph, J.; Bittner, S.; Kaiser, F.M.; Wiendl, H.; Kissler, S. IL-17 silencing does not protect nonobese diabetic mice from autoimmune
diabetes. J. Immunol. 2012, 188, 216–221. [CrossRef]
89. Ren, Y.Z.; Zhang, B.Z.; Zhao, X.J.; Zhang, Z.Y. Resolvin D1 ameliorates cognitive impairment following traumatic brain injury via
protecting astrocytic mitochondria. J. Neurochem. 2020, 154, 530–546. [CrossRef]
90. Whittington, R.; Planel, E.; Terrando, N. Impaired Resolution of Inflammation in Alzheimer’s Disease: A Review. Front. Immunol.
2017, 8, 1464. [CrossRef]
91. Abdelmoaty, S.; Wigerblad, G.; Bas, D.B.; Codeluppi, S.; Fernandez-Zafra, T.; El-Awady, E.-S.; Moustafa, Y.; Abdelhamid Ael,
D.; Brodin, E.; Svensson, C.I. Spinal actions of lipoxin A4 and 17(R)-resolvin D1 attenuate inflammation-induced mechanical
hypersensitivity and spinal TNF release. PLoS ONE 2013, 8, e75543. [CrossRef]
92. Zhang, L.Y.; Liu, Z.H.; Zhu, Q.; Wen, S.; Yang, C.X.; Fu, Z.J.; Sun, T. Resolvin D2 Relieving Radicular Pain is Associated with
Regulation of Inflammatory Mediators, Akt/GSK-3beta Signal Pathway and GPR18. Neurochem. Res. 2018, 43, 2384–2392.
[CrossRef]
93. Reglero-Real, N.; Colom, B.; Bodkin, J.V.; Nourshargh, S. Endothelial Cell Junctional Adhesion Molecules: Role and Regulation of
Expression in Inflammation. Arterioscler. Thromb. Vasc. Biol. 2016, 36, 2048–2057. [CrossRef]
94. Wang, Q.; Zheng, X.; Cheng, Y.; Zhang, Y.L.; Wen, H.X.; Tao, Z.; Li, H.; Hao, Y.; Gao, Y.; Yang, L.M.; et al. Resolvin D1
Stimulates Alveolar Fluid Clearance through Alveolar Epithelial Sodium Channel, Na,K-ATPase via ALX/cAMP/PI3K Pathway
in Lipopolysaccharide-Induced Acute Lung Injury. J. Immunol. 2014, 192, 3765–3777. [CrossRef]
95. Chattopadhyay, R.; Mani, A.M.; Singh, N.K.; Rao, G.N. Resolvin D1 blocks H2 O2 -mediated inhibitory crosstalk between SHP2
and PP2A and suppresses endothelial-monocyte interactions. Free. Radic. Biol. Med. 2018, 117, 119–131. [CrossRef]
96. Zhang, X.; Wang, T.; Gui, P.; Yao, C.; Sun, W.; Wang, L.; Wang, H.; Xie, W.; Yao, S.; Lin, Y.; et al. Resolvin D1 reverts
lipopolysaccharide-induced TJ proteins disruption and the increase of cellular permeability by regulating IkappaBalpha signaling
in human vascular endothelial cells. Oxid. Med. Cell. Longev. 2013, 2013, 185715. [CrossRef]
97. Shamoon, L.; Espitia-Corredor, J.A.; Dongil, P.; Menendez-Ribes, M.; Romero, A.; Valencia, I.; Diaz-Araya, G.; Sanchez-Ferrer, C.F.;
Peiro, C. Resolvin E1 attenuates doxorubicin-induced endothelial senescence by modulating NLRP3 inflammasome activation.
Biochem. Pharmacol. 2022, 201, 115078. [CrossRef]
Int. J. Mol. Sci. 2022, 23, 14883 15 of 16

98. Reuter, S.; Gupta, S.C.; Chaturvedi, M.M.; Aggarwal, B.B. Oxidative stress, inflammation, and cancer: How are they linked? Free
Radic. Biol. Med. 2010, 49, 1603–1616. [CrossRef]
99. Sulciner, M.L.; Serhan, C.N.; Gilligan, M.M.; Mudge, D.K.; Chang, J.; Gartung, A.; Lehner, K.A.; Bielenberg, D.R.; Schmidt, B.;
Dalli, J.; et al. Resolvins suppress tumor growth and enhance cancer therapy. J. Exp. Med. 2018, 215, 115–140. [CrossRef]
100. Mattoscio, D.; Isopi, E.; Lamolinara, A.; Patruno, S.; Medda, A.; De Cecco, F.; Chiocca, S.; Iezzi, M.; Romano, M.; Recchiuti, A.
Resolvin D1 reduces cancer growth stimulating a protective neutrophil-dependent recruitment of anti-tumor monocytes. J. Exp.
Clin. Cancer Res. 2021, 40, 129. [CrossRef]
101. Sun, L.; Wang, Y.; Wang, L.; Yao, B.; Chen, T.; Li, Q.; Liu, Z.; Liu, R.; Niu, Y.; Song, T.; et al. Resolvin D1 prevents epithelial-
mesenchymal transition and reduces the stemness features of hepatocellular carcinoma by inhibiting paracrine of cancer-associated
fibroblast-derived COMP. J. Exp. Clin. Cancer Res. 2019, 38, 170. [CrossRef] [PubMed]
102. Schnittert, J.; Heinrich, M.A.; Kuninty, P.R.; Storm, G.; Prakash, J. Reprogramming tumor stroma using an endogenous lipid
lipoxin A4 to treat pancreatic cancer. Cancer Lett. 2018, 420, 247–258. [CrossRef] [PubMed]
103. Yang, Y.; Cheng, Y.; Jin, S.; Gao, F. PI3K Mediates the Effect of Resolvin D1 on the Protein Expression of Epithelial Sodium Channel
in A549 Cells Treated with Lipopolysaccharide. J. Med. Res. 2013, 42, 48–50.
104. Lee, H.J.; Park, M.K.; Lee, E.J.; Lee, C.H. Resolvin D1 inhibits TGF-beta 1-induced epithelial mesenchymal transition of A549
lung cancer cells via lipoxin A4 receptor/formyl peptide receptor 2 and GPR32. Int. J. Biochem. Cell Biol. 2013, 45, 2801–2807.
[CrossRef]
105. Kuang, H.; Hua, X.; Zhou, J.; Yang, R. Resolvin D1 and E1 alleviate the progress of hepatitis toward liver cancer in long-term
concanavalin A-induced mice through inhibition of NF-κB activity. Oncol. Rep. 2016, 35, 307–317. [CrossRef]
106. Valdes, A.M.; Ravipati, S.; Menni, C.; Abhishek, A.; Metrustry, S.; Harris, J.; Nessa, A.; Williams, F.M.K.; Spector, T.D.; Doherty, M.;
et al. Association of the resolvin precursor 17-HDHA, but not D- or E-series resolvins, with heat pain sensitivity and osteoarthritis
pain in humans. Sci. Rep. 2017, 7, 10748. [CrossRef]
107. Zhang, L.L.; Terrando, N.; Xu, Z.Z.; Bang, S.S.; Jordt, S.E.; Maixner, W.; Serhan, C.N.; Ji, R.R. Distinct Analgesic Actions of DHA
and DHA-Derived Specialized Pro-Resolving Mediators on Post-operative Pain After Bone Fracture in Mice. Front. Pharmacol.
2018, 9, 412. [CrossRef]
108. Ma, Y.M.; Li, C.D.; Zhu, Y.B.; Xu, X.; Li, J.; Cao, H. The mechanism of RvD1 alleviates type 2 diabetic neuropathic pain by
influencing microglia polarization in rats. Zhongguo Ying Yong Sheng Li Xue Za Zhi 2017, 33, 277–281. [CrossRef]
109. Lu, Q.; Yang, Y.; Zhang, H.; Chen, C.; Zhao, J.; Yang, Z.; Fan, Y.; Li, L.; Feng, H.; Zhu, J.; et al. Activation of GPR18 by Resolvin D2
Relieves Pain and Improves Bladder Function in Cyclophosphamide-Induced Cystitis Through Inhibiting TRPV1. Drug Des. Dev.
Ther. 2021, 15, 4687–4699. [CrossRef]
110. Luo, X.; Gu, Y.; Tao, X.; Serhan, C.N.; Ji, R.R. Resolvin D5 Inhibits Neuropathic and Inflammatory Pain in Male But Not Female
Mice: Distinct Actions of D-Series Resolvins in Chemotherapy-Induced Peripheral Neuropathy. Front. Pharmacol. 2019, 10, 745.
[CrossRef]
111. Xu, Z.Z.; Zhang, L.; Liu, T.; Park, J.Y.; Berta, T.; Yang, R.; Serhan, C.N.; Ji, R.R. Resolvins RvE1 and RvD1 attenuate inflammatory
pain via central and peripheral actions. Nat. Med. 2010, 16, 592–597. [CrossRef]
112. Wang, Y.H.; Gao, X.; Tang, Y.R.; Chen, F.Q.; Yu, Y.; Sun, M.J.; Li, Y. Resolvin D1 Alleviates Mechanical Allodynia via ALX/FPR2
Receptor Targeted Nod-like Receptor Protein 3/Extracellular Signal-Related Kinase Signaling in a Neuropathic Pain Model.
Neuroscience 2022, 494, 12–24. [CrossRef]
113. Khasabova, I.A.; Golovko, M.Y.; Golovko, S.A.; Simone, D.A.; Khasabov, S.G. Intrathecal administration of Resolvin D1 and E1
decreases hyperalgesia in mice with bone cancer pain: Involvement of endocannabinoid signaling. Prostaglandins Other Lipid
Mediat. 2020, 151, 106479. [CrossRef]
114. Fredman, G.; Hellmann, J.; Proto, J.D.; Kuriakose, G.; Colas, R.A.; Dorweiler, B.; Connolly, E.S.; Solomon, R.; Jones, D.M.;
Heyer, E.J.; et al. An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes
instability of atherosclerotic plaques. Nat. Commun. 2016, 7, 12859. [CrossRef]
115. Salic, K.; Morrison, M.C.; Verschuren, L.; Wielinga, P.Y.; Wu, L.J.; Kleemann, R.; Gjorstrup, P.; Kooistra, T. Resolvin E1 attenuates
atherosclerosis in absence of cholesterol-lowering effects and on top of atorvastatin. Atherosclerosis 2016, 250, 158–165. [CrossRef]
116. Ho, K.J.; Spite, M.; Owens, C.D.; Lancero, H.; Kroemer, A.H.; Pande, R.; Creager, M.A.; Serhan, C.N.; Conte, M.S. Aspirin-triggered
lipoxin and resolvin E1 modulate vascular smooth muscle phenotype and correlate with peripheral atherosclerosis. Am. J. Pathol.
2010, 177, 2116–2123. [CrossRef]
117. Viola, J.R.; Lemnitzer, P.; Jansen, Y.; Csaba, G.; Winter, C.; Neideck, C.; Silvestre-Roig, C.; Dittmar, G.; Döring, Y.; Drechsler, M.; et al.
Resolving Lipid Mediators Maresin 1 and Resolvin D2 Prevent Atheroprogression in Mice. Circ. Res. 2016, 119, 1030–1038.
[CrossRef]
118. Elajami, T.K.; Colas, R.A.; Dalli, J.; Chiang, N.; Serhan, C.N.; Welty, F.K. Specialized proresolving lipid mediators in patients with
coronary artery disease and their potential for clot remodeling. FASEB J. 2016, 30, 2792–2801. [CrossRef]
119. Keeley, E.C.; Li, H.J.; Cogle, C.R.; Handberg, E.M.; Merz, C.N.B.; Pepine, C.J. Specialized Proresolving Mediators in Symptomatic
Women With Coronary Microvascular Dysfunction (from the Women’s Ischemia Trial to Reduce Events in Nonobstructive CAD
[WARRIOR] Trial). Am. J. Cardiol. 2022, 162, 1–5. [CrossRef]
120. Hamilton, J.A.; Hasturk, H.; Kantarci, A.; Serhan, C.N.; Van Dyke, T. Atherosclerosis, Periodontal Disease, and Treatment with
Resolvins. Curr. Atheroscler. Rep. 2017, 19, 57. [CrossRef]
Int. J. Mol. Sci. 2022, 23, 14883 16 of 16

121. Carrillo, I.; Rabelo, R.A.N.; Barbosa, C.; Rates, M.; Fuentes-Retamal, S.; Gonzalez-Herrera, F.; Guzman-Rivera, D.; Quintero, H.;
Kemmerling, U.; Castillo, C.; et al. Aspirin-triggered resolvin D1 reduces parasitic cardiac load by decreasing inflammation in a
murine model of early chronic Chagas disease. PLoS Negl. Trop. Dis. 2021, 15, e0009978. [CrossRef] [PubMed]
122. Lontchi-Yimagou, E.; Sobngwi, E.; Matsha, T.E.; Kengne, A.P. Diabetes mellitus and inflammation. Curr. Diabetes Rep. 2013, 13,
435–444. [CrossRef] [PubMed]
123. Barden, A.; Shinde, S.; Phillips, M.; Beilin, L.; Mas, E.; Hodgson, J.M.; Puddey, I.; Mori, T.A. The effects of alcohol on plasma lipid
mediators of inflammation resolution in patients with Type 2 diabetes mellitus. Prostaglandins Leukot. Essent. Fat. Acids 2018, 133,
29–34. [CrossRef] [PubMed]
124. Shevalye, H.; Yorek, M.S.; Coppey, L.J.; Holmes, A.; Harper, M.M.; Kardon, R.H.; Yorek, M.A. Effect of enriching the diet with
menhaden oil or daily treatment with resolvin D1 on neuropathy in a mouse model of type 2 diabetes. J. Neurophysiol. 2015, 114,
199–208. [CrossRef] [PubMed]
125. Qin, Q.; Hu, K.; He, Z.; Chen, F.; Zhang, W.; Liu, Y.; Xie, Z. Resolvin D1 protects against Aspergillus fumigatus keratitis in diabetes
by blocking the MAPK-NF-kappaB pathway. Exp. Eye Res. 2022, 216, 108941. [CrossRef]
126. Shimizu, T.; Saito, T.; Aoki-Saito, H.; Okada, S.; Ikeda, H.; Nakakura, T.; Fukuda, H.; Arai, S.; Fujiwara, K.; Nakajima, Y.; et al.
Resolvin E3 ameliorates high-fat diet-induced insulin resistance via the phosphatidylinositol-3-kinase/Akt signaling pathway in
adipocytes. FASEB J. 2022, 36, e22188. [CrossRef]
127. Deyama, S.; Ishikawa, Y.; Yoshikawa, K.; Shimoda, K.; Ide, S.; Satoh, M.; Minami, M. Resolvin D1 and D2 Reverse
Lipopolysaccharide-Induced Depression-Like Behaviors Through the mTORC1 Signaling Pathway. Int. J. Neuropsychopharmacol.
2017, 20, 575–584. [CrossRef]
128. Suzuki, H.; Hitora-Imamura, N.; Deyama, S.; Minami, M. Resolvin D2 attenuates chronic pain-induced depression-like behavior
in mice. Neuropsychopharmacol. Rep. 2021, 41, 426–429. [CrossRef]
129. Deyama, S.; Minami, M.; Kaneda, K. Resolvins as potential candidates for the treatment of major depressive disorder. J. Pharmacol.
Sci. 2021, 147, 33–39. [CrossRef]
130. Deyama, S.; Duman, R.S. Neurotrophic mechanisms underlying the rapid and sustained antidepressant actions of ketamine.
Pharmacol. Biochem. Behav. 2020, 188, 172837. [CrossRef]
131. Deyama, S.; Shimoda, K.; Ikeda, H.; Fukuda, H.; Shuto, S.; Minami, M. Resolvin E3 attenuates lipopolysaccharide-induced
depression-like behavior in mice. J. Pharmacol. Sci. 2018, 138, 86–88. [CrossRef]
132. Ishikawa, Y.; Deyama, S.; Shimoda, K.; Yoshikawa, K.; Ide, S.; Satoh, M.; Minami, M. Rapid and sustained antidepressant effects
of resolvin D1 and D2 in a chronic unpredictable stress model. Behav. Brain Res. 2017, 332, 233–236. [CrossRef]
133. Siddiqui, Y.D.; Omori, K.; Ito, T.; Yamashiro, K.; Nakamura, S.; Okamoto, K.; Ono, M.; Yamamoto, T.; Van Dyke, T.E.; Takashiba,
S. Resolvin D2 Induces Resolution of Periapical Inflammation and Promotes Healing of Periapical Lesions in Rat Periapical
Periodontitis. Front. Immunol. 2019, 10, 307. [CrossRef]
134. Menon, R.; Krzyszczyk, P.; Berthiaume, F. Pro-Resolution Potency of Resolvins D1, D2 and E1 on Neutrophil Migration and in
Dermal Wound Healing. Nano Life 2017, 7, 1750002. [CrossRef]
135. Pham, T.L.; Kakazu, A.H.; He, J.; Jun, B.; Bazan, N.G.; Bazan, H.E.P. Novel RvD6 stereoisomer induces corneal nerve regeneration
and wound healing post-injury by modulating trigeminal transcriptomic signature. Sci. Rep. 2020, 10, 4582. [CrossRef]
136. Ozgul Ozdemir, R.B.; Soysal Gunduz, O.; Ozdemir, A.T.; Akgul, O. Low levels of pro-resolving lipid mediators lipoxin-A4,
resolvin-D1 and resolvin-E1 in patients with rheumatoid arthritis. Immunol. Lett. 2020, 227, 34–40. [CrossRef]
137. Benabdoun, H.A.; Kulbay, M.; Rondon, E.-P.; Vallières, F.; Shi, Q.; Fernandes, J.; Fahmi, H.; Benderdour, M. In vitro and in vivo
assessment of the proresolutive and antiresorptive actions of resolvin D1: Relevance to arthritis. Arthritis Res. Ther. 2019, 21, 72.
[CrossRef] [PubMed]
138. Sun, W.; Ma, J.; Zhao, H.; Xiao, C.; Zhong, H.; Ling, H.; Xie, Z.; Tian, Q.; Chen, H.; Zhang, T.; et al. Resolvin D1 suppresses pannus
formation via decreasing connective tissue growth factor caused by upregulation of miRNA-146a-5p in rheumatoid arthritis.
Arthritis Res. Ther 2020, 22, 61. [CrossRef]
139. Flak, M.B.; Koenis, D.S.; Sobrino, A.; Smith, J.; Pistorius, K.; Palmas, F.; Dalli, J. GPR101 mediates the pro-resolving actions of
RvD5n-3 DPA in arthritis and infections. J. Clin. Investig. 2020, 130, 359–373. [CrossRef]
140. Funaki, Y.; Hasegawa, Y.; Okazaki, R.; Yamasaki, A.; Sueda, Y.; Yamamoto, A.; Yanai, M.; Fukushima, T.; Harada, T.; Makino,
H.; et al. Resolvin E1 Inhibits Osteoclastogenesis and Bone Resorption by Suppressing IL-17-induced RANKL Expression in
Osteoblasts and RANKL-induced Osteoclast Differentiation. Yonago Acta Med. 2018, 61, 8–18. [CrossRef]
141. Mattoscio, D.; Ferri, G.; Miccolo, C.; Chiocca, S.; Romano, M.; Recchiuti, A. Gene Expression of the D-Series Resolvin Pathway
Predicts Activation of Anti-Tumor Immunity and Clinical Outcomes in Head and Neck Cancer. Int. J. Mol. Sci. 2022, 23, 6473.
[CrossRef] [PubMed]