Maresin: Macrophage Mediator for Resolving Inflammation and Bridging Tissue Regeneration—A System-Based Preclinical Systematic Review

Maresins are lipid mediators derived from omega-3 fatty acids with anti-inflammatory and pro-resolving properties, capable of promoting tissue regeneration and potentially serving as a therapeutic agent for chronic inflammatory diseases. The aim of this review was to systematically investigate preclinical and clinical studies on maresin to inform translational research. Two independent reviewers performed comprehensive searches with the term “Maresin (NOT) Review” on PubMed. A total of 137 studies were included and categorized into 11 human organ systems. Data pertinent to clinical translation were specifically extracted, including delivery methods, optimal dose response, and specific functional efficacy. Maresins generally exhibit efficacy in treating inflammatory diseases, attenuating inflammation, protecting organs, and promoting tissue regeneration, mostly in rodent preclinical models. The nervous system has the highest number of original studies (n = 25), followed by the cardiovascular system, digestive system, and respiratory system, each having the second highest number of studies (n = 18) in the field. Most studies considered systemic delivery with an optimal dose response for mouse animal models ranging from 4 to 25 μg/kg or 2 to 200 ng via intraperitoneal or intravenous injection respectively, whereas human in vitro studies ranged between 1 and 10 nM. Although there has been no human interventional clinical trial yet, the levels of MaR1 in human tissue fluid can potentially serve as biomarkers, including salivary samples for predicting the occurrence of cardiovascular diseases and periodontal diseases; plasma and synovial fluid levels of MaR1 can be associated with treatment response and defining pathotypes of rheumatoid arthritis. Maresins exhibit great potency in resolving disease inflammation and bridging tissue regeneration in preclinical models, and future translational development is warranted.

When the body responds to pathogens, trauma, or tissue damage, inflammatory responses are driven by pro-inflammatory mediators and this acute inflammatory response is protective. However, if this progress is not controlled, chronic inflammatory diseases will evolve. In an ideal situation, the stimuli is resolved, and the tissue will gradually return to homeostasis. The resolution of inflammation was once believed to be passive, but now it is found to be an active process, involving lipid mediator class-switching from proinflammatory mediators to pro-resolving mediators such as maresin. Therefore, maresins have a vast therapeutic potential to alleviate chronic inflammatory disease. Additionally, since maresin was produced by a macrophage, the main player for tissue healing and regeneration, MaR1 has been shown to promote tissue regeneration in different organs and systems. Although there are many drugs available to suppress inflammation and pain, such as corticosteroids and NSAIDs, they are accompanied by side effects that can be harmful to the body in the long term [9,10]. Natural pro-resolving signals and molecules such as maresins should hold huge potential with limited adverse effects to control chronic inflammatory diseases.
To date, an increasing number of preclinical studies have been conducted on maresins; however, there is a lack of systematic synthesis of this translational information. Systematic reviews (SR) are usually conducted for clinical human studies, yet appraising preclinical human and animal studies have their merits and significance in the field of translational medicine. They can avoid redundancies of experiments and trials, give inferences for future experimental designs, and justify further investigation in clinical trials. Additionally, compared to human clinical trials, animal studies can offer a chance to test critical hypotheses that cannot be tested in humans. Thus, SR of preclinical human and animal studies may give us essential information to advance the field. Therefore, it is crucial to conduct quality systematic reviews on preclinical studies. In this article, we aim to conduct a systematic review of maresins for treating different diseases and conditions in different systems ( Figure 1).

Search Strategy
This systematic review was conducted following the Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and referring to the Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CAMA-RADES) [11]. Articles included were results of the search term "Maresin (NOT) Review" before August 2022 in the PubMed database. Our research questions are: "What clinical and preclinical studies have been reported about maresins, and what are the primary or functional outcomes?"

Inclusion and Exclusion Criteria
Two reviewers, Liu and Yang, screened the data independently and manually. Only original studies published in English that could address the PICO question were considered. Comments, editorials, hypotheses, review articles, and non-preclinical outcome-related research (biosynthesis, chemical structure, chromatography, discovery, drug development, and unrelated to maresin) were excluded based on titles and abstracts. Included articles were read carefully, and some were removed (reasons are in the flow chart). We classified those studies into 11 different categories, depending on the human body's organ systems. The organ systems are (1) oral, dental, and craniofacial system, (2) cardiovascular system, (3) digestive system, (4) endocrine system, (5) immune and lymphatic system, (6) integumentary and exocrine system, (7) musculoskeletal system, (8) nervous system, (9) reproductive system, (10) respiratory system, (11) urinary system. Where there were different opinions, e.g., articles were classified in different systems, there was uncertainty about which organ systems to categorize, or the articles spanned multiple systems, were

Search Strategy
This systematic review was conducted following the Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and referring to the Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CA-MARADES) [11]. Articles included were results of the search term "Maresin (NOT) Review" before August 2022 in the PubMed database. Our research questions are: "What clinical and preclinical studies have been reported about maresins, and what are the primary or functional outcomes?"

Inclusion and Exclusion Criteria
Two reviewers, Liu and Yang, screened the data independently and manually. Only original studies published in English that could address the PICO question were considered. Comments, editorials, hypotheses, review articles, and non-preclinical outcome-related research (biosynthesis, chemical structure, chromatography, discovery, drug development, and unrelated to maresin) were excluded based on titles and abstracts. Included articles were read carefully, and some were removed (reasons are in the flow chart). We classified those studies into 11 different categories, depending on the human body's organ systems. The organ systems are (1) oral, dental, and craniofacial system, (2) cardiovascular system, (3) digestive system, (4) endocrine system, (5) immune and lymphatic system, (6) integumentary and exocrine system, (7) musculoskeletal system, (8) nervous system, (9) reproductive system, (10) respiratory system, (11) urinary system. Where there were different opinions, e.g., articles were classified in different systems, there was uncertainty about which organ systems to categorize, or the articles spanned multiple systems, were determined by discussions with CW. Wang, and all authors agreed with the final decisions, including data and classifications. Detailed processes are presented in Figure 2.

Data Extraction
In this systematic review, we focus on the field of translational medicine and the connections between human organ systems. Therefore, only preclinical studies with systematic diseases were considered. Data from the included studies were extracted from the original main texts or the figures. If there were no raw data, we changed the results into relative proportions. We collated the disease models, the way maresins were administered, optimal concentration, and the effects they brought. Detailed information is provided in Table 1.

Data Extraction
In this systematic review, we focus on the field of translational medicine and the connections between human organ systems. Therefore, only preclinical studies with systematic diseases were considered. Data from the included studies were extracted from the original main texts or the figures. If there were no raw data, we changed the results into relative proportions. We collated the disease models, the way maresins were administered, optimal concentration, and the effects they brought. Detailed information is provided in Table 1. 37%), attenuating ventricular structural remodeling (remaining 52% of myocardial fibrosis area), decreasing ventricular electrical remodeling (decreased action potential duration (APD)90~37%, APD50~37%, electrical alternans (ALT) threshold~25%, suppressed the decrease in effective refractory period (ERP)) and myocardial apoptosis. 2. Alleviating cardiac oxidative stress after MI by activation of NRF2/HO-1 signaling (reduced the expression of fibrotic markers and malondialdehyde (MDA) level~17%, increased Cx43 expression~2.5 fold and serum superoxide dismutase (SOD) level~1.6 fold) and inhibition of TLR4/NF-kB signaling (decreased TLR4, p-p65, TNFα, and IL-6 protein levels~30-50%, and macrophage infiltration~36%).

Preclinical models Administration of maresins (Optimal) concentration Efficacy References
Human and mice precision-cut lung slices MCTRs, i.v.

Oral, Dental, and Craniofacial System
The oral, dental, and craniofacial system occupies more than half of the skull and coordinates mastication, ingestions, and pronunciation for communication. This system also represents an important individual identity as one smiles. Inflammation in the oral, dental, and craniofacial system, such as, periodontitis, not only influences one's food intake, pronunciation, and confidence, but it can also influence the risk and aggravation by other systemic chronic inflammatory diseases, e.g., diabetes, arthritis, and cardiovascular diseases [81][82][83][84]. As a result, MaR1, as part of the pro-resolving lipid mediator family, has shown the potential ability to control inflammation and exert its therapeutic benefits.

Periodontal Diseases
Periodontal disease is a chronic inflammatory disease, and patients with aggressive periodontitis (AgP, currently termed Grade C periodontitis) usually present with rapidly progressive alveolar bone loss around dentition. The level of 14-HDHA (hydrolysis product of precursor of MaR1) was found to be higher in the serum of patients with AgP, suggesting that the biosynthetic pathway or MaR1 and metabolites may be dysregulated in patients with AgP [85]. In a more homogeneous cohort of patients with localized aggressive periodontitis (LAP, currently termed Stage IV Grade C molar-incisal pattern periodontitis), MaR1 and the level of 12-lipoxygenase (12-LOX) were found to be lower from macrophages (only 36% and 30% the level of healthy control). Phagocytes of patients with LAP have lower ability in phagocytosis and killing pathogens. However, additional MaR1 administration enhanced phagocytosis (peaks at 1 nM), restored bactericidal capacity, and increased intracellular ROS generation [12]. Exogenous MaR1 also increases healthy human periodontal ligament cells' (hPDLCs') survival rate and autophagy. MaR1 also decreases hPDLCs' apoptosis and inflammatory factors production such as IL-6, IL-8, TNF-α, and IL-1β, under P. gingivalis (peaks at 10 nM) stimulation through the activation of the glycogen synthase kinase-3β (GSK-3) and β-catenin pathway [13].

Human Periodontal Ligament Stem Cells (hPDLSCs)
MaR1 can reverse the activation of human periodontal ligament stem cells (hPDLSCs) by TNF-α and IL-1β, which includes the expression of pluripotency, migration, viability, and differentiation into a PDL-like cell phenotype [14]. The study also showed that pig PDLSCs (pPDLSCs) biosynthesize maresin conjugate in tissue regeneration 3 (MCTR3). Under inflammatory conditions, pretreatment of MCTR3 inhibits pPDLSCs from producing prostaglandin E2 (PGE2) in a dose-dependent manner (optimal: 10 nM~100 nM) and reduces the production of IL-6 and IL-8 at the early stage [86].
Collectively, maresins have various therapeutic applications in the oral, dental, and craniofacial systems, regulating phagocytes and PDL stem cells. Maresins also have therapeutic potential in treating periodontitis and temporomandibular disorder, as well as promoting the healing and regeneration of oral tissues. Table 1 is the related compilation of preclinical models of the oral, dental, and craniofacial system.

Cardiovascular System
The cardiovascular system is responsible for a large percentage of the total body circulation and is an important pathway linking the other systems. Common diseases of this system include atherosclerosis, myocardial infarction, hypertension, and sepsis. Cardiovascular diseases (CVDs) are largely caused by fatty substances built up in the arteries, and they can increase the risks of blood clots and the above-mentioned major medical adverse events [88][89][90]. Following the published investigations, MaR1 demonstrates potential therapeutic ability in the cardiovascular system.

Cardiomyopathy
In terms of sepsis-induced cardiomyopathy (SIC), maresin conjugate in tissue regeneration 1 (MCTR1, 0.15 nmol/mouse, i.v.) was found to reduce neutrophil infiltration and enhance cardiac function via the IL-17 signaling pathway, and also improve mitochondrial biogenesis and function [16,17]. Pretreatment of MaR1 (100 ng, i.p.) followed by booster injections ((100 ng per mouse) every 2 days, i.p.) to SIC mice showed that MaR1 could protect the heart from injury and dysfunction [18]. In the process of tissue repair, MaR1 induced cardiomyocyte hypertrophy through the IGF-1 paracrine pathway, and the production of IGF-1 was mediated by the RORα/IGF-1/PI3K/Akt pathway. [91].
Generally, MaR1 and its related metabolites have cardiovascular protection functions and/or inhibit the progression of CVDs, and some of them can also prevent the coagulation of blood. Table 1 is the related compilation of preclinical models of the cardiovascular system.

Digestive System
The digestive system is comprised of the gastrointestinal (GI) tract, liver, pancreas, and gallbladder. The digestive system breaks down and absorbs nutrients from food and liquids with enzymes. Inflammatory digestive system diseases such as inflammatory bowel disease (Crohn's disease and ulcerative colitis), pancreatitis, and liver injury can cause irreversible tissue damage and seriously affect body function, and are potentially life-threatening.

Colitis
Colitis is usually relevant to inflammatory bowel disease (IBD). Maresin 1 (50 µg/kg; oral gavage) can increase the relative abundance of P. xylanivorans (a probiotic with healthy effects on gut inflammation) while decreasing the expression of IL-1β and TNF-α in dietinduced obese (DIO) mice [25]. In another murine model experiment, evidence showed that MaR1 improved the disease activity index and reduced body weight and colonic tissue damage, protecting mice against colitis. MaR1 (0.1, 0.3, and 1 µg/animal; e.v.) decreased ICAM-1 mRNA expression and the levels of inflammatory cytokines, inhibiting TLR4 and NF-κB pathway and activating Nrf2 signaling. Furthermore, MaR1 enhanced the macrophage M2 phenotype and decreased myeloperoxidase (MPO) activity and reactive oxygen species (ROS) by improving the expression of tight junction proteins and reducing the infiltration of neutrophils and macrophages [26,100].

Hepatitis and Liver Fibrosis
Hepatitis is one of the most common liver diseases, and liver fibrosis is a result of most types of chronic liver diseases, such as cirrhosis, hepatocellular carcinoma, and liver failure. MaR1 inhibited thiobarbituric acid reactive substances and increased the activities of antioxidative mediators (ROS levels decreased). MaR1 also inhibited NF-κB pathway activation and mitogen-activated protein kinases (MAPKs), showing antioxidative and anti-inflammatory effects, attenuating hepatic injury, oxidative stress, and lipid peroxidation. MaR1 improved liver function by reducing hepatocyte apoptosis and increasing macrophage apoptosis [27,102].

Obesity-Related Liver Diseases
Obesity-related liver diseases include liver steatosis, metabolic dysfunction, and nonalcoholic fatty liver disease (NAFLD).
Injury to hepatocyte mitochondria is common in metabolic-dysfunction-associated fatty liver disease. MaR1 has optimal hepatic mitochondrial and metabolic efficiency, rescuing hepatocytes from mitochondrial dysfunction induced by obesogenic and fibrogenic insults [103].

Non-Alcoholic Steatohepatitis and Liver Ischemia-Reperfusion Injury
Retinoic acid-related orphan receptor α (RORα) increased the transcriptional activity of 12-LOX and thereby increased MaR1, which can enhance the RORα ability to activate the M2 polarity of liver macrophages. Therefore, MaR1 can protect the liver from non-alcoholic steatohepatitis [31].
Hepatic ischemia/reperfusion (I/R) injury can be a major complication following liver surgery contributing to post-operative liver dysfunction. MaR1 (4 ng/g; i.p.) alleviated IR liver injury, facilitated by the activation of hepatocyte cell division, increased IL-6 cytokine levels, nuclear localization of NRF-2, decreased NF-κB activity, and the activation of the N-formyl peptide receptor 2 (FPR2, also called ALXR)/Akt signaling pathway. MAI (mitotic index) activity of hepatocytes was characterized by an intense cell division with 3.7-and 5.25-fold increases in the MaR1-sham and MaR1-IR groups, respectively. Moreover, MaR1-IR showed an increase of 41% in cell division related to MaR1-sham livers. IL-6 was increased 1.4 times in the MaR1-IR group compared to IR groups, while it was 0.2 and 6 times less than the IR and MaR1-IR groups, respectively, in the MaR1-sham group. Furthermore, the increase in nuclear Nrf2 of the MaR1-IR group was more than 7-fold that of the control [32,101,106,107]. MaR1 also attenuated acute liver injury by ameliorating inflammation [33].
In conclusion, MaR1 can repair tissue after damage and attenuate inflammatory diseases in the digestive system, including colitis, hepatitis, and other liver diseases. Table 1 is the related compilation of preclinical models of the digestive system.

Endocrine System
The endocrine system comprises internal glands that maintain the body's homeostasis through regulatory hormonal cascades [108]. Studies on maresin's effects on the endocrine system have focused on obesity and diabetes, both of which feature persistent inflammation and are related to brown and white adipose tissues and the liver, which regulate insulin sensitivity.

Obesity
Obesity is a complex disease affecting large populations and involving adipose tissue and endocrine responses. The production of bioactive SPMs, including MaR1 and proinflammatory mediators in the visceral adipose tissue of obese patients, was found to be significantly imbalanced [109]. In diet-induced obese (DIO) mice, MaR1 (2 µg/kg, i.p., 10 days) reduced subcutaneous depot weight (from 2.4 ± 0.0 to 1.9 ± 0.1 g), serum white adipose tissue (WAT)-secreted lectin (from 43.9 ± 2.5 to 34.7 ± 2.7 ng/mL), and fasting glucose (167.9 ± 12.3 to 145.9 ± 8.4 mg/dL), while insulin levels and homeostatic model assessment were decreased insignificantly. While insulin tolerance tests (ITT) were enhanced by MaR1 (2 µg/kg, i.p., 20 days) in leptin-deficient ob/ob mice, Glut-4 expression was increased, and Dpp-4 expression was reduced in both models [36]. Similarly, MaR1 (50 µg/kg, oral gavage, 10 days) given to DIO mice lowered fasting glycemia and reduced ITT glucose levels by around one-third. However, insulin-induced AKT phosphorylation, which regulates glucose transporter type 4 (GLUT4) translocation, was only partially restored in the muscle and not in epididymal WAT. In lean mice with acute MaR1 treatment (50 µg/kg, i.p., 3 h), Akt phosphorylation in skeletal muscle and epididymal WAT was improved [37]. Moreover, fibroblast growth factor (FGF) 21 expression, associated with the regulation of insulin sensitivity, was increased in the liver and decreased in epididymal WAT of DIO mice. Both effects were reversed by MaR1 (50 µg/kg, oral gavage, 10 days), and inhibition of FGF receptor components was counteracted [38].

Cold-Induced Resolution of Inflammation
Cold exposure stimulates β3-adrenergic receptors of brown adipose tissue (BAT), producing 14-HDHA, MaR2, and MaR2 isomers, which then act on the liver via circulation. Treatments of MaR2 (5 µg/kg/day, i.p., 28 days; 10 µg/kg/day, i.p., 26 days) on DIO mice did not change body weight yet downregulated plasma TNF-α levels and liver pro-inflammatory gene expression, possibly via the upregulation of triggering receptor expressed on myeloid cells-2 (TREM2) in monocytes and Kupffer cells. Notably, manifestations of hepatic steatosis, such as liver weight, triglyceride levels, lipogenic gene expression, steatosis, and alanine transaminase (ALT) index, were not altered in the latter treatment, nor was inflammatory gene expression in BAT [39].

Type 2 Diabetes Mellitus (T2DM)
Plasma maresin levels were significantly lower in T2DM patients, especially those with diabetic foot ulcers. Notably, plasma levels of maresin were negatively correlated to BMI, waist circumference, waist-hip ratio, triglyceride, fasting plasma glucose (PG), 2hPG, glycated hemoglobin (HbA1C), and homeostasis model assessment for insulin resistance (HOMA-IR). On the other hand, its level positively correlated with acute insulin response, the first phase (0-10 min) insulin secretion, and homeostasis model assessment for beta-cell function (HOMA-β) [110]. Between tuberculosis patients with or without diabetes, the DHA-MaR metabolome group showed different network profiles with other lipid metabolomes, yet MCTR3 is one of the most abundant SPMs in the serum in both groups [111].

Obesity and T2DM Treatments Related to Maresin
Weight loss and red wine failed to alter MaR1 levels released by patients with metabolic disease and T2DM, respectively. At the same time, one-anastomosis gastric bypass increased serum MaR1 in obese patients, which was lower than lean controls before intervention [112][113][114]. In another study on bariatric surgery, serum MaR1 levels had no significant difference between morbidly obese non-diabetic and diabetic patients. In contrast, both groups had higher 14-hydroxy docosahexaenoic acid (14-HDHA) than mildly obese non-diabetic controls. Interestingly, after surgery, serum MaR1 levels in morbidly obese non-diabetic subjects were significantly reduced (from 30.0 to 0 pg/mL) compared to their diabetic counterparts (9.5 to 8.8 pg/mL). Within the diabetic group after surgery, diabetic remitters exhibited a 0% change in MaR1 and reduced 58.2% of 14-HDHA; in non-remitters, MaR1 decreased by 36.9%, and 14-HDHA increased by 875.7%, reflecting the complexity of using its pathway metabolite14-HDHA as a sole biomarker [115].
Collectively, MaR1 successfully counteracted effects induced by obesity and T2DM, not only in the biochemical hierarchy but also in clinical manifestations, including lowering glucose levels, elevating insulin secretion, and resolving liver inflammation. Table 1 is the related compilation of preclinical models of the endocrine system.

Immune/Lymphatic System
The immune system serves as the defense system against external and internal noxious stimuli. Innate immunity acts through inflammation and phagocytosis against bacterial infection and trauma, which can lead to sepsis if uncontrolled. Adaptive immunity involves lymphocytes and lymphatic organs that target specific pathogens and monitors immune pathways comprehensively via the inhibition and expression of biomarkers. Though immune responses are developed to eliminate unwanted stimuli, hyperreactive host defenses can cause more tissue damage.

T Cell Differentiation and Lymphatic Obstruction
MaR1 (10 nM) downregulated cytokines produced by CD8 + and CD4 + T cells and reduced IL-2 production by around half in anti-CD3/CD28-stimulated T cells without decreasing T cell proliferation or expression of inhibitory receptors. in particular, MaR1 inhibited the differentiation of naïve CD4 + cells into Th1 or Th17 cells by downregulating T bet and RORc while favoring differentiation into Treg by upregulating the expression of Foxp3 + (by~30%) and CTLA-4 (by~5%), and the production of IL-10 (by~50%) [45]. Surgery-induced lymphatic obstruction (SLO) in the ileocecal region of African green monkeys showed low levels of endogenous SPMs on day 7 post-surgery, yet cumulative levels of D-series resolvins, lipoxins, and maresins combined increased on day 21 and 61 in the ileum and colon, paralleled with a resolution of inflammation that manifested on day 7, including thickened, shortened ileocecal mesentery covered by fibrin, edematous bowel loops and hyperplasia of stiffened lymph node [121].
Collectively, maresins regulated phenotypes of immune cells to reduce damage and promote repair as well as enhanced bacterial phagocytosis. Maresins also reduced cytokine release, striking a balance between controlled inflammation for a defense that limits selfdamage. Table 1 is the related compilation of preclinical models of the immune and lymphatic system.

Integumentary/Exocrine System
The integumentary system consists of the skin, the body's largest organ, and associated tissues, including the epidermis, dermis, and hypodermis, where subcutaneous adipose and connective tissue are located. The conjunctiva is a mucous layer connecting the inner surface of the eyelid to the anterior surface of the eyeball, which serves as an anatomical and immune barrier against external stimuli [122]. As the integumentary system is in constant contact with the external world, integrity must be maintained to protect the inner body.

Adipose Tissue
The adipose tissue not only protects organs and provides energy but also secretes a variety of lipid mediators. To understand the correlation of SPM profiles and brown adipose tissue (BAT) dysfunction in aging, obesogenic mice, it was found that maresins were the second most abundant LMs in young chow diet mice and one of the main contributors to differences between age and diet groups. Interestingly, almost all maresin derivative levels in BAT of aged mice fed with the high-fat diet, but with 15% replacement of dietary lipids to DHA-rich fish oil concentrate, were more than 3-fold compared to other groups, including young chow diet mice [127]. Moreover, in a TNF-α-induced lipolysis cell model, an abnormal increase in glycerol secretion in 3T3-L1 adipocytes was totally counteracted by MaR1 (100 nM, at 48 h). Levels of hormone-sensitive lipase (HSL) and perilipin were also reduced by TNF-α to 30% (HSL) and 45% (perilipin) of basal levels. Still, they were restored by MaR1 (100 nM, at 48 h) to 50% (HSL) and 75% (perilipin). Meanwhile, MaR1 (100 nM, at 48 h) showed its ability to prevent TNF-α-induced autophagy by restoring~25% of p62 protein expression and returning the LC3II/LC3I ratio to the basal level, though cell viability was not altered [128]. Similarly, 24 h co-treatment of MaR1 (10 nM) with TNF-α (10 ng/mL) in primary human adipocytes reversed TNF-α-induced chemerin gene expression and protein secretion back to the basal level [48]. In short, maresins were replenished by DHA supplementation in vivo and inhibited inflammation in in vitro models.
Collectively, maresins counteracted external stimuli in the skin, maintained tear film homeostasis in the conjunctiva, prevented histamine-induced mucin overproduction, and regulated inflammation responses in the adipose tissue, counteracting adverse effects of inflammation. Table 1 is the related compilation of preclinical models of the integumentary and exocrine systems.

Musculoskeletal System
The musculoskeletal system includes bones, muscles, cartilage, ligaments, tendons, and connective tissues, supporting body weight. Arthritis, as an important disease of the musculoskeletal system, is the swelling and tenderness of one or more joints. The main symptoms of arthritis are joint pain and stiffness, and the most common types of arthritis are osteoarthritis and rheumatoid arthritis. The research investigates if maresin can be useful for musculoskeletal diseases such as arthritis, Achilles tendinopathy, or muscle dysfunction.

Achilles Tendinopathy and Bone/Muscle Regeneration
In tendon-derived stromal cells from patients with Achilles tendinopathy or Achilles rupture, MaR1 (10 nM) regulated the pro-inflammatory phenotype and promoted resolution, countering inflammation [129].

Arthritis
Research insights into osteoarthritis. In equine synoviocytes, the osteoarthritis mediator gene expression osaR1 (200 nM) group was significantly increased compared to the control group [133]. MaR1 suppressed IL-1B-induced rat fibroblast-like synoviocytes and MMP13 secretion by activating the P13k/Akt pathway while inhibiting the NF-κB pathway [134].
Rheumatoid arthritis (RA) is an autoimmune disease that may damage a wide variety of body systems, including the skin, eyes, lungs, heart, and blood vessels. Compared with controls, the MaR1 concentration was higher in patients with inactive RA and lower in patients with active RA. Expression of the Treg transcription factor FoxP3 was the highest in inactive RA and the lowest in active RA, while the Th17 transcription factor RORc showed a reverse trend in the collagen-induced arthritis mouse model. The intervention of MaR1 (0, 20, and 100 ng, i.v.) improved the imbalanced Treg/Th17 ratio. MaR1 increased the Treg cell portion while reducing the Th17 cell proportion dose dependently. Furthermore, miR-21 was verified as MaR1 downstream mRNA, which was upregulated by MaR1, modulating the Treg/Th17 balance and thus ameliorating the RA progression [50]. MCTR3 potently decreased joint inflammation and promoted tissue repair. MCTR3 was mediated via the reprogramming of circulating monocytes to yield macrophages, upregulating arginase-1 to enhance the pro-resolving inflammation and tissue repair function [135].
In summary, maresin is proven to have a significant effect on inflammation resolution and tissue regeneration, helping to ameliorate inflammatory diseases such as arthritis or musculoskeletal injuries. It may be a potential therapy for inflammatory disease in the future. Table 1 is the related compilation of preclinical models of the musculoskeletal system.

Nervous System
The nervous system regulates perception, cognition, and responsiveness to stimuli. Neuroinflammation could lead to cognitive disorders, cerebrovascular diseases, other dysfunctions, and chronic pain.

Cognitive Disorders
Alzheimer's disease (AD) is a multifactorial inflammatory disease causing cognitive decline. In mice receiving bilateral hippocampal Aβ injection, MaR1 (0.01 µg, i.c.v.)treated mice were faster in the Morris Water Maze (MWM) [51]. Intranasal delivery of the SPM-combined solution (RvE1, RvD1, RvD2, MaR1, and NPD1, 40 ng per LM) given to App NL-G-F/NL-G-F mice thrice a week for 9 weeks reduced microgliosis and recovered 57% of gamma oscillation power [52]. Furthermore, in humans, MaR1 of cerebrospinal fluid was lower in the mild cognitive impairment group compared to their subjective counterparts but was negatively correlated with the mini-mental examination score (MMSE); in the entorhinal cortex, MaR1 was higher in AD patients [136,137]. MaR1 was lower in mice with the APOE4 genotype compared to APOE3 and higher in females and enhanced Aβ phagocytosis in vitro [138,139]. In another form of dementia, frontotemporal dementia carriers with C9orf72 expansion had higher maresin levels than those with other mutations [140].

Cerebrovascular Diseases
Ischemia in the brain impairs the delivery and utilization of oxygen and nutrients, leading to cerebral dysfunction. MaR1 (0.05 µg, intrathecal) decreased escape latency in MWM by 20~30 s maximally and alleviated the blood-brain barrier, BBB) changes in rats with chronic cerebral hypoperfusion [55]. In mice with ischemia/reperfusion injury, MaR1 (1 ng, intracerebroventricular) decreased~40% of original infarct volume and reduced brain damage via modulating silent information regulator 1 (SIRT1) signaling [56,141]. Regarding stroke, patient plasma MaR1 showed no correlation with the MMSE score within 7 days of stroke onset, while another study reported negative correlations with the California Verbal Learning Test on the 7th day and 6-month follow-up, suggesting that MaR1's impacts are sophisticated [142,143].

Pain
Inflammatory pain is characterized by hypersensitivity, while neuropathic pain results from neural anomalies. MaR1 pre-and post-treatments (optimal: 10 ng, i.t.) alleviated acute and chronic inflammatory pain in mice, reducing the difference in the withdrawal threshold between the baseline (at zero-time) and after 1-5 h carrageenan stimulation in mechanical (by max:~2 g) and thermal hyperalgesia (by max:~5 s); MaR1 pretreatment (10 ng, i.t.) also reduced flinches and time spent licking the paw by~50%, mitigating overt pain [60]. Similarly, MaR2 (optimal: 30 ng, i.p.) reduced LPS-induced mechanical and thermal hyperalgesia, lowering ∆reaction by 2~4 g and increasing latency by 5~10 s; the injured/non-injured paw weight ratio was also increased from~0.6 to~0.8 by MaR2 [61]. Neuropathic pain was also attenuated in rats by MaR1 (100 ng/10 µL, i.t.) after spinal nerve ligation, raising the ipsilateral mechanical withdrawal threshold by~10 g and thermal paw withdrawal by latency by~10 s [62]. Parallel results were obtained from MaR1 (optimal: 100 ng, i.t., 3 d) given to rats with non-compressive lumbar disc herniation having radicular pain, which is associated with NLR family pyrin domain containing 3 (NLRP3) inflammasome and caspase 1 activation [63,64].
In mice with peripheral nerve (sciatic nerve crush) injury, MaR1 (500 ng, applied onto damaged nerves using hemostatic gelatin sponge) reduced gastrocnemius atrophy and performed better than nerve growth factor (NGF) in the rotarod, von Frey, and Hargreaves tests, improving motor and sensory functions. MaR1 (optimal: 100 ng, i.t.) mitigated neuropathic pain and (50 ng, intraplantar) maintained pain threshold, unlike NGF [65]. Furthermore, MaR1 used as peri-(500 ng, i.v.) and post-operative treatments (500 ng, i.t.) showed the most potent effects by inhibiting fracture-associated post-operative pain in mice compared to DHA and other SPMs [66]. Lastly, K/BxN-induced mechanical hypersensitivity without joint swelling in rheumatoid arthritis was ameliorated in mice treated with MaR1 (100 ng, i.p.), with a later onset and longer duration after repeated injections [67].
As therapeutic candidates, maresins exerted neuroprotective and analgesic effects without cytotoxicity or hypersensitivity. Table 1 is the related compilation of preclinical models of the nervous system.

Reproductive System
Both male and female reproductive systems contain external organs and internal organs. The major function of the reproductive system is to ensure the survival of the species. The reproductive system produces ovum and sperm cells, transports and sustains these cells, nurtures the developing offspring, and produces hormones.

Human Milk
Human milk contains nutrients and bioactive products relevant to infant development and immunological protection. It possesses specialized pro-resolving mediators, including maresins, that enhance human macrophage efferocytosis and bacterial containment. The MaR1 level in healthy human milk (4-8 weeks post-partum) is 20.8 ± 6.3 ( pg/mL). Treating MaR1 (50 ng, i.p.) in a mouse peritonitis model shortens the resolution interval and magnitude of PMN infiltration by 76% and 58%, respectively [68].

Localized Provoked Vulvodynia (LPV)
Localized provoked vulvodynia (LPV) is the most common cause of chronic dyspareunia in premenopausal women, characterized by pain with a light touch to the vulvar vestibule surrounding the vaginal opening. The devastating impact of LPV includes sexual dysfunction, infertility, depression, and even suicide. In LPV, the vestibule expresses a unique inflammatory profile with elevated levels of pro-nociceptive pro-inflammatory mediator prostaglandin E2 (PGE2) and interleukin-6 (IL-6), which are linked to lower mechanical sensitivity thresholds. In a murine vulvar pain model, topical treatment with the SPM, maresin 1, decreased sensitivity by increasing the pain threshold and suppressed PGE2 levels. Docosahexaenoic acid (DHA), a precursor of maresin 1, was also effective in reducing PGE2 in vulvar fibroblasts and rapidly restored mouse sensitivity thresholds. Overall, SPMs and their precursors may be safe and efficacious for LPV [69].

Polycystic Ovary Syndrome
Polycystic ovary syndrome (PCOS) is an endocrinological disorder that affects 5-15% of women of reproductive age and is a frequent cause of infertility. Major symptoms include hyperandrogenism, ovulatory dysfunction, and often obesity and/or insulin resistance. PCOS also represents a state of chronic low-grade inflammation that is closely interlinked with metabolic features. MaR1 and MaR2 serum levels in the PCOS group were 81.8 and 231.0 pg/mL, respectively, while in the healthy group they were 21.5 and 93.0 pg/mL, respectively. The ratio (sum of pro-inflammatory molecules)/(sum of SPMs plus hydroxylated intermediates) reflecting the inflammatory state was significantly lower in the group of healthy women. In conclusion, there is a strong pro-inflammatory state in PCOS patients. Further research may clarify whether supplementation with DHA may improve this state [144].

Pre-Eclampsia (PE)
Recent data indicated an imbalance of leukotriene B4 (LTB4) and MaR1 levels in preeclampsia (PE). Research showed that plasma concentrations of LTB4 were higher in PE women than in normotensive pregnant women, who presented higher levels of LTB4 than non-pregnant women. In addition, PE women had a decreased MaR1/LTB4 ratio. The findings suggested that the PE state resulted in the systemic overproduction of LTB4 in relation to MaR1, and it may be involved with disease pathogenesis [145].
In conclusion, maresin has been proven to reduce tissue inflammation and damage. The relation between maresin levels and the above diseases shows that maresin may be one of the potential therapeutics in the female reproductive system. Table 1 is the related compilation of preclinical models of the reproductive system.

Respiratory System
The respiratory system is a network of organs and tissue that helps us breathe, including the airway, lungs, and vessels. Some conditions, such as viruses or bacterial infections, can cause inflammation in the respiratory system. MaR1 has been proven to suppress inflammation and the production of inflammatory cytokines while increasing anti-inflammatory cytokines.

Acute Respiratory Distress Syndrome (ARDS)
Acute respiratory distress syndrome (ARDS) is a devastating condition of acute lung inflammation. Patients with ventilation for fewer than 7 days showed higher MaR1 values than those who were ventilated for more than 14 days. In addition, MaR1 concentrations were also increased in patients who stayed in ICU for fewer than 7 days, compared with those who stayed longer than 14 days [146]. MaR1 was significantly increased during platelet-neutrophil interactions, restraining neutrophil-platelet aggregates (N-PAs) and acute pulmonary inflammation to restore homeostasis of the injured lung [147].

Virus and Bacterial Infection: COVID-19 and Bacterial Pneumonia
Plasma from COVID-19 patients presented higher amounts of pro-inflammatory mediators compared to the healthy group (65.7 vs. 10.2 pg/mL, respectively), and the ratio between total plasma pro-inflammatory mediators versus total SPMs was 13.2 to 0.4 times, respectively [148]. Secondary bacterial pneumonia is a common complication of Influenza A virus (IAV) infection, leading to excess morbidity and mortality. Research showed that MCTRs increased macrophage resilience mechanisms after IAV to protect against secondary infection from Streptococcus pneumoniae [149].

Chronic Rhinosinusitis and Asthma
Research showed that MCTRs are the most abundant cysteinyl lipid mediator and could attenuate airway contraction in human precision-cut lung slices [70]. MaR1 (10 ng, i.v.) suppressed the activation of the NF-κB signaling pathway, thus reducing COX-2 and ICAM-1, preventing inflammatory cell infiltration in the bronchoalveolar lavage fluid and excessive mucus production. Meanwhile, maresin inhibited the activation of the NLRP3 inflammasome, the Th2-type immune response, and oxidative stress [71,150].

Acute Lung Injury (ALI)
Acute lung injury is characterized by lung inflammation and diffuse neutrophil infiltration, controlled by neutrophil apoptosis. The percentage of neutrophil apoptosis in the MaR1-treated group was about three times that of the control group. Maresin-1 accelerated the resolution of inflammation in lipopolysaccharide-induced acute lung injury (LPS-induced ALI) and reduced the production of pro-inflammatory cytokines while upregulating the production of IL-10 [151,152]. MaR1 alleviated LPS-induced ALI by protecting the endothelial glycocalyx, which limited the access of certain molecules to the cell membrane and upregulated the expression of the tight junction protein to decrease lung injury permeability [153,154]. In addition, MaR1 (2 ng/g in the murine model and the pulmonary epithelial cell line) inhibited cell death, inflammatory cytokine levels, and oxidative stress through the inactivation of the ALX Homeobox 1 (ALX)/PTEN-induced putative kinase 1 (PINK1)-mediated mitophagy pathway, protecting against LPS-induced ALI [72]. The alveolar fluid clearance (AFC) rates of LPS, LPS with maresin-1 treatment, and the control group were 10.1 ± 1.1,18.9 ± 2.1, 25.6 ± 2.9 (%), respectively. Maresin-1 significantly promoted AFC by upregulating the epithelial sodium channel and Na + -K + -adenosine triphosphatase expression in vivo [73].

Airway Inflammation and Lung Fibrosis
Airway inflammation associated with acute and repetitive exposure to organic dust is a high-risk factor for chronic bronchitis and obstructive pulmonary disease. In organic dust exposure studies, MaR1 significantly decreased bronchoalveolar lavage neutrophil infiltration and intracellular adhesion molecule-1 (ICAM-1) expression [74]. MaR1 also reduced cytokines' production such as IL-6, IL-8, and TNF-α of bronchial epithelial cells dose-dependently [155]. Lung fibrosis results from lung fibroblast migration, proliferation, and differentiation into a myofibroblast-like cell type induced by TGF-β. MaR1 protected tissue and reversed the epithelial-to-mesenchymal transition (EMT) phenotype by decreasing TGF-β, enhancing the survival rate (best dose response at 1 µg) [75,156,157].
In summary, MaR1 showed a significant effect of resolving inflammation and promoting tissue regeneration. The suppression of the inflammation and production of inflammatory/pro-inflammatory cytokines can be useful for lung inflammatory diseases, restoring lung tissue back to homeostasis. Table 1 is the related compilation of preclinical models of the respiratory system.

Urinary System
The urinary system's function is to filter blood and create urine as a waste by-product. The organs of the urinary system include the kidneys, renal pelvis, ureters, bladder, and urethra.

Cystitis
Inflammation is a central process in most benign bladder disorders, and the outcome is a delicate balance between initiating factors and resolving factors. Inflammation in tissue is associated with weight gain, most commonly from edema. In murine model research, it showed that SPMs, including MaR1 (25 µg/kg, i.p.), promoted epithelial wound/barrier repair, alleviated inflammation, and resulted in reduced bladder weights. The percentage of scratch closure of the MaR1 group was twice that of the control group. These results provided promising therapeutic targets for inflammatory bladder diseases [76].

Diabetic Nephropathy (DN)
Diabetic nephropathy (DN) is a major complication of diabetes mellitus. MaR1 inhibited the NLRP3 inflammasome, TGF-β1, and fibronectin (FN) in mouse glomerular mesangial cells, suggesting that MaR1 may have a protective effect on DN by mitigating inflammation and early fibrosis [77].

Sepsis-Associated Acute Kidney Injury (S-AKI)
Sepsis-associated acute kidney injury (S-AKI) is a common complication in hospitalized and critically ill patients, which increases the risk of multiple comorbidities and is associated with extremely high mortality.
The 7-day survival rates of the sham group, the cecal ligation and puncture (CLP) group, the MaR1 low dose (LD-MaR1, 0.5 ng) group, and the MaR1 high dose (HD-MaR1, 1 ng) group were 100%, 16.67%, 58.33%, and 75%, respectively. Research showed that MaR1 significantly increased the 7-day survival rate of septic mice and the anti-inflammatory factor while reducing bacterial load and pro-inflammatory cytokines. In addition, MaR1 dose-dependently reduced renal injury scores and serum creatinine and urea nitrogen levels in septic mice while inhibiting renal neutrophil infiltration and myeloperoxidase (MPO) activity [78]. In conclusion, MaR1 attenuated kidney inflammation by reducing neutrophil infiltration and inhibiting the NF-κB pathway activity, apoptosis, oxidative stress, and mitochondrial dysfunction to protect against septic AKI [158].
Ferroptosis is unique among different types of regulated cell death and closely related to organ injury, and nuclear factor-erythroid-2-related factor 2 (Nrf2) is crucial to the regulation of ferroptosis. Maresin conjugates in tissue regeneration 1 (MCTR1) inhibited ferroptosis in sepsis-associated acute kidney injury (SA-AKI) and elevated the expression of Nrf2. The percent survival of the CLP group was about twice that of the MCTR + CLP group. As a result, MCTR1 ameliorates multi-organ injury and improves survival in animal models of sepsis [79].

Renal Ischemia/Reperfusion Injury
Inflammation and oxidative stress play a crucial role in the pathogenesis of renal ischemia/reperfusion injury (IRI). In a murine model, the histologic score of the IRI + MaR1 group (1.0 ng, i.v.) was about two-thirds that of the IRI group. Meanwhile, MaR1 remarkably mitigated renal IRI-induced inflammation and oxidative stress. The results indicated that MaR1 markedly protected against renal IRI by the reduction in histologic changes and renal dysfunction by inhibiting the TLR4/MAPK/NF-κB pathways, which mediate anti-inflammation, and by activating the Nrf2 pathway, which mediates antioxidation [80].
To sum up, MaR1 inhibits inflammation, which helps to increase the survival rate associated with diabetes and kidney disease. Its ability to ameliorate organ injury and histologic changes suggests that MaR1 may be a future therapeutic target for the above diseases. Table 1 is the related compilation of preclinical models of the urinary system.

Discussion
The relative relationship between the action timing of maresins and the onset of diseases may affect the degree of disease mitigation. Based on the experiments conducted to date, the concentrations of maresins administered are usually between micrograms and nanograms, and there should be a range of optimal concentrations for each situation, which is worthy of further study to obtain the best choice. The modes of administration are mostly by injection, and some are administered orally or with special carriers. In some experiments, additional dosages or adjustments of the duration of action are used to achieve the effect, but the subsequent mechanism of maresins is not yet known. The mechanism of maresins may be quite complex due to the intricacies of the human environment and the large number of immune cells and cytokines involved in the inflammatory response.
Preclinical studies on maresins related to human organ systems have reported their efficacy and potential in treating different inflammatory diseases and conditions. There are many other mechanistic studies that have also supported their therapeutic action and are worth discussing. The following is additional significant information about maresins as biomarkers, interactions in platelet aggregation, supplementation, and other resolving actions.

MaR1 in Human Tissue Fluid and as a Biomarker
Although maresin 1 was first found in self-limiting peritonitis exudate from mice, it was soon discovered that human macrophage also produces MaR1 and presents in human serum [159]. MaR1 was also found in several sources of human tissue fluid and could potentially serve as a biomarker. Saliva was found to have a greater amount of MaR1 in periodontitis patients (0.69 vs. 0.49 ng/mL in control), and patients with cardiovascular disease (CVD) and generalized periodontitis had a more pronounced level. However, within the observed period in the study, no correlation was found with the rate of periodontitis progression, but evidence suggested that an increase in MaR1 and a reduction in protectins' (PD) salivary levels could be predictors of developing CVD and/or periodontal disease [160,161]. Moreover, it found that MaR1, 14-HDHA, and 7(s)-MaR1 have correlations with different subgingival microbiota of subgingival plaque between the healthy group, periodontitis before scaling and root planning (SRP) treatment, and periodontitis after SRP treatment [162]. In addition, serum from patients with post-menopausal osteoporosis (PMOP) (124.68 ± 31.35 pg/mL) and osteopenia (140.1 ± 30.5 pg/mL) are different from the healthy group (167.4 ± 24.9 pg/mL). Serum MaR1 levels were positively correlated with femoral neck, lumbar spine, and hip bone mineral density. The results suggest that MaR1 may serve as a new non-invasive diagnostic biomarker for PMOP [163]. Moreover, the urine level of MaR1 is significantly lower (about 50%) in subjects with stage 3-4 nephropathy than in healthy subjects and those with stage 1-2 nephropathy. In patients with T2DM (with or without kidney disease), MaR1 serum concentration is lower (about 50%) compared to healthy controls, and the diabetic kidney disease (DKD) group had the lowest concentration. Additionally, MaR1 concentration was correlated with high-density lipoprotein cholesterol (HDL-C) and the estimated glomerular filtration rate (eGFR). In conclusion, a decreased serum MaR1 level was correlated with the development of DN and DKD, which could be an indicator [77,164,165]. MaR1 is also present in joint synovial fluid. Regarding joint-related diseases, DMARDs are used to treat patients with RA [166,167]. In order to predict the effectiveness of disease-modifying antirheumatic drugs (DMARDs), the research found that the plasma concentration of maresin, as a biomarker, is predictive of DMARD responsiveness and RA pathotypes [168]. In the plasma of amyotrophic lateral sclerosis (ALS) patients, a reduction in 14-HDHA was found, demonstrating an imbalance in the resolution process of inflammation [169]. In addition, C-reactive protein (CRP), which is an inflammation protein marker produced by the liver in the plasma, was associated with EPA and DHA levels dose dependently [170].

Platelets' Aggregation and Supplementation
Maresin 1, as one of the specialized pro-resolving mediators (SPM), was significantly increased during platelet-neutrophil interactions, restraining neutrophil-platelet aggregates (N-PAs) and acute pulmonary inflammation from restoring homeostasis of the injured lung [147]. Aggregation is a problem during cold storage of apheresis platelets, and SPM treatment (MaR1: 100 nM) reduced the activation and preserved the functions of platelets at seven days [171]. 14S-HpDHA (≥1 µM), the precursor of maresin, also reduced the aggregation of platelets by 90%, implying that the intake of DHA may be beneficial in treatment [5]. However, in terms of the supplementation of n-3 fatty acids, whether it increases the concentration of endogenous maresin-associated products in the blood or tissue when fighting against bacteria, in the model of Alzheimer's disease, or during human pregnancy in different stages, still needs further investigation [172][173][174][175][176]. Ingestion of fish oil can also upregulate peripheral blood MaR2 and MaR2n-3 DPA levels (4.5 g total fatty acids, 2-4 h), and the concentration of MaR1n-3 DPA (4.5 g total fatty acids) was negatively correlated with the expression of monocyte activation marker CD49d [177]. For patients with obesity, after consuming 2 g/d of marine oil for about one month, the plasma level of MaR1 increased 4.7-fold, and B cell IgG decreased [178]. In short, MaR1 may have the ability to prevent the aggregation of platelet storage, and daily ingestion of fish oil might modulate the functions of inflammatory cells.

Other Modulating Functions and Cancer Cell Suppressibility
MaR1 production from M2 macrophages could be enhanced by PMN microparticles and phagocytosis of apoptotic PMNs, while the MaR1 level was lower in zymosan-induced peritonitis when vacuolar-ATPase was blocked. Neogenin1 deficiency is also associated with an increase in exudate MaR1 and enhanced macrophage phagocytosis via 12/15 LOX activity [159,179,180]. In contrast, the heme oxygenase-1 (HO-1)/carbon monoxide (CO) pathway interacts with SPMs in a positive feedback manner, with macrophage phagocytosis of zymosan reaching its maximal potential when CO and MaR1 (0.01 nM) were concomitantly present. An MaR1 (0.1 nM)-induced increase (30-40%) in phagocytosis was also abrogated by HO-1 inhibition [181]. In microRNA (miRNA)-4661-transfected mice with zymosan-induced peritonitis, biosynthesis of SPMs, including MaR1, was increased, yet MaR1 (10 nM) reduced miR-4661 expression in vehicle-and zymosan-treated primary human macrophages and neutrophils. MaR1 (10 nM) also reversed the upregulation of activator protein (AP)-1 and NF-κB1 signaling induced by zymosan, but effects on miR-4661 downstream pathways were inhibited by pertussis toxin [182]. For physiological hypoxia, M2 macrophage efferocytosis of apoptotic PMNs and senescent erythrocytes was enhanced up to 10-fold via upregulation of endogenous SPM levels, including MaR1 and MaR2, when these cells were co-incubated in hypoxic environments, which could mimic inflammatory sites, bone marrow, and the spleen. As neutrophils depend mostly on glycolysis, hypoxia elevated neutrophil SPM production by~5-fold and MaR1 by~3-fold, thus ameliorating neutrophil-induced inflammation [183]. Moreover, MaR1 (10-100µM) exhibited suppressibility of breast, pancreatic, and colon cancer cells' growth to different extents (range from 62 to 92%), suggesting that there might be an optimal ω-3 fatty acids choice to inhibit the growth of each cancer cell [184]. The main limitation of this system-based systematic review is that most of the studies are preclinical studies, but it is also the focus of this review to synthesize all the translational information from animal studies, which is extremely critical. Compared with systematic human reviews, data extractions can be more challenging because most of the literature does not contain raw data or detailed numeric information in paragraphs but the data are presented as graphs. Therefore, many of the values presented in the table are presented with relative ratios calculated from the original figures. Furthermore, this article is written in terms of organ systems and diseases so that we can clearly see which diseases or conditions are being studied. However, the reference value of cell experiments, animal experiments, and human experiments are not identical and should be categorized more carefully to eliminate confusion.
Despite the fact that current published studies on maresins are mostly in the preclinical stage, their huge potential applications in each organ system are well-demonstrated. Future translational studies and human trials are expected and warranted. Moreover, further investigations into the pharmacokinetics, bioavailability, and safety profiles are necessary to build their potential for clinical translation.

Conclusions
Maresins have demonstrated their competence to resolve inflammation for organ protection and tissue regeneration in various diseases and systems. The nervous system has the highest number of studies, followed by the cardiovascular, digestive, and respiratory systems. In different animal disease models, various delivery methods and therapeutic dose responses have gradually been tested by different research groups. These integrated findings highlight the importance of studying maresins in various organ systems and experimental contexts. It underscores the need for further translational research to fully understand the therapeutic potential, mechanisms of action, and optimal dosing with delivery methods for clinical applications of maresin.