Drug Candidates for the Treatment of Immune Disease

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (15 October 2022) | Viewed by 33473

Special Issue Editor

Faculté de Pharmacie, Université Libre de Bruxelles, Campus Plaine CP 205/5, 1050 Brussels, Belgium
Interests: medicinal chemistry; organic synthesis; asymmetric synthesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

Diseases involving immune disorders are a major problem in medicine, not only because of autoimmune diseases such as rheumatoid arthritis, lupus, and Crohn’s disease, but also because of the need to prevent transplant rejection and the effects of anticancer therapy. The medical armamentarium comprises a large number of substances that perform relatively well in helping patients to control these problems: corticosteroids, anticancer drugs with immunosuppressive properties (methotrexate, azathioprine, etc.), ciclosporin, rapalogues, monoclonal antibodies and several enzyme inhibitors. However, there are still numerous problems regarding the use of these drugs, and among them, side effects (especially opportunistic infections and cancers) and narrow therapeutic indices are the most severe. The research should continue in this field to find new compounds that will be safer for fighting these chronic pathological situations. 

A significant number of drugs acting on the immune system have been approved, and most of them are enzyme inhibitors. These enzymes are involved in the synthesis of nucleic acid bases (e.g., inosine-5′-monophosphate dehydrogenase for mycophenolic acid and dihydroorotate dehydrogenase for leflunomide) or in signaling pathways (e.g., mTOR and JAK). However, to avoid side effects, it is clear that future immunomodulators should have more specific actions on the precise mechanisms involved in the immune disorders to limit life-threatening side effects. 

Several enzymes have recently been described as potential new targets in autoimmune disorders. They represent new hopes for drugs having both high efficacy and safety. The biggest challenge remains obtaining selective and potent inhibitors of these enzymes. Since 2000, a series of attractive targets have been identified, such as indoleamine 2,3-dioxygenase 1, cyclic GMP-AMP synthase, pyruvate kinase M2 and arginase 1. 

We are pleased to welcome papers reviewing the most recent research on this topic in the present thematic issue. 

We look forward to your contribution.

Dr. Francois Dufrasne
Guest Editor

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Published Papers (11 papers)

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Research

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10 pages, 696 KiB  
Article
Danazol in Refractory Autoimmune Hemolytic Anemia or Immune Thrombocytopenia: A Case Series Report and Literature Review
Pharmaceuticals 2022, 15(11), 1377; https://doi.org/10.3390/ph15111377 - 09 Nov 2022
Cited by 3 | Viewed by 1786
Abstract
Danazol is a treatment option for autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP). Three patients with AIHA and eight patients with ITP between 2008 and 2022 were enrolled in the Rheumatology Outpatient Clinic of Chang Gung Memorial Hospital, Kaohsiung. Those patients were [...] Read more.
Danazol is a treatment option for autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP). Three patients with AIHA and eight patients with ITP between 2008 and 2022 were enrolled in the Rheumatology Outpatient Clinic of Chang Gung Memorial Hospital, Kaohsiung. Those patients were refractory or intolerant to conventional therapy and were treated with danazol. All the patients received an initial dose of danazol (200–400 mg). The observation period was 6 months. Three patients (100%) with AIHA and six (75%) with ITP achieved treatment response after 6 months of danazol therapy. The dose of glucocorticoid for responders could be reduced to ≤5 mg/day of prednisolone, and the immunosuppressants, except hydroxychloroquine and azathioprine for systemic lupus erythematosus, could be discontinued. Adverse events were acne in two (18.2%) patients and transient dose-related liver function impairment in one (9.1%) patient in the current series. Danazol therapy appears to be a favorable alternative for refractory AIHA and ITP by altering the erythrocyte membrane to resist osmotic lysis and protecting platelets against complement-mediated lysis. In this report, we also performed a literature review and searched the PubMed/Cochrane Library for articles published from 1984 to January 2022 on danazol therapy for patients with AIHA and ITP. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Immune Disease)
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11 pages, 2085 KiB  
Article
Sedative and Immunosuppressive Effects of Dexmedetomidine in Transplantation
Pharmaceuticals 2021, 14(8), 825; https://doi.org/10.3390/ph14080825 - 22 Aug 2021
Cited by 4 | Viewed by 2189
Abstract
Dexmedetomidine, an α2-adrenergic receptor agonist, is used as an anti-anxiety medication. It exerts a cholinergic effect, thereby reducing the release of tumor necrosis factor alpha (TNF-α). We hypothesized that the use of dexmedetomidine as a sedative agent in transplantation would also protect allografts. [...] Read more.
Dexmedetomidine, an α2-adrenergic receptor agonist, is used as an anti-anxiety medication. It exerts a cholinergic effect, thereby reducing the release of tumor necrosis factor alpha (TNF-α). We hypothesized that the use of dexmedetomidine as a sedative agent in transplantation would also protect allografts. We examined our patients who underwent living donor liver transplantation. Subsequently, we generated a series of mouse models to investigate the effect of dexmedetomidine on sedation-based tolerance post transplantation. A total of 49 liver recipients were enrolled in this study, of which 23 (47%) were administered dexmedetomidine through 24 h infusion on postoperative day 1. A trend toward the improvement of hepatocyte injury along with better liver function was observed in the dexmedetomidine-treated group during the first postoperative week. In animal models, dexmedetomidine inhibited the proliferation of CD4+ and CD8+ T cells and TNF-α production in a dose-dependent manner. We used dexmedetomidine to treat skin-transplanted mice and observed a significantly prolonged graft survival in mice that were administered a higher dose of dexmedetomidine. Our results revealed that dexmedetomidine exerts a dual effect of sedation and immunosuppression. This light-sedation approach will not only make patients calmer in the intensive care unit but also protect allografts from injury. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Immune Disease)
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Review

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26 pages, 1726 KiB  
Review
Current Advancement of Immunomodulatory Drugs as Potential Pharmacotherapies for Autoimmunity Based Neurological Diseases
Pharmaceuticals 2022, 15(9), 1077; https://doi.org/10.3390/ph15091077 - 29 Aug 2022
Cited by 4 | Viewed by 2796
Abstract
Dramatic advancement has been made in recent decades to understand the basis of autoimmunity-mediated neurological diseases. These diseases create a strong influence on the central nervous system (CNS) and the peripheral nervous system (PNS), leading to various clinical manifestations and numerous symptoms. Multiple [...] Read more.
Dramatic advancement has been made in recent decades to understand the basis of autoimmunity-mediated neurological diseases. These diseases create a strong influence on the central nervous system (CNS) and the peripheral nervous system (PNS), leading to various clinical manifestations and numerous symptoms. Multiple sclerosis (MS) is the most prevalent autoimmune neurological disease while NMO spectrum disorder (NMOSD) is less common. Furthermore, evidence supports the presence of autoimmune mechanisms contributing to the pathogenesis of amyotrophic lateral sclerosis (ALS), which is a neurodegenerative disorder characterized by the progressive death of motor neurons. Additionally, autoimmunity is believed to be involved in the basis of Alzheimer’s and Parkinson’s diseases. In recent years, the prevalence of autoimmune-based neurological disorders has been elevated and current findings strongly suggest the role of pharmacotherapies in controlling the progression of autoimmune diseases. Therefore, this review focused on the current advancement of immunomodulatory drugs as novel approaches in the management of autoimmune neurological diseases and their future outlook. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Immune Disease)
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21 pages, 1397 KiB  
Review
Interaction between Mesenchymal Stem Cells and the Immune System in Rheumatoid Arthritis
Pharmaceuticals 2022, 15(8), 941; https://doi.org/10.3390/ph15080941 - 28 Jul 2022
Cited by 5 | Viewed by 2632
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease that causes damage to joints. This review focuses on the possibility of influencing the disease through immunomodulation by mesenchymal stem cells (MSCs). There is an occurrence of rheumatoid factor and RA-specific autoantibodies to citrullinated proteins in [...] Read more.
Rheumatoid arthritis (RA) is an autoimmune disease that causes damage to joints. This review focuses on the possibility of influencing the disease through immunomodulation by mesenchymal stem cells (MSCs). There is an occurrence of rheumatoid factor and RA-specific autoantibodies to citrullinated proteins in most patients. Citrulline proteins have been identified in the joints of RA patients, and are considered to be the most suitable candidates for the stimulation of anti-citrulline protein antibodies production. Fibroblast-like proliferating active synoviocytes actively promote inflammation and destruction in the RA joint, in association with pro-inflammatory cells. The inflammatory process may be suppressed by MSCs, which are a population of adherent cells with the following characteristic phenotype: CD105+, CD73+, CD90+, CD45−, CD34− and HLA DR−. Following the stimulation process, MSCs are capable of immunomodulatory action through the release of bioactive molecules, as well as direct contact with the cells of the immune system. Furthermore, MSCs show the ability to suppress natural killer cell activation and dendritic cells maturation, inhibit T cell proliferation and function, and induce T regulatory cell formation. MSCs produce factors that suppress inflammatory processes, such as PGE2, TGF-β, HLA-G5, IDO, and IL-10. These properties suggest that MSCs may affect and suppress the excessive inflammation that occurs in RA. The effect of MSCs on rheumatoid arthritis has been proven to be a suitable alternative treatment thanks to successful experiments and clinical studies. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Immune Disease)
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25 pages, 3690 KiB  
Review
Drug Candidates for Autoimmune Diseases
Pharmaceuticals 2022, 15(5), 503; https://doi.org/10.3390/ph15050503 - 20 Apr 2022
Cited by 5 | Viewed by 2530
Abstract
Most of the immunosuppressive drugs used in the clinic to prevent organ rejection or to treat autoimmune disorders were originally isolated from fungi or bacteria. Therefore, in addition to plants, these are valuable sources for identification of new potent drugs. Many side effects [...] Read more.
Most of the immunosuppressive drugs used in the clinic to prevent organ rejection or to treat autoimmune disorders were originally isolated from fungi or bacteria. Therefore, in addition to plants, these are valuable sources for identification of new potent drugs. Many side effects of established drugs limit their usage and make the identification of new immunosuppressants necessary. In this review, we present a comprehensive overview of natural products with potent anti-inflammatory activities that have been tested successfully in different models of chronic inflammatory autoimmune diseases. Some of these candidates already have passed first clinical trials. The anti-inflammatory potency of these natural products was often comparable to those of established drugs, and they could be used at least in addition to standard therapy to reduce their dose to minimize unwanted side effects. A frequent mode of action is the inhibition of classical inflammatory signaling pathways, such as NF-κB, in combination with downregulation of oxidative stress. A drawback for the therapeutic use of those natural products is their moderate bioavailability, which can be optimized by chemical modifications and, in addition, further safety studies are necessary. Altogether, very interesting candidate compounds exist which have the potential to serve as starting points for the development of new immunosuppressive drugs. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Immune Disease)
14 pages, 1384 KiB  
Review
New Applications of JAK/STAT Inhibitors in Pediatrics: Current Use of Ruxolitinib
Pharmaceuticals 2022, 15(3), 374; https://doi.org/10.3390/ph15030374 - 19 Mar 2022
Cited by 7 | Viewed by 4567
Abstract
Janus kinases (JAK) are a family of tyrosine kinases (JAK1, JAK2, JAK3, and TYK2) that transduce cytokine-mediated signals through the JAK–STAT metabolic pathway. These kinases act by regulating the transcription of specific genes capable of inducing biological responses in several immune cell subsets. [...] Read more.
Janus kinases (JAK) are a family of tyrosine kinases (JAK1, JAK2, JAK3, and TYK2) that transduce cytokine-mediated signals through the JAK–STAT metabolic pathway. These kinases act by regulating the transcription of specific genes capable of inducing biological responses in several immune cell subsets. Inhibition of Janus kinases interferes with the JAK–STAT signaling pathway. Besides being used in the treatment of cancer and inflammatory diseases, in recent years, they have also been used to treat inflammatory conditions, such as graft-versus-host disease (GVHD) and cytokine release syndrome as complications of allogeneic hematopoietic stem cell transplantation and cell therapy. Recently, the FDA approved the use of ruxolitinib, a JAK1/2 inhibitor, in the treatment of acute steroid-refractory GVHD (SR-aGVHD), highlighting the role of JAK inhibition in this immune deregulation. Ruxolitinib was initially used to treat myelofibrosis and true polycythemia in a high-dose treatment and caused hematological toxicity. Since a lower dosage often could not be effective, the use of ruxolitinib was suspended. Subsequently, ruxolitinib was evaluated in adult patients with SR-aGVHD and was found to achieve a rapid and effective response. In addition, its early low-dose use in pediatric patients affected by GVHD has proved effective, safe, and reasonably preventive. The review aims to describe the potential properties of ruxolitinib to identify new therapeutic strategies. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Immune Disease)
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10 pages, 7097 KiB  
Review
Pharmaceutically Active Microbial AhR Agonists as Innovative Biodrugs in Inflammation
Pharmaceuticals 2022, 15(3), 336; https://doi.org/10.3390/ph15030336 - 10 Mar 2022
Cited by 4 | Viewed by 2520
Abstract
Alterations of the microbiome occur in inflammatory and autoimmune diseases, a finding consistent with the role of the microbiome in the maintenance of the immune system homeostasis. In this regard, L-tryptophan (Trp) metabolites, of both host and microbial origin, act as important regulators [...] Read more.
Alterations of the microbiome occur in inflammatory and autoimmune diseases, a finding consistent with the role of the microbiome in the maintenance of the immune system homeostasis. In this regard, L-tryptophan (Trp) metabolites, of both host and microbial origin, act as important regulators of host–microbial symbiosis by acting as aryl hydrocarbon receptor (AhR) ligands. The intestinal and respiratory barriers are very sensitive to AhR activity, suggesting that AhR modulation could be a therapeutic option to maintain the integrity of the epithelial barrier, which has substantial implications for health even beyond the mucosal site. A number of studies have highlighted the capacity of AhR to respond to indoles and indolyl metabolites, thus positioning AhR as a candidate indole receptor. However, the context-and ligand-dependent activity of AhR requires one to resort to suitable biopharmaceutical formulations to enable site-specific drug delivery in order to achieve therapeutic effectiveness, decrease unwanted toxicities and prevent off-target effects. In this review, we highlight the dual activity of the microbial metabolite indole-3-aldehyde at the host–microbe interface and its ability to orchestrate host pathophysiology and microbial symbiosis and discuss how its proper clinical development may turn into a valuable therapeutic strategy in local and distant inflammatory diseases. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Immune Disease)
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10 pages, 420 KiB  
Review
The Use of Janus Kinase Inhibitors in Axial Spondyloarthritis: Current Insights
Pharmaceuticals 2022, 15(3), 270; https://doi.org/10.3390/ph15030270 - 22 Feb 2022
Cited by 10 | Viewed by 3406
Abstract
Current pharmacological treatments of axial spondyloarthritis (axSpA) are limited to non-steroidal anti-inflammatory drugs (NSAIDs) and biological agents, including TNFα inhibitors and IL-17 inhibitors. Despite the availability of these agents, many patients either fail to respond adequately, lose their initial therapeutic response over time, [...] Read more.
Current pharmacological treatments of axial spondyloarthritis (axSpA) are limited to non-steroidal anti-inflammatory drugs (NSAIDs) and biological agents, including TNFα inhibitors and IL-17 inhibitors. Despite the availability of these agents, many patients either fail to respond adequately, lose their initial therapeutic response over time, or develop undesirable side effects, thus highlighting the need for new treatment options. Janus kinase (JAK) and signal transducers and activators of transcription (STAT) are a group of intracellular kinases that play a role in the signaling pathway induced by cytokines and certain growth factors associated with the inflammatory process of axSpA. There are several lines of evidence implicating the JAK–STAT pathway in the pathophysiological process of axSpA, including genetic data, the use of certain JAK in the intracellular signal of specific cytokines involved in axSpA (IL-23, IL-22, and IL-6), and data from experimental models of SpA. This provides a rationale for the assessment of JAK inhibitors (JAKi) in clinical trials with patients with axSpA. In this review, we examine the role of JAK–STAT signaling in the pathogenesis of axSpA and summarize the results from recent clinical trials of JAKi (tofacitinib, upadacitinib, and filgotinib) in patients with axSpA. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Immune Disease)
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20 pages, 592 KiB  
Review
The Effect of Acknowledged and Novel Anti-Rheumatic Therapies on Periodontal Tissues—A Narrative Review
Pharmaceuticals 2021, 14(12), 1209; https://doi.org/10.3390/ph14121209 - 23 Nov 2021
Cited by 12 | Viewed by 2865
Abstract
Rheumatoid arthritis (RA) and periodontal disease (PD) are chronic complex inflammatory diseases with several common susceptibility factors, especially genetic and environmental risk factors. Although both disorders involve a perturbation of the immune–inflammatory response at multiple levels, one major difference between the two is [...] Read more.
Rheumatoid arthritis (RA) and periodontal disease (PD) are chronic complex inflammatory diseases with several common susceptibility factors, especially genetic and environmental risk factors. Although both disorders involve a perturbation of the immune–inflammatory response at multiple levels, one major difference between the two is the different locations in which they develop. RA is triggered by an exaggerated autoimmune response that targets joints, while periodontal disease occurs as a consequence of the subgingival periodontopathogenic microbiota. Current treatment models in both pathologies involve the stratification of patients to allow therapeutic individualization according to disease stage, complexity, progression, lifestyle, risk factors, and additional systemic diseases. Therapeutic guidelines for RA comprise of five main classes of drugs: non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, glucocorticoids, and disease-modifying anti-rheumatic drugs (DMARDs): biologic and non-biologic. Although various treatment options are available, a definitive treatment remains elusive, therefore research is ongoing in this area. Several alternatives are currently being tested, such as matrix metalloproteinases (MMP) inhibitors, toll-like receptors (TLR) blockers, pro-resolution mediators, anti-hypoxia inducing factors, stem cell therapy, NLRP3 inhibitors and even natural derived compounds. Although the link between PD and rheumatoid arthritis has been investigated by multiple microbiology and immunology studies, the precise influence and causality is still debated in the literature. Furthermore, the immunomodulatory effect of anti-rheumatic drugs on the periodontium is still largely unknown. In this narrative review, we explore the mechanisms of interaction and the potential influence that anti-rheumatoid medication, including novel treatment options, has on periodontal tissues and whether periodontal health status and treatment can improve the prognosis of an RA patient. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Immune Disease)
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18 pages, 1856 KiB  
Review
The Immunomodulatory and Anti-Inflammatory Effect of Curcumin on Immune Cell Populations, Cytokines, and In Vivo Models of Rheumatoid Arthritis
Pharmaceuticals 2021, 14(4), 309; https://doi.org/10.3390/ph14040309 - 01 Apr 2021
Cited by 29 | Viewed by 4821
Abstract
Rheumatoid arthritis (RA) is a widespread chronic autoimmune disorder affecting the joints, causing irreversible cartilage, synovium, and bone degradation. During the course of the disease, many immune and joint cells are activated, causing inflammation. Immune cells including macrophages, lymphocytes, neutrophils, mast cells, natural [...] Read more.
Rheumatoid arthritis (RA) is a widespread chronic autoimmune disorder affecting the joints, causing irreversible cartilage, synovium, and bone degradation. During the course of the disease, many immune and joint cells are activated, causing inflammation. Immune cells including macrophages, lymphocytes, neutrophils, mast cells, natural killer cells, innate lymphoid cells, as well as synovial tissue cells, like fibroblast-like synoviocytes, chondrocytes, and osteoclasts secrete different proinflammatory factors, including many cytokines, angiogenesis-stimulating molecules and others. Recent studies reveal that curcumin, a natural dietary anti-inflammatory compound, can modulate the response of the cells engaging in RA course. This review comprises detailed data about the pathogenesis and inflammation process in rheumatoid arthritis and demonstrates scientific investigations about the molecular interactions between curcumin and immune cells responsible for rheumatoid arthritis development to discuss this herbal drug’s immunoregulatory role in RA treatment. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Immune Disease)
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Other

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12 pages, 1876 KiB  
Systematic Review
Progranulin in Musculoskeletal Inflammatory and Degenerative Disorders, Focus on Rheumatoid Arthritis, Lupus and Intervertebral Disc Disease: A Systematic Review
Pharmaceuticals 2022, 15(12), 1544; https://doi.org/10.3390/ph15121544 - 12 Dec 2022
Cited by 2 | Viewed by 1709
Abstract
Progranulin (PGRN) is a glycoprotein formed by 593 amino acids encoded by the GRN gene. It has an important role in immunity and inflammatory response, as well as in tissue recovery. Its role in musculoskeletal inflammatory diseases such as rheumatoid arthritis (RA), systemic [...] Read more.
Progranulin (PGRN) is a glycoprotein formed by 593 amino acids encoded by the GRN gene. It has an important role in immunity and inflammatory response, as well as in tissue recovery. Its role in musculoskeletal inflammatory diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and intervertebral disc degeneration disease (IVDD), is, nowadays, an important target to investigate. The objective of this review is to systematically sum up all the recent findings concerning PGRN as a target in the development and resolution of the inflammatory diseases. PubMed was examined with the terms combinations (Progranulin) AND (Lupus Erythematosus, Systemic), (Progranulin) AND (Arthritis, Rheumatoid), and (Progranulin) AND (Intervertebral Disc Degeneration). PubMed was examined with the terms combinations (Atsttrin) AND (Lupus Erythematosus, Systemic), (Atsttrin) AND (Arthritis, Rheumatoid), and (Atsttrin) AND (Intervertebral Disc Degeneration). Moreover, research through Web of Science was performed searching the same items. The inclusion criteria were: studies whose main topic were progranulin, or atsttrin, with emphasis on the three selected diseases. On the other hand, the exclusion criteria were studies that only focused on diseases not related to RA, lupus or IVDD, in addition to the previous published literature reviews. Since few results were obtained, we did not filter by year. The records assessed for eligibility were 23, including all the studies with the information in state of art of progranulin and its capability to be a potential target or treatment for each one of the selected diseases. As these results are descriptive and not clinical trials, we did not perform risk of bias methods. Within these results, many studies have shown an anti-inflammatory activity of PGRN in RA. PGRN levels in serum and synovial fluids in RA patients were reported higher than controls. On the other hand, serum levels were directly correlated with SLE disease activity index, suggesting an important role of PGRN as a player in the progression of inflammatory diseases and a therapeutical approach for the recovery. This review has some limitations due to the small number of studies in this regard; therefore, we highlight the importance and the necessity of further investigation. No external funding was implicated in this systematical review. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Immune Disease)
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