Histamine plays an important role in the pathophysiological mechanism of allergic diseases, and the antagonistic effect of histamine has become an important way to study anti-allergic drugs, wherein the anti-allergic drugs used in clinical practice are mainly H1 receptor antagonists. Currently, there are many varieties of H1 receptor antagonists in clinical applications, which can be divided into ethylenediamine antagonists, amino ether antagonists, propylamine antagonists, tricyclic antagonists, piperazine antagonists and piperidine antagonists depending on their chemical structures. This article mainly reviews the research progress of allergic reactions with histamine H1 receptor antagonists and expounds the important aspects of the design and synthesis of various new compounds.Histamine is formed by the decarboxylation of histidine catalyzed by enzymes. It is an endogenous biologically active substance involved in multiple complex physiological processes as an important chemical transmitter. Histamine receptors have four subtypes, H Histamine is formed by the decarboxylation of histidine catalyzed by enzymes. It is an endogenous biologically active substance involved in multiple complex physiological processes as an important chemical transmitter. Histamine is released under endogenous and exogenous stimulations and interacts with receptors. Histamine receptors have four subtypes, H1, H2, H3 and H4, all of which are G protein coupling receptors (GPCRs) with different physiological functions.10–13Histamine, chemically known as 4(5)-(2-aminoethyl)imidazole, is an endogenous biologically active substance involved in multiple complex physiological processes as an important chemical transmitter. Histamine is formed by the decarboxylation of histidine catalyzed by enzymes.1 receptors are distributed in endothelial cells, smooth muscle, adrenal medulla, heart and central nervous system. Exogenous antigens can cause anaphylaxis, combine with antibody immunoglobulin on target cell mast cell nucleus and granulocyte, change the function of target cell membrane, release histamine and other allergic media, and make histamine distribute in H1 receptor function of tissues and organs.14 After the activation of the H1 receptor, phosphatidase C is activated through G proteins, which promotes the increase in Ca2+ concentration, thereby increasing the vasodilation and capillary permeability, leading to plasma exudation, local tissue redness and swelling, and allergic symptoms of bronchial and gastrointestinal smooth muscle contraction.15–17 H2 receptors are distributed in gastric wall cells, vascular smooth muscles, heart and central nervous system. H2 receptor stimulation could promote gastric acid secretion, stimulate the heart and inhibit uterine contraction.18 Histamine, acetylcholine and gastrin receptors could be found on the surface of gastric mucosa cells. When the corresponding ligands interact with these receptors, they could activate the secretion of gastric acid. The H3 receptor is located in the central and peripheral nerve endings of the presynaptic membrane, and it could function as their receptor, inhibiting histamine release and synthesis.19–23 H3, as a different receptor, controls the release of other neurotransmitters. H3 receptor has important physiological functions, such as cardiac function, gastric acid secretion, anaphylaxis, sleep wake cycle control, cognition and memory, convulsion, diarrhea or reducing gastric acid secretion.24–30 The H4 receptor is only found in the small intestine, spleen, thyroid and immunocompetent cells. The H4 receptor is related to the regulation of immune functions, such as allergic reactions, asthma, cancer and other immune diseases.31–35H36–39 It could be caused by a variety of exogenous substances like allergens that include heterologous serum (such as tetanus antitoxin), certain animal proteins , bacteria, viruses, parasites, animal fur, plant pollen, dust mites in the air, and chemicals and drugs. Allergens could stimulate human B cells to produce immunoglobulin E, which combines with antibodies on human mast cells and sensitized cells, damages the cell membrane and leads to degranulation, and releases histamine, 5-hydroxytryptamine, leukotrienes, bradykinin and other active substances in the granules.40–46 The allergic reaction can manifest as skin redness and swelling, rash, itching, patches as well as allergic rhinitis, bronchial asthma, laryngeal edema and other symptoms. The clinical manifestations of anaphylaxis include decreased blood pressure, increased heart rate, pale skin, edema, and shock and even death in severe cases.47–51Anaphylaxis is an allergic disease that occurs when the body is exposed to specific allergens.52–55 Currently, the anti-allergic drugs used in clinical practice are mainly H1 receptor antagonists.56–60 H1 receptor antagonists were first reported in 1933 to relieve bronchospasm in animals induced by the inhalation of excessive histamine. Since the 1930s, scientists around the world have conducted a large number of structural modifications by using structure activity relationship (SAR) studies, and dozens of classic anti-allergy drugs have been listed for clinical use. In the history of drug development, they have been listed as the first generation H1 receptor antagonists. The second generation H1 receptor antagonists were marketed after the 1980s. These compounds have characteristics of high selectivity towards the H1 receptor, no sedation effect, separation of the antihistamine effect from the central nervous system and fewer side effects. They were known as non-sedation H1 receptor antagonists.61 The third generation H1 receptor antagonists are active optical isomers of the second generation H1 receptor antagonists or their metabolites. This generation has greater safety and lower toxic and side effects; thus, their application scope has been expanding in recent years.62–65 Currently, there are many varieties of H1 receptor antagonists in clinical application, which can be divided into ethylenediamine antagonists, amino ether antagonists, propylamine antagonists, tricyclic antagonists, piperazine antagonists and piperidine antagonists depending on their chemical structures.66–70 This article mainly reviews the research progress of allergic reactions with histamine H1 receptor antagonists (2011–2017), including the research on the design and synthesis of various new compounds.Histamine plays an important role in the pathophysiological mechanism of allergic diseases, and the antagonistic effect of histamine has become an important way to study anti-allergic drugs.2.et al. have reported a series of compounds based on loratadine that have both H1 receptor antagonist activity and 5-lipoxygenase inhibitory activity. Liu et al. successfully synthesized a series of loratadine derivatives with C-alkyl butenamide, and found that several of them were able to inhibit histamine induction. Yue W. et al.71 further optimized the structure of loratadine based on previous studies, and designed and synthesized a series of loratadine derivatives . However, it could lead to arrhythmias with acquired long QT syndrome, which includes torsades DE pointes, and sudden death due to the blockage of rapidly activated delayed rectification K+ current IKr and its underlying human ether-a-gogo related gene (hERG) K+ channel (IC50 = 0.9 nmol L−1). In order to find a new type of H1 receptor antagonist with low hERG blocking activity, Xiao J. et al.72 carried out systematic structural modification based on astemizole -4 and 5-tetramethylene thiophenes (compounds 3a–c) were synthesized in three steps by adapting the Gewald reaction. Afterwards, compounds 3a–c were diazotized to yield a series of 3-substituted amino-5,6-tetramethylene thieno-triazin-4(3H)-ones (compounds 4a–c). In this reaction, the starting compounds 2-amino-3-(N-substitutes carboxamido)-4 and 5-tetramethylene thiophenes (compounds 3a–c) react with NaNO2 in the presence of HCl yielding the respective triazine-4-ones. The synthetic route was characterized by mild reaction conditions, simple operation and cheap and easy to obtain reagents.Numerous uses of substituted triazines have been reported, such as anti-inflammatory, analgesic activity, purine confrontation, antitumoral and trypanocidal activity. Very little studies have been conducted on heterocyclic compounds such as 1, 2, 3-triazine and other triazines, this kind of compounds and similarity based on the structure of these compounds and other triazines like 1,2,4-triazine and 1,3,5-triazin. It was found that 1,2,3-triazine derivatives possess prostaglandin inhibition property, analgesic, anti-inflammatory and antihistaminic properties. Gollapalle L. ynthesis , the staH-pyrazol-1-yl)piperidin-1-yl)-1H-benzo[d]imidazole -1-(4-fluoro benzyl)-2-(1-methylpiperidine-3-acyl)-1H-benzimidazole  studies, determining that a change in the direction of the basic center in lead compound 2 was a key step in establishing the required H1 affinity and selectivity. Based on this discovery, Satheesh B. et al. designed and synthesized a series of H1-antihistamines . Introduction of the appropriate arene-containing moiety R1 was accomplished by alkylation of compound 3. The final step included the alkylation or reductive amination and the removal of Boc to obtain the final product . Further separation of enantiomers was achieved by chiral SFC when chiral acids were not used for the synthesis of benzimidazole. The synthetic route was characterized by mild reaction conditions, cheap and easy to obtain reagents, relatively high yield and good versatility.1-(4-Fluorobenzyl)-2-methylthio)methyl)-5-aryl-1,3,4-oxadiazoles (compound 4) and 2-((bis(trimethylsilyl)-methylsulfonyl) methyl)-5-aryl-1,3,4-oxadiazoles (compound 5) were synthesized by the reaction of compound 2/compound 3 with benzohydrazides in the presence of phosphorus oxychloride. The synthetic route has high reaction yields (79% to 88%), mild reaction conditions and conventional reagents.Silicon substitution (C/Si exchange) has attracted extensive attention in drug-like scaffold materials due to its unique biological activity, chemical reactivity and physical and chemical properties compared with the parent carbon compounds. 1,3,4-Oxadiazole derivatives have been reported as promising antiallergic drugs. Dinneswara R. ompounds  in a stuet al.76 found that the extract of Kujin has inhibited the up-regulation of H1R and IL-4 gene expression in rats sensitized by TDI, and confirmed (R)-maackiain as the main anti-allergy component of Kujin. (R)-Maackiain is found in low concentration in plants, which made it difficult to extract; so, it was obtained by chemical synthesis (ii) dichloride [PdCl2(PhCN)2] was prepared as reported previously. The synthesis of (R)-3-benzylmaackiain was performed as follows. To a solution of 7-benzyloxy-2H-1-benzopyran and 2-bromo-4,5-methylene dioxyphenyl in anhydrous DMF suspended in potassium acetate, PdCl2(PhCN)2 was added in one portion. The resulting suspension was stirred at 40 °C. After 24 h, the addition of PdCl2(PhCN)2 to the resulting reaction mixture was carried out. The latest procedure was repeated after 48 h and 72 h. Finally, the resulting mixture was stirred for additional 24 h. This synthetic route achieved the first chemical synthesis of (R)-maackiain, but it had disadvantages, such as long synthetic route, low yield, the use of precious metal Pd in the synthesis process, and long overall reaction time, which need to be further optimized.Over the years, Kujin has been widely used to treat allergic diseases and many others. Phytochemical studies have shown that it contains quinolizidine, alkaloids, flavonoids, and triterpenoids. Kujin and its active components have many biological properties, such as anti-inflammatory, antiasthmatic, antitumor and antibacterial. Hiroyuki M. ynthesis . In the et al. proved that quinazolinone derivatives have strong antihistamine activity with alow sedative effect. Manavalan G. et al.77 designed and synthesized a series of 1-substituted-4-(3-chlorophenyl)-triazoloquinazolin-5(4H)-ones 2CH3, –CH2Cl) to obtain compounds with improved biological activity. In the process of synthesis, compound 3 (3-(3-chlorophenyl)-2-thioxo-quinazolin-4(3H)-one) was belonged to the key intermediate. Dithiocarbamic acid methyl ester was prepared with 3-chloro aniline, carbon disulfide and sodium hydroxide in dimethyl sulfoxide, then methylated with dimethyl sulfate, which was reacted to produce the required compound 4 in ethanol has a good yield (86%). Compound 3 was dissolved in a solution of 2% ethanol sodium hydroxide, stirred at room temperature, and methylated with dimethyl sulfate to give 3-(3-chlorophenyl)-2-(methylthio) quinazolin-4(3H)-one (compound 4). The nucleophilic displacement of the methylthio group of compound 4 with hydrazine hydrate was carried out using ethanol as the solvent, affording compound 5 (3-(3-chlorophenyl)2-hydrazinyl-quinazolin-4(3H)-one). Finally, the compound 5 with a variety of one carbon donors such as acetic acid, propionic acid, formic acid, butyric acid and chloroacetyl chloride under refluxing provided 1-substituted-4-(3-chlorophenyl)-triazolo quinazolin-5(4H)-ones (compounds 6a–e). The synthetic route has high reaction yield (80% to 85%), mild reaction conditions and uses conventional reagents.Quinazolinones have a wide range of biological and pharmacological effects, such as analgesic, anti-inflammatory, antifungal, antiviral and antihistamine activities. Veerachamy A. 4H)-ones  based on1 receptor antagonists for the treatment of allergic reactions. These compounds bind to both H1 and H3 receptors. Based on the structure optimization of phthalazinone, Panayiotis A. et al.78 introduced different substituents, and designed and synthesized a series of novel phthalazinone amide compounds  phthalimide to give compound 2 (yield 87%), and then, deprotected using hydrazine to afford compound 3 with 77% yield. Afterwards, compound 3 was acylated with a variety of carboxylic acids in the presence of TBTU to give compounds 4d, 4f, 4g and 4h, or with the corresponding acid chloride to give compounds 4a, 4b, 4c and 4e. Alkylation of compound 1 with 2,2,2-trifluoro-N-(2-iodoethyl)acetamide resulted in trifluoroacetamide (compound 5), which was alkylated with iodomethane and deprotected, to obtain the secondary amine (compound 6). The latter was acylated in the presence of 4-methoxybutanoic acid and TBTU to obtain tertiary amide (compound 7g). Compound 1 reacted with ethyl 4-bromobutyrate to give compound 8, which was converted to a carboxylic acid 9, and finally, transformed into amides 10b and 10f. The synthetic route has good versatility and uses conventional reagents, but the partial yield was low (yield 29%), which should be further improved.The compounds containing the phthalazinone scaffold were obtained through structural optimization and subsequently used as histamine Hompounds . In the 1 antagonists are competitive drugs that inhibit histamine action on tissues containing H1. Fexofenadine (2-[4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)piperidino]butyl]phenyl]-2-methylpropanoic acid)   is a selcompound , and desarbazide . Herein,3.1 receptor antagonists. This article mainly reviews the research progress of allergic reactions with histamine H1 receptor antagonists and expounds the important aspects of design, synthesis and biological activity of various new compounds. These novel H1 receptor antagonists, with regards to their chemical structure design, are mostly obtained by optimizing the structure of the reported compounds with antiallergic activity (including natural products, 1 receptor antagonists in the future will tend to optimize the structure of natural products as lead compounds. In the process of synthesis, most synthetic routes use conventional solvent reaction to synthesize target compounds. These synthetic routes were characterized by simple operation, mild reaction conditions, cheap reagents and a good overall yield, which will provide certain foundation for future industrialization. However, some synthetic routes use multiple catalysts or precious metals (such as Pd, Histamine plays an important role in the pathophysiological mechanism of allergic diseases, and the antagonistic effect of histamine has become an important way to study anti-allergic drugs. The anti-allergic drugs used in clinical practice were mainly HThe authors declare that they have no conflict of interest.


Correction to: Applied Biochemistry and Biotechnology10.1007/s12010-021-03732-4Yongmei Lan and Jin Zhao contributed equally.They are corresponding authors.1,2, Linghong Zhu3, Yanqing Ma1, Bo Wang3, Caihong Ci1, Jingni Zhang3, Yunsong Zhou1,Chunjiang Dou1, Qiaoling Gu1,Yan An1, Yongmei Lan1*, Jin Zhao1,4*Zilong ZhangThe original article has been corrected. The correct author position and new acknowledgements should be:AcknowledgementsStudy on the relationship between ethnic characteristics, environmental factors, and disease spectrum of Gansu endemic minorities, the project of cultivating innovative team of Northwest University for Nationalities funded by the basic scientific research business of central universities (project number 31920190030), and the key project of Northwest University for Nationalities funded by the basic scientific research business of central universities.Health and Family Planning Guidance Project of Qinghai Health and Family Planning Commission 2019 (Project No. 2019-wjzdx-41).Cell culture innovation team. Project source: school-level innovation team construction project in 2020 .


This premise supports the rationale that renalase's timely supplementation may prove valuable for pathologic conditions, such as cytokine storm and related acute respiratory distress syndrome. Therefore, the aim for this review is to acknowledge the scientific rationale for renalase employment in the experimental model of COVID-19, targeting the acute phase mechanisms and halting fibrosis progression, based on its proposed molecular pathways. Novel therapies for COVID-19 seek to exploit renalase's multiple and distinctive cytoprotective mechanisms; therefore, this review should be acknowledged as the thorough groundwork for subsequent research of renalase's employment in the experimental models of COVID-19.The hallmark of the coronavirus disease 2019 (COVID-19) pathophysiology was reported to be an inappropriate and uncontrolled immune response, evidenced by activated macrophages, and a robust surge of proinflammatory cytokines, followed by the release of reactive oxygen species, that synergistically result in acute respiratory distress syndrome, fibroproliferative lung response, and possibly even death. For these reasons, all identified risk factors and pathophysiological processes of COVID-19, which are feasible for the prevention and treatment, should be addressed in a timely manner. Accordingly, the evolving anti-inflammatory and antifibrotic therapy for severe COVID-19 and hindering post-COVID-19 fibrosis development should be comprehensively investigated. Experimental evidence indicates that renalase, a novel amino-oxidase, derived from the kidneys, exhibits remarkable organ protection, robustly addressing the most powerful pathways of cell trauma: inflammation and oxidative stress, necrosis, and apoptosis. As demonstrated, systemic renalase administration also significantly alleviates experimentally induced organ fibrosis and prevents adverse remodeling. The recognition that renalase exerts cytoprotection  The coronavirus disease 2019 (COVID-19), from its outbreak in China, in December 2019, until May 2022, according to the World Health Organization (WHO) [At the time of writing, expertise on COVID-19 advances daily, and the global vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has begun to be widely accepted , 4. TherNevertheless, as explained elsewhere, COVID-19 clinical presentations may be asymptomatic or mild cases , whereasin vivo and in vitro) demonstrated pleiotropy to rapidly and effectively alleviate inflammation, oxidative stress, apoptosis, necrosis, and organ fibrosis [Additionally, a novel protein, renalase, was identified. The most recent evidence of renalase's cellular mechanisms, pathophysiology, possible therapeutic validity and its experimentally  , 4, 9 maβ pathways [β upregulation appears to be indirect, via angiotensin II, knowing that coronaviruses downregulate angiotensin-converting enzyme (ACE) 2 and diminish angiotensin II clearance in the lungs [Finally, the coronavirus itself presumably possesses profibrotic characteristics. Nucleocapsid of SARS-CoV was documented to directly promote TGF-pathways , 63; thepathways , also enhe lungs .β (TGF-β) signaling pathways, including both canonical (Smad-dependent) and noncanonical phosphatidylinositide 3 kinase, protein kinase B (PI3K/Akt), extracellular signal-regulated kinases 1 and 2 (ERK 1/2), and p38 mitogen-activated protein kinase (MAPK) are majorly attributed to fibroproliferation; therefore, a pharmacological targeting of these pathways should prove effective [Taken together, it is meaningful to expect post-COVID fibrosis development. Owing to their pathological characteristics, fibrotic changes are unlikely to be resolved, particularly in COVID-19 patients who were confronted with severe clinical forms and a longer duration of the disease or who potentially have an underlying lung disease . Therefoffective . In thisffective , 36–38.Renalase, a relatively “young” flavoprotein, was introduced into the scientific world in 2005, and was identified as the flavin adenine dinucleotide (FAD)-nicotinamide adenine dinucleotide (NADH) oxidase –70. The de novo renalase synthesis and secretion [via a superoxide (O2–)-dependent mechanism, with nicotinamide adenine dinucleotide phosphate (NAD(P)H) as a co-factor [β-NAD(P)H to metabolically available, noninhibitory β-NAD(P)H form [κβ, hypoxia-inducible factor (HIF)-1α, tumor necrosis factor (TNF)-α, Kruppel family member zinc binding protein 8 (ZBP89), and specificity protein (Sp)1, several of which are related to inflammatory response [2+-ATPase 4b (PMCA4b) [κβ, extracellular signal-regulated kinase 1 and 2 (ERK1/2), p38, cyclic adenosine monophosphate (cAMP), phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), and Ca2+. The unique conclusion of all research is that renalase, after triggering its receptor (PMCA4b), sets in motion several molecular pathways, which aim to modulate “renalase-dependent” signaling, in order to exert pleiotropic, presumably context- and time-dependent actions, towards cytoprotection, and will be comprehensively discussed throughout this review. Finally, notable tissue distribution, substantial circulating forms, and remote mechanisms of action indicate systemic function for renalase, supporting the hypothesis of its important role in an organ protection following injury, and presumably in COVID-19.The human renalase gene is located on chromosome 10, and it contains 11 exons , 67. Theecretion . Howevero-factor , 68, 78.P)H form . Outstanresponse . Upon up(PMCA4b) , 43, 70,κβ, provoking a surge of proinflammatory cytokines  and interferon regulatory factors (IRFs) that induce interferon expression [The basic pathophysiology of COVID-19 may be summarized as follows: SARS-CoV-2, after entering the respiratory cells throughout the association of its protein S and a angiotensin-converting enzyme (ACE)2, as a receptor, expressed in different tissues  [pression –14. At tpression –14, resupression , 12, folpression . Taken tpression , includiIn line with these findings, a growing body of research evidenced that renalase confers impressive cytoprotective traits, in a manner far more complex than simply being a catalytic enzyme, offering a possibility that its supplementation during the course of various diseases, and hypothetically COVID-19, may provide some beneficial, anti-inflammatory, and antioxidant effects.α, demonstrating a significant and positive correlation with HIF-1α expression in the setting of ischemic myocardial damage [α/renalase axis presumably functions with the purpose of compensation, and/or adaptation to a low oxygen environment, supporting the possible link of renalase and COVID-19-related ARDS. However, HIF-1α represents a ubiquitous transcriptional factor that is a key regulator of cellular actions as a response to hypoxia, whose activation results in the transcription of different genes, with renalase being among them. The same research reported that in the experimental model of an ischemic cardiac injury, premedication with recombinant renalase resulted in diminished myocardial injury  and in significantly improved heart function. An appealing theory of renalase's pathophysiology was offered, presuming that its antihypoxic traits rely on renalase's capability for energy metabolism regulation during hypoxia, particularly in modulation of nicotinamide adenine dinucleotide (NAD+) and ATP levels in cells [in vitro and in vivo, in a similar hypoxic milieu, of an experimental model of ischemic kidney injury [α regulation at transcriptional level, presumably for reasons of delayed cytoprotection in the hypoxia.Notably, the discovery that the promoter region of the renalase gene contains four plausible targets for hypoxia-inducible factor (HIF)-1l damage , led to l damage , 28, 35.in cells . Similary injury . Particuα activation occurs early during the course of the disease, initiating a few meaningful pathways [α signalization results in the activation of innate immune cells, leading to increased cytokine production, and tissue macrophage accumulation, while the second mechanism proposes involvement of endothelial cells, followed by increased expression of vascular endothelial growth factor and integrins, leading to increased vascular permeability and subsequent neutrophils accumulation [α is greatly involved in the cytokine storm drive, and it is reasonable to believe that, in a similar manner, it induces renalase transcription, aiming to compensate for hypoxia, and maybe even to control or mediate possible detrimental effects of proinflammatory stimuli, and leukocytic lung accumulation, induced by HIF-1α.These observations may be of a particular interest for this current pandemic, knowing that hypoxia represents initial pathophysiological phenomenon during COVID-19, and is attributed to all clinical forms of the disease . Howeverpathways –83. The mulation –83. Takeα, the other crucial transcriptional factor for renalase gene expression was discovered to be a nuclear factor (NF)-κβ, yet again confirming that renalase may have a prominent role in inflammatory, and oxidative mechanisms modulation [κβ functions as a powerful regulator of inflammatory and antiapoptotic gene expression, and is commonly activated upon proinflammatory signals, such as cytokines, antigens, and bacterial products, and hypoxia, in order to inhibit apoptosis, and to promote cell survival [κβ evokes the transcription of proinflammatory cytokines, adhesion molecules, and enzymes involved in inflammation that, as evidenced, may be renalase [α-adrenergic receptors in the proximal tubular epithelial cells, resulting in the NF-κβ activation and subsequent renalase secretion [via the same α1-adrenergic receptors' stimulation, through p38 MAPK and NF-κβ pathways [κβ, and signal transducer and activator of transcription 3 (STAT3), to amplify the actions of IL-6, in order to further induce numerous proinflammatory cytokines, including IL-6 and monocyte chemoattractant protein (MCP)-1 [κβ and STAT3) induce renalase transcription, most likely aiming to control, and even suppress inflammation, as STAT3 was also recently evidenced as a transcriptional factor for renalase [α/renalase axis, in the context of renalase being a mediator of inflammation. Presumably, in the conditions of pathologic hyperinflammation, as presented in the cytokine storm, HIF-1α, IL-6, and renalase are all supposed to participate significantly, but have never been linked before in such a context. The recognition of HIF-1α and IL-6, as being important pathogenetic factors in COVID-19, gives renalase a potential, yet unrecognized, role in COVID-19. Finally, pharmacological suppression of cytokines during hyperinflammatory response may increase the risk of secondary infection [Besides HIF-1dulation , 32, 73,survival . At the renalase , 32, 73.ecretion . Similarpathways , so it mpathways , 70, 86. (MCP)-1 . It may nfection , whereasnfection , 88. Mornfection . In thisα, a cytokine greatly involved in the modulation of inflammation, infection, apoptosis, and acute organ injury is also evidenced to be responsible for renalase upregulation [α from the injured tissues into the circulation, resulting in activation of NF-κβ and subsequent renalase secretion. In line with these factors, pharmacological inhibition of both, TNF-α (Humira) and NF-κβ , signaling pathways significantly hinders renalase expression [α may cause adverse effects through its inadequate and inappropriate actions, as being one of the most important cytokines during the cytokine storm, as described above. However, this particular research [α/NF-κβ/renalase axis exhibits favorable outcomes, summarized as reduced cell cytotoxicity , and apoptosis (measured as decreased caspase-3 activity), a phenomenon that may be of a great advantage in COVID-19. It was recently confirmed that renalase is upregulated following stress signals, such as experimental fasting, aiming to protect intestinal cells from injury. Increased small intestinal renalase expression was observed following NF-κβ p65 upregulation [α-adrenergic receptors expressed on leukocytes [In addition to the aforesaid, TNF-gulation . Indeed,pression . Moreoveresearch  confirmegulation , furtherukocytes . Knowingβ, IL-6, and TNF-α [These understandings may be finally underlined with the most recent results of the pioneer studies of renalase's role in the SARS-CoV-2-related pandemic and interpreted through the context of the aforementioned postulations –92. It wnd TNF-α . At the nd TNF-α . Its addnd TNF-α  further nd TNF-α . MoreoveTaken together, regarding the pathophysiology of COVID-19, decreased renalase plasma levels may be a relevant pathogenic factor (or a biomarker) resulting in (or predicting) a poor outcome, or may be relevant to guide patients' management, and therapeutic approach. These observations warrant much-needed research in patients with severe COVID-19, in analyzing whether renalase administration may probe the roles of proinflammatory cytokines, thus silencing inflammatory cascade in the severe COVID-19, to effectively reduce acute disease severity, as demonstrated in preclinical models.in vitro, results in a rapid increase of phosphorylated ERK1/2, p38, and PI3K/Akt, while downregulating c-Jun N-terminal kinases (JNK) [via renalase supplementation has been proven to be protective [Renalase-dependent cell signaling may also be debated in the context of COVID-19, since the triggering of renalase receptor, PMCA4b , 25, in es (JNK) , 70. Actes (JNK) , 76, 93.es (JNK) . It is bes (JNK) . Moreovees (JNK) , providiotective , 25, wheotective , 34, 36,κβ and HIF-1α, which are evidenced transcriptional factors for renalase expression [Increasing evidence supports the hypothesis that exacerbated reactive oxygen species (ROS) production acting synergistically with the deterioration of antioxidant activity represents a notable mechanism in the pathophysiology of SARS-CoV-2-related disease, as well as in the progression of the respiratory failure, causing lung damage, and eventually death , 96, 97.pression , 70, 86,pression , 16, clain vivo, demonstrated that, beside catecholamine infusion that promptly activates circulating forms of renalase [in vivo, renalase antioxidant properties in the small intestine [κβ p65 activation, whereas at the same time, renalase evidenced positive correlation with the degree of oxidative stress, namely, with increased markers of lipid peroxidation and carbonylated proteins. The upregulation of p65 promotes antioxidant gene expression in line with renalase for maintenance of antioxidative activity. A very appealing concept was established by observing that renalase was more uniformly expressed in the ileum compared to the jejunum. Nevertheless, the ileum represents a part of intestine that is specifically included in immunity, rich in intestinal bacteria that likely make the response to oxidative stress sensitive, underpinning renalase as the final defense tool for oxidative stress cell protection, resembling the function of glutathione peroxidase [2O2 , concentration was established, including the incubation time period in the culture of the hepatocellular carcinoma cell line subjected to oxidative damage. Such an outcome may be attributed to renalase's powerful and prompt responsiveness to a burst of ROS, whereas renalase feedback was confirmed to be dependent upon the intensity and duration of the oxidative injury [2O2 is considered to be a stable and milder form of reactive oxygen species, but may be easily converted to hydroxyl radicals, more reactive and more toxic forms of ROS [in vitro antioxidants preincubation superoxide dismutase (SOD) and catalase (CAT), the same antioxidants' intraperitoneal preinjection in vivo renalase cell expression was significantly mitigated, implying that renalase may be successfully abolished by antioxidative therapy. Moreover, serum levels of the liver enzymes, indicating necrosis of the hepatocytes , and serum renalase positively correlated, whereas all concentrations significantly decreased when antioxidant therapy (SOD and CAD) was administered. Renalase, owing to its prompt reaction to oxidative stress, warrants primacy in becoming a marker for the severity of oxidative tissue injury and for assessment of the effects of applied antioxidant therapy [in vivo, and, in vitro, in liver ischemic injury. Renalase was validated as directly mitigating cellular and mitochondrial ROS production, lessened malondialdehyde (MDA) formation, and boosted SOD activity and glutathione (GSH) levels [via activation of sirtuin (SIRT)1. For better clarification of these premises, SIRT1 is known to be the NAD+-dependent type III deacetylase that is notably involved in cell survival and metabolic homeostasis [κβ, among other downstream targets, for the management of inflammation, oxidative stress, and apoptosis [Nevertheless, studies in rats, renalase , renalasrenalase , gave suntestine . Nonetheroxidase . Similarroxidase . Neverthe injury . Nonethes of ROS . Besides therapy . Related therapy , conside) levels . By impr) levels . Indeed,) levels . A notabeostasis , 103. Inpoptosis , 103. Th+ levels, and cellular redox metabolism [+/NADH ratio within the cells. At the same time, it was discovered that renalase functions as an oxidase/anomerase, utilizing molecular oxygen for conversion of α-NAD(p)H to β-NAD+ [+) to reduced (NADH) nicotinamide adenine dinucleotide in the damaged tissue [+ in energy metabolism and electron transfer reactions [+ may upgrade SIRT1 activity [+ possess essential function in the positive regulation of SIRT1 [+ [+ functions as a receptor in adhesion and signaling pathways, whereas both NAD+ and NADH have relevant protective roles in processes, such as oxidative stress and mitochondrial dysregulation, and improve the function of NAD+-dependent sirtuins [One of the first experimental models while testing the hypothesis of renalase's antioxidant properties postulated a few theories  that wertabolism . Nevertho β-NAD+ , which ao β-NAD+ , 24. Moreactions , 106, whactivity , 105. Itof SIRT1 , 105. AcSIRT1 [+ , 24. Mor+ are enhanced through its endogenous synthesis [via renalase enhanced secretion and/or administration. In the opposite setting, decreased NAD+/NADH ratio favors organ injury in a low oxygen environment, implying that the same mechanism of injury may be, at least in part, responsible for hypoxia-induced lung damage during COVID-19. Accordingly, a very appealing discovery of unbalanced p53/SIRT1 axis and its impact to lymphocyte homeostasis  in severe acute respiratory syndrome SARS-CoV-2-related infection was recently offered [+ [In line with this, pronounced biological actions of NADynthesis  and purp offered . SIRT1 e offered , offerinfered [+  for SIRTfered [+ .α, monocyte chemoattractive protein (MCP)-1, and macrophage inflammatory protein (MIP)-2, all markers of systemic inflammation, suggesting that renalase most likely rises to counteract proinflammatory cascade, therefore exerting anti-inflammatory effects [in vitro and in vivo after toxic kidney injury [α levels, and MCP-1 expression, as well as reduced macrophages infiltration. Additionally, kidney function ameliorated, validated by restored serum concentrations of blood urea nitrogen and creatinine, whereas pathohistological changes  were rescued. The same observations were confirmed in vitro, as renalase preconditioning decreased ROS expression and caspase-3 levels in the cell culture, once again proving that renalase exerts antioxidation, anti-inflammation, and antiapoptosis, and that may be valuable treatment in conditions related to this deleterious phenomenon, such as COVID-19. Additionally, renalase knockout animals had a significant elevation of cathecholamine plasma levels [α1 and α2, expressed abundantly on numerous inflammatory cells [α1 receptor stimulation results in increased proinflammatory cytokine production in circulating monocytes and macrophages [Similar renalase antioxidative traits were evidenced in the related research of renal ischemic injury , likely  effects . Renalasy injury . In addia levels  that mayry cells , 109, corophages , 109; throphages . Moreoverophages , finallyvia various mechanisms, with antiapoptotic mediation being significantly expressed. As previously mentioned, renalase's modulation of apoptosis occurs through the augmentation of Bcl-2 expression, and hindering of caspase activation [in vitro, promoted myocardial cells apoptosis and necrosis during an ischemic myocardial injury, whereas its administration significantly minimized the consequences of ischemia, including cardiomyocytes apoptosis [in vitro and in vivo reduces clinical perils by the reduction of ROS, inflammation, apoptosis, necrosis, and toxic catecholamine effects, which may be a brand new approach to battle COVID-19-induced cytokine storm and its detrimental consequences.Besides the reactive oxygen species formation, apoptosis was also confirmed to be one of the mechanisms for host invasion by SARS-CoV-2. However, SARS-CoV-2-encoded accessory protein, designated as ORF3a, was demonstrated to induce apoptosis, measured as activated caspase-3, a marker of caspase-dependent apoptosis , 111. Cotivation , 30, 32,tivation . Finallypoptosis . A revieα upregulation [β and ROS, as evidenced [As stated, the pathophysiological hallmark of the SARS-CoV-2-related infection represents extreme and rapid activation of the innate immune response –14, 113,gulation , and undgulation  mediatesgulation  and is egulation , 26, 42 videnced , the vervidenced –70, so tα, monocyte chemoattractive protein (MCP)-1, and macrophage inflammatory protein (MIP)-2, therefore a substantial renal [in vivo induced acute pancreatitis [vice versa. A detailed summary of discussed research is presented in As previously stated, renalase knockout mice demonstrate a significantly increased expression of TNF-al renal , 22, 23 al renal . Accordial renal . Recognial renal  further reatitis . Based oreatitis . Whetherreatitis , 69, 70,reatitis , 118. Threatitis . In viewreatitis , it may reatitis , 42, basreatitis , and vicWhether renalase may fine-tune the stimuli for macrophages to acquire a specific functional profile (pro- and antifibrotic) in the pulmonary tissue, in the same manner as demonstrated in the kidney, and pancreatic tissue, may be a captivating goal for more in-depth profiling to identify the proper renalase to macrophages signaling in the state of fibroproliferation and will be discussed more in the final section.β1-mediated epithelial-mesenchymal transition and alleviation of its progression [A silent information regulator two proteins (sirtuins or SIRTs) are widely recognized as upregulators of various sets of proteins related to cells' prosurvival mechanisms –122, whigression –128; oxigression , both thgression , indicatvia regulation of the effectiveness of NF-κβ signaling [β of activated B-cells, providing anti-inflammation, which enable metabolic adjustment, survival, autophagy, and mitochondrial biogenesis; the actions required for cell survival [κβ-induced inflammatory responses [β, IL-6, and TNF-α, whereas downregulation of SIRT1 enhances replication of the viruses, causing an uncontrolled surge of proinflammatory cytokines [The SIRTs family constitutes several proteins (1-7), whereas the best characterized sirtuin, (SIRT) 1, was documented to be a pleiotropic nuclear protein, promoting anti-inflammatory actions, ignaling , and strignaling . Moreovesurvival –122, whiesponses . The othesponses , 134. Inesponses , implyinesponses , 134. Inesponses , once agesponses , 136. Upytokines , 138 in ytokines  that areytokines , 12, 13,ytokines . Given tytokines , 141.+-dependent protein deacetylases, sirtuins necessitate NAD+ for its activation [α-NADH converting it to β-NAD+ [via increasing levels of NAD+ [vice versa, considering that the lack of renalase significantly downregulates NAD+ activity [+ levels, and therefore, enhance SIRT1 activity, resulting in the deacetylation and modulation of the activity of SIRT1 downstream targets, particularly the peroxisome proliferator-activated receptor-γ coactivator 1α, the forkhead box O1, and O3 transcription factors [via SIRT1 activation, evidently through the elevation of NAD+ levels [+ levels [+ levels in older individuals, and in patients with comorbidities associated with severe COVID-19 symptoms, such as diabetes and cardiovascular disease, likely promotes the setting for detrimental cytokine storm [+-dependent enzymes, including SIRT1, presumably inhibit the production of viral progeny [+-dependent enzymes, such as members of the poly-ADP-ribose polymerases (PARPs) families, exhibit antiviral potential, whereas SARS-CoV-2 proteins induce hyperactivation of PARPs, followed by cellular NAD+ depletion [+, as evidenced, provide the proof of principle that renalase may be indirectly implicated in the modulation of sirtuins activities. In accordance with this feasibility, renalase was shown to protect against cisplatin-induced renal injury, by reducing mitochondrial fission and tubular epithelial cell apoptosis in a SIRT3-dependent manner, presumably via early MAPK signal activation [In line with what we have previously discussed, an appealing hypothesis was postulated that renalase's ability to improve mitochondrial function, and at the same time provide antioxidative action, was due to its capacity to increase the activity of sirtuins 1 and 3, as documented up until now. However, being a family of NADtivation , 120, aso β-NAD+ , so it m of NAD+ , 24, 42, factors , 120. Mo+ levels . This ma+ levels . Such unne storm . Accordi progeny , 142, su progeny , 143. Itepletion . These otivation , 25, 30.+ levels may control SIRTs-mediated events during coronavirus 2 infection that, as stated, appear to be compelling participants in both inflammatory and fibrotic stages of pulmonary fibrosis [via regulation of NAD+ intercellular levels, providing advantage for sitruins' defense properties, may prove highly relevant against SARS-CoV-2 infection [Taken together, it is reasonable to believe that renalase's ability to fine-tune pleiotropic proteins, SIRT1  and SIRTfibrosis –130. Thenfection . If veriin vitro, are also endorsed by the induction of autophagy via the silencing of the PI3K/Akt pathway signalization [Taking into consideration the previously provided hypothesis regarding the potential renalase/sirtuin axis, another tempting, but as of now, only a theoretical approach may be offered that renalase, by upgrading sirtuin activity, likely modulates the process of autophagy. Beyond sirtuins, another possible link between renalase and autophagy arises from the fact that modulation of the PI3K/Akt signaling network, evidenced as a renalase downstream signal , 25, 42,lization .For greater clarification of this hypothesis, it must be highlighted that autophagy represents a conserved and a highly complex, multiple-step process, involved in the degradation and recycling of intracellular components , 149. Itin vitro inhibition of the SARS-CoV-2 infection (154). This response is likely, at least in part, due to the activation of the NAD+-dependent deacetylases (sirtuins), whereas SIRT1, specifically, is evidenced as an mTOR-independent inducer of autophagy [in vitro and in vivo, likely induce and inhibit autophagy (and mitophagy), through the upregulation of different downstream signaling, as excessively reviewed elsewhere [in vivo, preserves mitochondrial function , and rescues mitochondrial network morphology, as evidenced by suppression of mitochondrial fission-related protein (Drp1) alteration, as stated [+ levels, followed by activation of SIRT1 [β [via autophagy, mitophagy, and cellular metabolism alteration, supports the concept of renalase's competence in modulating some regulatory points of autophagy, at least by sirtuin activation. The other potentially shared targets of both renalase and autophagy that may be argued in support of treatment for COVID-19 may be MAPKs pathways, particularly ERK/1/2 and JNK signalization. These signaling networks are being evidenced as renalase downstream signals [via the regulation of the Bcl-2-interacting protein (beclin 1) [in vitro promote substantial changes in the phosphorylation of ERK1/2 and PI3K/Akt pathways, mechanisms that essentially correspond to renalase pathophysiology [Within this context, it may be entirely possible that molecules modulating autophagy, at various levels, particularly regarding the multiple step biology, may be anticipated as a therapeutic solution for COVID-19 , 149. Asutophagy , 149. Inlsewhere , 154–158lsewhere . In addilsewhere . In thatSIRT1 [β , leadingSIRT1 [β , 115. Re signals , 42, 70,eclin 1) , and areeclin 1) . In regaysiology , 34, 36 Based upon the experimentally acquired knowledge on renalase pathophysiology, it may be hypothesized that renalase, sirtuins, and several types of downstream signaling , and autophagy share some common aspects, to a point that renalase may be hypothesized as being indirectly implicated as a key player for the control of autophagy. In addition, as vigorously argued throughout the review, renalase has been suggested as an essential player for the processes of inflammation and resolution, in settings that also encompass the process of autophagy . Such peβ pathway, and antifibrotic mediators, and remarkable differentiation of lung epithelial mesenchymal cells, and other cells into pulmonary fibroblasts [Pulmonary fibrosis is a highly heterogeneous pathological process and, among broad etiology factors, may be caused by viral infection. In the majority of patients, this process is refractory to therapeutical treatment; therefore, it is ultimately important to research new agents to prevent the initiation of lung fibrosis and disease progression , 16. Theroblasts –59. The roblasts .phox, p47phox, and p67phox), resulting in lessened glomerular hypertrophy and renal interstitial fibrosis [via inhibition of M1 macrophage polarization and promoting anti-inflammation by enhancing M2-like macrophage polarization, as discussed [α, IL-1β, IL-6, IL-12, IL-18, and IL-23) for neutrophils recruitment [κβ, STAT1, STAT3, IFN-γ regulatory factor, HIF-1α, and activator protein (AP)1 [α, NF-κβ, and STAT3 are documented to be transcription factors for renalase expression [β1 expression, finally emerging as liver fibrosis progression [via renalase supplementation. Albeit, theoretically very appealing, this hypothesis needs comprehensive experimental investigation before clinical employment.Notably, renalase supplementation reduces inflammatory drive in kidneys through downregulation of proinflammatory cytokine expression, and NADPH oxidase components 1 , 166. Ampression . The hypgression . Howevergression . This hyβ1-induced epithelial to mesenchymal transition (EMT) in proximal tubule epithelial cells, a pathological phenomenon that is widely recognized to be similarly involved in the development of lung fibrosis. It has to be outlined that the process of epithelial to mesenchymal transition (EMT) refers to a complex cellular process [via signalization upregulated by ROS, proinflammatory cytokines, including HIF-1α, TNF-α, and TGF-β1 [β is evidenced to be a key molecular inducer of the EMT molecular programming, through the activation of PI3K/Akt and MAPKs signalization [β1-induced EMT is obtained owing to renalase's capacity (in vitro) to lessen the expression of α-smooth muscle actin (α-SMA), fibronectin, and collagens (I and III), while the expression of E-cadherin was restored. However, renalase was, in vitro, confirmed to initiate the inhibition of TGF-β-mediated upregulation of α-SMA and downregulation of E-cadherin. In this context, TGF-β1-stimulated cells obtained higher levels of phospho-ERK1/2, which were reversed following adenoviral renalase supplementation. In a similar manner, in rats with diabetic nephrosclerosis [via the silencing of ERK1/2 signals, whereas a more recent study evidenced that recombinant renalase significantly alleviated pressure overload-induced fibrosis in the heart, being highly associated with p38 and ERK1/2 signaling [Furthermore, reports confirm that renalase supplementation, following renal injury, hindered the expression of the interstitial matrix components, and mitigated renal fibroproliferative response . It is e process , 169, dud TGF-β1 , 169. Wiclerosis , renalasignaling .α-SMA actin presence  [α-SMA, vimetin, and fibronectin) [β1 pathway [α-SMA, and fibronectin, and the suppression of alveolar epithelial to mesenchymal transition, through the inhibition of the ERK1/2 pathway. If proven that renalase exerts the same effects in lungs, likewise kidneys, it may remarkably improve the outcome of ARDS patients, regardless of its underlying cause. Within the context of renalase's remote roles, additional mechanisms of renalase's antifibrotic traits were identified [in vitro studies confirmed that ROS demonstrate a pivotal role in TGF-β-induced EMT, through the activation of MAPK (non-Smad) pathways in renal epithelial cells, leading to renal interstitial fibrosis [β1-induced EMT in bronchial epithelial cells, resulting in minimized pulmonary fibrosis [vice versa [Therefore, clear evidence exists that renalase mitigates renal interstitial fibrosis through the inhibition of the ERK1/2 signaling pathways . The desenalase) , these cenalase) , 16, 167enalase) , may equonectin) , 171–173entified , providifibrosis , and thafibrosis . The parfibrosis . In linece versa , 176. Hoce versa . These oce versa . The afoThe final consideration relating to the possible “duality” of renalase's actions implies that renalase most likely functions in a context- or time-dependent signaling , employing its impressive ability for context-related adjustments of the MAPK pathways , 34, 36.The COVID-19 pandemic represents a gargantuan health care, social, economic, and political burden in general, while its long-term consequences will seriously continue to challenge the entire community. For these reasons, all identified risk factors and pathophysiological processes of SARS-CoV-2-related disease, which are feasible for the prevention and treatment, should be addressed in a timely manner. Accordingly, the evolving anti-inflammatory and antifibrotic therapy for severe COVID-19 and hindering post-COVID-19 fibrosis development should be comprehensively investigated.α, IL-6, MCP-1, MIP-2, and TGF-β1) release, and ROS generation, an increase in antiapoptotic factors (Bcl-2), and prevention of caspase-3 activation, inflammasome silencing, increasing the intracellular concentration of NAD+, thereby sirtuins (1 and 3) activation, hence preserving mitochondrial biogenesis, and dynamics, epithelial to mesenchymal transition suppression, a decrease in the profibrotic markers expression , and interference with MAPKs signaling network. This review, based on the mounting quantities of published data, supports the hypothesis that exogenous renalase administration, presumably coupled with other COVID-19 protocol-approved drugs, may prove beneficial during COVID-19-related lung injury. Albeit that renalase expression was not investigated in pulmonary tissue, so far, its sustained plasma concentration, systemic behavior and multifaceted nature, various tissue distribution, similar triggering, and distinctive roles provide a substantial rationale that its protective manner may be obtained for the lungs, in a similar manner as evidenced in other organs.A complex interaction exists between renalase, inflammation, oxidative stress, apoptosis, and fibroproliferation, which is emphasized by the experimentally evidenced renalase's remarkable actions, presumably in order to mitigate adverse fibroproliferative outcome. Effective anti-COVID-19 approach may take advantage of renalase's pleitropic effects including: lessening of neutrophils and macrophages accumulation, and macrophage phenotype shifting (M1/M2), a decrease of the proinflammatory cytokines (TNF-Novel therapies for COVID-19 seek to exploit renalase's multiple and distinctive cytoprotective mechanisms; therefore, this review should be acknowledged as the thorough groundwork for subsequent research of renalase's employment in the experimental models of SARS-CoV-2 infection. Finally, it is of utter importance for the entire scientific society to comprehensively explore and conjoin all available knowledge to win the battle against this devastating pandemic.


Inflammatory bowel diseases (IBDs) are chronic and disabling conditions that, uncontrolled, lead to irreversible bowel damage and associated comorbidities. Despite the new era of biological therapies, IBDs remain not curative. The treatment purpose is to induce endoscopic remission, reduce the progression of the disease and improve the quality of life. Optimal and early treatment could enable the prevention of their complications. Small molecules, administrated as oral agents, have the capacity of overcoming the limitations of biologic agents . Of special interest are results from the use of oral sphingosine 1-phosphate (S1P) receptor modulators , based on S1P activities to target lymphocyte recirculation in the mucosa, acting as immunosuppressive agents. Most S1P modulators are reported to be safe and effective in the treatment of both UC and CD. High and satisfactory rates of clinical remission as well as endoscopic improvement and remission can be achieved with these molecules. Safety alarms remain rather low, although the S1P binding to two of its G protein-coupled receptors, 2 and 3 (S1PR2 and S1PR3), may be associated with cardiovascular risks. Cost-effectiveness studies and head-to-head trials are needed to better define their place in therapy. This review summarizes these emerging data published by PubMed and EMBASE databases and from ongoing clinical trials on the safety and efficacy of selectivity of S1P modulators in the treatment of IBD. Inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn’s disease (CD), are chronic, disabling conditions affecting the gastrointestinal tract and characterized by an abnormal immune response to intestinal microflora in genetically susceptible individuals ,2. For tSince the advent of biologic agents targeting different inflammatory pathways , the management of moderate-to-severe IBDs has been revolutionized. Indeed, their use in therapy allows steroid-free remission, induces mucosal and histological healing and lowers surgeries and hospitalizations, considerably improving the quality of life of IBD patients ,7,8,9. SIn this framework of discovering and developing more effective treatments for IBDs, novel oral small molecules, simultaneously targeting multiple cytokines  or controlling the migration of inflammatory cells, such as sphingosine 1-phosphate (S1P) receptor modulators, are currently under clinical investigation. Small-molecule drugs are characterized by a low molecular weight of less than 1 kDa and can easily diffuse through cell membranes. The oral route of administration, the main pharmacokinetic features  and the low/absent antigenicity make these drugs particularly advantageous over biologics. Specifically, the binding S1P with its type 1 and type 5 receptors  regulates several biological functions . The inAmong the available S1P receptor modulators, fingolimod, siponimod, etrasimod and ozanimod have already been approved by regulatory authorities for the treatment of multiple sclerosis ,19,20. Thttps://www.clinicaltrials.gov (accessed on 7 June 2022), was also employed up to 2022 to review the latest results of the ongoing clinical trials investigating this pharmacological mechanism. PubMed/MEDLINE and Embase databases were searched up to May 2022 to identify relevant studies investigating the efficacy and safety of S1P receptor modulators in the treatment of IBD. The following text words and corresponding Medical Subject Heading/Entree terms were used: “sphingosine 1-phosphate,”, “ozanimod”, “etrasimod”, “amiselimod” and “fingolimod”, individually and in combination with “inflammatory bowel disease(s)”, “IBD”, “ulcerative colitis” and “Crohn’s disease”. No publication date restrictions were applied. Articles were included in this review based on their relevance; additional publications were identified through their reference lists. Finally, a hand-search of abstracts from the annual meetings of Digestive Disease Week, the American College of Gastroenterology, the European Crohn’s and Colitis Organization and the United European Gastroenterology Week, as well as of S1P, a bioactive lipid mediator derived from mammalian cell membrane sphingolipids, is a pleiotropic molecule able to control several cellular processes by binding with varying affinities its five S1PR1-5, resulting in numerous and often complementary clinical effects . HoweverConsidering the role of S1PRs in the regulation of immune cells trafficking, activation and differentiation, their modulation has become an appealing novel target for the treatment of immune-mediated disorders.The signal transduction of S1PRs occurs via the coupling of heterotrimeric G proteins, which, once activated, induce the RAS–ERK1/2 pathway, small GTPases, phospholipases, phosphatidylinositide 3-kinase (PI3K) and adenylyl cyclase. This cascade initiates multiple cellular effects .Fingolimod/FTY720 is an oral non-selective S1P modulator that binds S1PR1-3-4-5 . FingoliIn the field of IBDs, fingolimod exhibited encouraging results in animal models of IBDs. Indeed, treatment with this drug ameliorated chronic colitis in IL-10-gene-deficient mouse models and in Th1-mediated-2,4,6-trinitrobenzene-sulfonic-acid colitis ,33. UnfoOzanimod/RPC1063 is a new oral S1P receptor modulator that binds with high selectivity to S1P1 and S1P5 receptors, preventing the mobilization of lymphocytes from peripheral lymphoid organs to inflammatory sites . In regaThe efficacy and safety data from two phase III trials had already led to the approval of ozanimod for the treatment of relapsing forms of multiple sclerosis ,38.Ozanimod lacks immunogenicity, has a high oral bioavailability, achieves peak concentrations after approximately 6 h and has a short half-life of about 19 h .p = 0.048 and p = 0.14, respectively) [p = 0.002 and p = 0.03, respectively) [Regarding UC, the TOUCHSTONE phase II, double-blind, randomized clinical trial firstly reported that ozanimod achieved better clinical, endoscopic and histologic outcomes in patients with moderate to severe UC compared to placebo . In partctively) . Endoscoctively) . p < 0.001) and maintenance  were observed [p < 0.001) and maintenance  [In the subsequent randomized, double-blind, placebo-controlled phase III study, the TRUE NORTH trial, in the treatment arm with ozanimod, higher clinical response  rates during both induction  was detected (mean change of −2.2); endoscopic remission (SES-CD score ≤4 and ≥2 point decrease in the SES-CD score with no sub-score >1) and endoscopic response (≥50% decrease in SES-CD) were achieved by 10.1% and 23.2% of the patients, respectively . Moreovehttps://clinicaltrials.gov, accessed on 7 June 2022) are currently ongoing and/or actively recruiting.Several phase III placebo-controlled trials for ozanimod in patients with moderately to severely active CD , ozanimod demonstrated a good safety profile in IBD patients. Most of the AEs reported by II and III phase trials were not directly related to the drug, and the absolute number of the observed drug-related AEs was very low. In detail, in the TRUE NORTH trial, the serious AEs rate and the treatment discontinuation rate were higher in the placebo arm . AlthougIn the STEPSTONE trial, no cases of bradycardia or arrhythmias occurred in the treated CD patients .Due to a slightly increased risk of macular edema (two episodes during induction and one during maintenance), an ophthalmological evaluation at baseline is only recommended in patients at a high risk of macular edema  ,41,43. Furthermore, although a mean decrease of approximately 45% from baseline was observed in lymphocyte count (26.8% and 31.7% in the induction cohorts and 43.5% in the maintenance cohort), no severe infectious safety signals have been reported ,41,43. TThe elevation of transaminases occurred in 2.6% and in 1.6% of IBDs -treated Based on these efficacy and safety data, ozanimod was approved by regulatory authorities for the treatment of moderate to severe UC. Newly published data on the OLE extension of the TRUE NORTH clinical trial have confirmed the efficacy and safety profile of ozanimod with rates of 0.9% of serious infections and of 0.4% of macular edema in the maintenance cohort . FinallyRecent data on long-term cardiac safety of ozanimod (from the phase 3 ulcerative colitis (UC) True North trial and multiple sclerosis (MS) 12-month SUNBEAM and 24-month RADIANCE trials) have shown that, in maintenance, cardiac-related AEs occurred in 1.3% (3/230) of treated patients in the continuous ozanimod group, and no clinically significant heart rate or electrocardiographic changes were related to chronic treatment up to month 24 of ozanimod therapy .In the first real-world experience in relatively treatment-refractory UC patients, ozanimod showed a good tolerability and an efficiency and safety profile consistent with trials’ results . Of noteThe most recent post hoc analysis data on mucosal healing (MH) in UC patients treated with ozanimod showed that 44/230 (19.1%) patients achieved MH at week 10, being MH associated with ameliorated clinical outcomes  at week 52 irrespective of previous treatment with anti-TNF . Table 2Etrasimod/APD334 (ArenaTM) is an investigational, once-daily orally administered selective S1P1R, S1P4R and S1P5R modulator. This molecule has been proven with promising results in several immune-mediated diseases , including also IBDs. Concerning pharmacokinetics, etrasimod metabolization primarily involves hepatobiliary excretion thorough processes such as oxidation, dehydrogenation, glucuronidation and sulfation . Preliminary data had reported that etrasimod rapidly decreases mean lymphocyte counts both in healthy volunteers and in UC patients with UC, with a subsequent lymphocyte recovery within 5% of baseline levels after 7 days from discontinuation ,50. https://clinicaltrials.gov, accessed on 7 June 2022), including moderately-to-severely active UC with previous failure or intolerance to conventional or biologic therapy randomly assigned to etrasimod 1 mg (n = 52) or 2 mg (n = 50) or placebo (n = 54), etrasimod (2 mg/day) was shown to significantly improve clinical symptoms at week 12, assessed through a modified Mayo Clinic score (MCS) compared with a placebo  [p < 0.001) [p = 0.003) [As concerns UC, in the phase-2 OASIS study  . In more< 0.001) . Among t= 0.003) .p = 0.006 and p = 0.03) [Interestingly, histologic improvement (Geboes score <3.1) and histologic remission (Geboes score <2.0) were reported in 31.7% and in 19.5% of patients in the treatment arm (etrasimod 2 mg/day), respectively, vs. 10.2% and 6.1% in the placebo group, respectively ( = 0.03) . With re = 0.03) . Cardiac = 0.03) .Efficacy data were confirmed in the open-label extension (OLE) of the OASIS trial: at the end of treatment (week 46 or 52), 64% (72/112) and 33% (37/112) of the patients achieved clinical response and clinical remission, respectively, while 43% (48/112) of the patients showed endoscopic improvement, and endoscopic improvement was sustained from week 12 in more than two-thirds of patients [The results of the OLE of the OASIS study reported that most AEs (94.4%) were of mild or moderate severity, and the most commonly occurring AEs were the worsening of UC  and anemia  . NeitherRegarding cardiac AEs, one patient experienced heart rate lowering , without a need for dose change or treatment discontinuation . Moreovehttps://clinicaltrials.gov, accessed on 7 June 2022) is currently enrolling moderately to severely active UC patients.The ELEVATE phase III trial  [As concerns induction with etrasimod in UC patients, in the ELEVATE UC 12, clinical remission was observed in 24.8% of treated patients vs. 15.2% of the placebo group, respectively (= 0.026) .p ˂ 0.001) and over four-times-higher at 52 weeks  [Preliminary results from the ELEVATE UC 52 have shown that the clinical remission rate was over three-times-higher in the treatment group with etrasimod compared with placebo at 12 weeks  . Of note˂ 0.001) . Furtherhttps://clinicaltrials.gov, accessed on 7 June 2022) is the ongoing phase II/III study aiming to enroll 1265 patients to evaluate the safety and efficacy of etrasimod, and it will assess, in its five sub-studies, the efficient dose of this molecule in the induction, maintenance/extension and long-term extension. Regarding CD, CULTIVATE  have a half-life time 10-fold longer than ozanimod (380–420 h), reaching the steady-state concentration after about 10 weeks . The phahttps://clinicaltrials.gov, accessed on 7 June 2022).Regarding its efficacy in IBD, amiselimod was demonstrated to inhibit chronic colitis in mice models, preventing the egress of lymphocytes into the periphery and inhibiting the infiltration of Th1 and Th17 cells into the colon . HoweverThis review elucidated the role of S1P modulation as the emerging therapies’ target in the treatment of IBD. S1P1 agonists are a new generation of oral small molecules, with a short half-life and no risk of immunogenicity.As emerges from the above exposed data, S1PRs modulators have been demonstrated to be well tolerated ,43,51,52However, the long-term safety profile of these agents requires further monitoring to establish possible dose dependency, defining possible inter-individual variability in terms of pharmaco-kinetics and reversibility.Encouraging preclinical and clinical data exploring the efficacy of S1P modulators have demonstrated the inhibition of lymphocyte egress from the lymph nodes as a valid pharmacological strategy to induce remission in IBD. Rapid response , remissiS1P modulators are not limited by potential immunogenicity, in contrast to most of the currently approved biologic agents.An additional advantageous aspect of S1P1 modulators is the rather rapidity for lymphocytes to return to normal levels after drug withdrawal ,50, whicFurther benefits of this drugs’ class include the maintenance of T cell effector’s memory response and possible low manufacturing cost.Moreover, several studies have demonstrated that circulating S1P activate endothelial S1PRs, regulating angiogenesis and stabilizing blood vessels in the development and homeostasis ,63. FinaIn our view, the open issues regarding S1P modulators mainly concerns their positioning within current treatment algorithms, depending on disease location  and their potential as combination therapies for the treatment of moderate-to-severe, multi-failure IBD patients . The benRecent research comparing the efficacy and safety data of ozanimod and ustekinumab in UC patients reported a comparable response in both biologically naïve and biologically exposed patients, with no statistically significant differences between the two drugs . HoweverThe addressing of these unanswered questions warrants head-to-head trials and comparative effectiveness studies. Finally, predictive biomarkers for patients’ molecular profiling, to predict potential responders as well as to monitor responsiveness, are highly needed to facilitate and better support therapeutic strategies.


WTCS provided information regarding WTC dust exposure intensity. Hierarchical clustering of the linear biomarker data identified two clusters within WTCS and two clusters within NYUBAR controls. Comparison of the WTCS clusters showed that one cluster had significantly increased levels of circulating matrix metalloproteinases , soluble inflammatory receptors , suppression of tumorigenicity (ST)2, triggering receptor expressed on myeloid cells (TREM)1, IL-6Ra, tumor necrosis factor (TNF)RI, TNFRII), and chemokines . Furthermore, this WTCS cluster was associated with WTC exposure variables, ash at work, and the participant category workers; but not with the exposure variable WTC dust cloud at 9/11. A comparison of WTC exposure categorial variables identified that chemokines , circulating receptors , MMPs , and vascular markers  significantly increased in the more exposed groups. Circulating biomarkers of remodeling and inflammation identified clusters within WTCS and were associated with WTC exposure.The destruction of the World Trade Center (WTC) on September 11, 2001 (9/11) released large amounts of toxic dusts and fumes into the air that exposed many community members who lived and/or worked in the local area. Many community members, defined as WTC survivors by the federal government, developed lower respiratory symptoms (LRS). We previously reported the persistence of these symptoms in patients with normal spirometry despite treatment with inhaled corticosteroids and/or long-acting bronchodilators. This report expands upon our study of this group with the goal to identify molecular markers associated with exposure and heterogeneity in WTC survivors with LRS using a selected plasma biomarker approach. Samples from WTC survivors with LRS ( The destruction of the World Trade Center (WTC) towers on September 11, 2001 9/11) caused acute and/or chronic exposure to dust and fumes with subsequent persistent respiratory symptoms in responders, local residents, and workers ,4. Many /11 causeApproximately 15 years after the destruction of the towers, we studied a subgroup of WTC survivors who had persistent LRS (WTCS) with normal spirometry to evaluate responses to optimized treatment for irritant-induced asthma ,15. The The study was approved by the NYU Grossman School of Medicine institutional review board. All study participants signed informed consent. The approval numbers are S 13-00448 for the Uncontrolled Lower Respiratory Symptoms in the WTC Survivor Program which is also listed at ClinicalTrials.gov, identifier NCT02024204; and H-9698 for the NYUBAR registry (Disease Modifying Genes in Severe Asthma), which is also listed at ClinicalTrials.gov, identifier NCT00212537.WTCS were defined as patients from the WTC EHC who had participated in the original study . The cliSpirometry was performed before and after administration of a bronchodilator to determine pre- and post-bronchodilator Forced Vital Capacity (FVC) and pre- and post-bronchodilator Forced Expiratory Volume in 1 s (FEV1) . The spin = 55). This registry was created to study patients with asthma as well as controls and details have been published previously [For control group comparison, plasma samples from the NYU Bellevue Asthma Registry (NYUBAR) ,15 were eviously ,15. The n = 43), however, some had samples obtained at visit 2 (n = 2), or at the end of the study . Plasma samples were immediately prepared, aliquoted, and stored frozen at −80 °C until analysis. We were able to test the samples from all of the 73 WTCS participants using multiplex assays for 34 biomarkers , CC chemokine ligand (CCL)11, IL-8 (leukocyte), Glycoprotein (GP130), IL-6Ra, TNFRI, TNFRII, MMP3, MMP8, MMP7, MMP12, MMP13; n = 64 for MMP2 and TIMP1; n = 73 for all other analytes. The hierarchical clustering algorithm only included samples with a full biomarker dataset (no missing data) with an n = 58 for the WTCS samples.The original clinical trial was not a biomarker study . Therefoomarkers . Howevern = 55 samples. n = 54 for MMP13; n = 52 for TNFα, IL-1β, IL-6, IL-33; n = 47 for MMP2, and TIMP1. The hierarchical clustering algorithm only included samples with a full biomarker dataset (no missing data) with an n = 41 for the NYUBAR controls.For the NYUBAR controls, we obtained data for most analytes from The multiplex assays were performed per manufacturers’ protocols with premixed magnetic microsphere kits from R&D Systems  or Millipore  with a FlexMAP3D instrument  and xPONENT software .Most runs were performed with 1 or 2 plates each (40 or 88 samples). The sample dilution was at least 1:2, and up to 1:2000 as indicated in x-axis, 7 serially diluted standards) the mean of the mean fluorescence intensity was calculated (y-axis). Interpolation from log-transformed concentrations (pg/mL) and log transformed mean fluorescence intensity values was performed using asymmetric sigmoidal, 5PL, least squares fit interpolation as instructed by each kit and programming of the xPONENT software that controls the multiplex Flexmap3D instrument.The sample concentrations were calculated based on the standard curves. For each standard curve concentration . Furthermore, technically, the run-to-run comparability was ensured by testing random duplicate samples on random plates. This strategy was used for the determination of CRP, Angiogenin, ST2, MMP1, CHI3L1/YKL-40, Angiopoietin-2, IL-1RA, CCL20/MIP-3α, RAGE, Periostin, VCAM1, CCL17/TARC, TREM1, MMP2, TIMP1, TNFα, IL-33, IL-1ß, IL-6, IL-13, IL-4, IL-8. For the IL-13, IL-4, IL-8 kit, additional internal standards were tested in duplicate at 2 concentrations in each run. For the TNF RII/TNFRSF1B, TNF RI/TNFRSF1A, SP-D, MMP3, MMP7, MMP8, MMP12, MMP13, IL-8/CXCL8, IL-6R alpha, GP130, CCL11/Eotaxin kit, we did not have duplicate samples or additional standards to ensure optimal run-to-run compatibility; however, we observed that for each analyte, the mean fluorescence intensity across the samples was comparable for each of the 7 runs used to test all of the samples. Therefore, for each analyte, we selected 3 standard curves that most optimally covered the full range of mean fluorescence data generated by all the samples to calculate a single composite standard curve. The standard concentration (X) was plotted against the 3 values for the mean of the mean fluorescence intensity (Y) of the 3 selected standard curves with their 7 serially diluted data points. This composite standard curve was used to perform interpolation of log-transformed concentrations (pg/mL) and log transformed mean fluorescence intensity values using asymmetric sigmoidal, 5PL, least squares fit to calculate the concentration of each analyte in each of the 128 samples analyzed ,33,34.For all assay runs and analytes, the standard curves showed high goodness of fit with the adjusted R-squared values being at least 0.95, and for most assay runs 0.99 or more, and for some runs 1.0.The finalized analyte concentration (pg/mL) in each sample considered the dilution factor. For samples in which values were outside of the range of the standard curve, either below or above the detection range, we generated numeric values, either at least 2-fold below the limit of detection, or 2-fold above the detection range. For an analyte that had measured values below the detection limit in some of the samples, for example with a detection limit of 1 pg/mL all measurements below the limit (not detected) were given the numerical value of 0.05 pg/mL. For an analyte that had measured values above the detection range in some of the samples, for example with upper detection value of 12 µg/mL, the samples above this limit were given the numerical value of 25 µg/mL.n = 58) and NYUBAR control . Hierarchical clustering on biomarker values was performed using the method Ward from linear, standardized biomarker data using the JMP Pro16.2 software . The hierarchical clustering was performed with samples (listed in rows) on biomarker values (listed in columns). The biomarker values were standardized by subtracting the column means and divided by the column standard deviations. The resulting WTCS clusters  were compared for biomarker analyte levels with logistic regression to adjust for age, body mass index (BMI), gender, and race/ethnicity on log transformed biomarker concentrations. WTC exposures were considered as categorical variables: WTC dust cloud exposure on the day of 9/11 (no/yes), workplace with ash (no/yes), WTCS participant category (worker/resident). The variable workers included local workers and clean-up workers. The variable resident included residents and others. We also had information on other WTC exposure categories (for example ash at home (no/yes)), but there was not enough data variability or sample size to perform group comparisons. Data for some categorical variables contained some missing data causing variability in the actual sample size used in specific statistical analyses. Multivariable logistic regression was also used to assess significance of association between WTC exposure status and the two WTCS clusters with adjustment for age, BMI, gender, and race/ethnicity. Bivariate comparisons between WTCS clusters 1 and 2 for selected categorical variables including race/ethnicity, gender, exposures categories (worker/resident) and workplace ash status (yes/no) were also performed with the Fisher’s exact test. Group comparisons  were also performed with two-tailed, unpaired non-parametric Mann–Whitney test. p values of <0.05 were considered significant. The calculations were performed with the R software . Graphs were produced with JMP 16.2 Pro  or Graphpad Prism , December 7, 2021, GraphPad Software, San Diego, CA, USA, www.graphpad.com).Median and interquartile range were used to summarize continuous variables. Count and percentage were used to summarize categorical variables. Hierarchical clustering was performed with an algorithm that had no missing values from all of the 34 biomarker analytes, with samples from WTCS . Logistic regression was used to adjust for the co-variates age, BMI, gender, and ethnicity/race  designated as previously described [p = 0.037), IL-1RA (p = 0.013), TREM1 (p ≤ 0.001) and the vascular marker VCAM1 (p = 0.016). The comparisons were performed with the Mann Whitney test. There was no difference in the groups of WTCS defined by LRS status with respect to age and BMI (p > 0.05 Mann–Whitney test), or gender and ethnic group .We also compared clinical status of LRS  with similar spirometry values. We used a WTCS group with persistent LRS and normal spirometry who had participated in a previous study , where wThe identification of well-separated clusters among the WTCS participants or the NYUBAR control participants was not surprising because previously published work had shown circulating markers of allergy in both groups. Among the WTCS participants nearly ½ had circulating, allergen specific IgE , and appFor the interpretation of our data, it is important to know if the values of the biomarkers measured by our assays correspond to published levels of analytes, particularly in control participants. In part, concentrations of circulating biomarkers depend on the medium analyzed, plasma vs. serum ,49,50. SWTCS cluster 2 was characterized by circulating inflammatory and remodeling markers including MMP1, 2, 3, 8, 12, 13, soluble receptors RAGE, IL-1RA, IL-6Ra, TNFRI, TNFRII, and chemokines IL-8, and CCL17. Many of these biomarkers, in particular MMP’s and RAGE, have previously been reported to be very important to understand the responses in the WTC responders, signifying either a prediction of protection or worsening of lung function ,25,26,57p = 0.9). These results do not exclude the possibility that molecular metabolic shifts occurred in WTCS participants from either cluster 1 or 2; this needs to be investigated in future studies.The WTC responder analysis also identified very important metabolic, vascular and additional inflammatory ,65,66,67While we cannot directly compare biomarker levels between our study that was performed with plasma and the published data from WTC responder firefighters, which was performed with serum ,24,25,26p = 0.015). The MMP2 gene is not located in the major MMP cluster on chromosome 11, but on chromosome 16 [p values for race/ethnicity, BMI, age, gender when comparing the clusters gives us confidence that our findings do not simply reflect variations due to ethnicity.Ethnic determinants of genetic diversity  and of dosome 16 . The finIt is possible that the persistence of toxins acquired during the WTC exposure drives the persistence of processes reflected by the increased biomarkers seen in our study. Dr. Shao’s and Dr. Trasande’s groups have shown persistent increases, more than 12 years after 9/11, in serum dioxins and furans in WTC exposed children who experienced dust at home . InitialAlternatively, it is possible that the WTC exposure led to de novo development of aberrant inflammatory responses, such as an increase in allergic and asthmatic responses described in children exposed to WTC dust , in WTC The asthma control score did not improve in the majority of the study participants  and studIn conclusion, our study expands upon previous studies of blood biomarkers in WTC exposed populations using a sample of WTCS with ongoing LRS years after exposure. We provide evidence for an association between intensity of WTC exposures and blood-based biomarkers of inflammation, repair, and aging in WTC survivors. More specifically, our study identified heterogeneity (clusters) among the WTC survivors with LRS based on circulating biomarkers 15 years following the disaster. These biomarkers could reflect WTC exposure, persistent inflammation, ongoing repair, and aging processes. A better understanding of the molecular changes associated with the respiratory condition in the WTC survivors could be used to devise future personalized treatment.


Inflammasomes are intracellular signaling complexes of the innate immune system, which is part of the response to exogenous pathogens or physiological aberration. The multiprotein complexes mainly consist of sensor proteins, adaptors, and pro-caspase-1. The assembly of the inflammasome upon extracellular and intracellular cues drives the activation of caspase-1, which processes pro-inflammatory cytokines IL-1β and IL-18 to maturation and gasdermin-D for pore formation, leading to pyroptosis and cytokine release. Inflammasome signaling functions in numerous infectious or sterile inflammatory diseases, including inherited autoinflammatory diseases, metabolic disorders, cardiovascular diseases, cancers, neurodegenerative disorders, and COVID-19. In this review, we summarized current ideas on the organization and activation of inflammasomes, with details on the molecular mechanisms, regulations, and interventions. The recent developments of pharmacological strategies targeting inflammasomes as disease therapeutics were also covered. Innate immunity provides the most rapid and conserved defense against cellular damage caused by pathogenic infections, injuries, and cellular stresses. This response depends on the monitoring of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) through sensors called pattern recognition receptors (PRRs), located in both immune cells and non-immune cells ,2. DistiThe concept of the inflammasome was first defined by Dr. Jurg Tschopp in 2002 , upon idNLRs function as the primary sensors for inflammasome formation. Structurally, these family members are composed of an N-terminal pyrin domain (PYD), a central nucleotide-binding and oligomerization domain (NACHT), and C-terminal leucine-rich repeats (LRRs). While the NACHT and LRR domains are present in all NLR proteins (except NLRP10), the PYD determining the interaction partners is the most variable . Upon acAnother critical and direct substrate of caspase-1 is GSDMD, the primary executor of pyroptosis. Caspase-1 processes cytosolic GSDMD to release its N-terminal domain from an autoinhibited conformation ,37, a hiThis review summarized the recent advances in understanding the organization and activation mechanisms of the inflammasomes, the diseases relevant to their dysfunctions, and the natural and designed inhibitors targeting the inflammasome signaling for a therapeutic purpose.Bacillus anthracis lethal toxin [The NLRP1 inflammasome was the first one identified, initially described as a caspase-activating complex comprising caspase-1/5, Pycard/ASC, and NALP1 . Human Nal toxin , or a real toxin . In cont+ efflux caused by pyroptosis can further trigger the assembly of the NLRP3 inflammasome and promote NLRP3-caspase-1-dependent cytokine maturation [The NLRP3 inflammasome is the most extensively studied. Human NLRP3 comprises a PYD, a NACHT, and an LRR domain . The NACturation ,66,67. TNLRC4 was initially identified as a pro-apoptotic protein named the ICE-protease-activating factor (IPAF) based on its similarity to apoptotic protease-activating factor 1 (APAF1) . BesidesNucleic acids are predominant PAMPs and ubiquitous in living organisms. In addition to cytosolic DNA sensors such as cGAS and the critical roles of cGAS-STING signaling in cellular physiology ,78,79,80Clostridium difficile TcdB, a major virulence factor of Clostridium difficile, covalently modifies RhoA and inactivates these GTPases, which triggers the assembly of pyrin inflammasomes in an ASC-dependent manner [Pyrin  is encoded by the gene MEFV. In 1997, several groups disclosed that the mutations of the MEFV gene in humans are responsible for the monogenic autoinflammatory disease familial Mediterranean fever (FMF) . Later, t manner . Howevert manner ,90. NeveInflammasome activation is generally considered a two-step process, a priming step  and an activation step . Initially, the priming step is characterized by the transcriptional induction of NLRP3, pro-IL-1β, and pro-IL-18 through an inflammatory stimulus, including TLR ligands and cytokines such as TNFα . The enh+ efflux, Ca2+ signaling, Na+ influx, and Cl− efflux), can also activate the NLRP3 inflammasome [Multi-faceted pathogenic and sterile inflammatory signals can activate NLRP3, such as foreign PAMPs from fungi, bacteria, and viruses, and host-derived molecules such as reactive oxygen species (ROS), extracellular ATP, and crystalline and particulate matters . Additionally, perturbing intracellular homeostasis, including lysosomal destabilization, mitochondrial dysfunction, and ion fluxes , leading to a K+ efflux and subsequent NLRP3 activation [+/H+ ionophore, is commonly used as an NLRP3 inflammasome agonist via the K+ efflux [+ is sufficient to activate the NLRP3 inflammasome, while the high extracellular concentration prevents it [+ efflux to trigger the NLRP3 inflammasome activation [+ efflux in NLRP3 activation, the exact nature underlying it is still not fully understood.The Ker DAMPs ,98. For tivation . Nigeric+ efflux . Notablyvents it ,101. A p2+, thus, inducing CaSRs signaling and leading to NLRP3 inflammasome activation in rheumatoid arthritis [Calcium-sensing receptor (CaSR) signaling is able to promote NLRP3 inflammasome activation by decreasing the intracellular cyclic AMP (cAMP) level ,103, as rthritis . ADP relrthritis .− efflux facilitates NLRP3 inflammasome activation have been presented. While some studies indicated that the Cl− efflux is responsible for the upstream signaling for NLRP3 activation, some groups showed that the Cl− efflux is required for ASC oligomerization [− level has previously been shown to promote IL-1β secretion [Distinct opinions regarding how the Clrization ,108. Theecretion . Later, ecretion .2+ and Na+ influxes and mediates the K+ efflux through TWIK2 [2+ flux, regulated by the K+ efflux, is presumed to be critical in NLRP3 inflammasome activation [Additionally, ion fluxes have frequently been found coordinated in NLRP3 activation. For instance, ATP activates P2X7R, which promotes the Cagh TWIK2 . The Ca2tivation , althougtivation ,112. The+ efflux and Ca2+ influx [+ efflux in human monocytes [Studies have shown that particulate stimuli such as alum and cholesterol crystals activate the NLRP3 inflammasome by causing lysosomal rupture and the release of the particulates into the cytoplasm. This notion is supported by dipeptide Leu-Leu-OMe, a soluble lysosomotropic agent, which is sufficient to activate the NLRP3 inflammasome . Similar+ influx , emphasionocytes .Additionally, NLRP3 stimuli can promote the disassembly of the trans-Golgi network into the dTGN, which serves as a scaffold for NLRP3 aggregation and activation . AnotherBesides lysosomes, mitochondria are considered central organelles in regulating the NLRP3 inflammasome activation. Mitochondria can serve as the docking platform for the NLRP3 inflammasome assembly. Upon activation, NLRP3 translocates from the cytosol and ER to the mitochondria and mitochondria-associated membrane, and associates with the adaptor protein ASC ,62,63. SSmall molecules, such as imiquimod and CL097, can drive NLRP3 inflammasome activation by targeting mitochondria and inducing mtROS production . mtROS, + efflux [Several co-activators of NLRP3 have been identified, including dsDNA-binding protein PKR , guanyla+ efflux . Recentl+ efflux . HoweverEmerging evidence in recent years has suggested a critical role of NLRP3 PTMs in inflammasome priming and activation. Ubiquitination-mediated protein degradation controls NLRP3 inflammasome activation by regulating the availability of NLRP3. The lifespan of NLRP3 is coordinated by F-box/LRR-repeat protein 2 (FBXL2) and F-box-only protein (FBXO3) . FBXL2 uIntriguingly, ubiquitination has a dual role in NLRP3 inflammation activation. The deubiquitination of NLRP3 contributes to inflammasome activation. For instance, the BRCA2-containing complex subunit 3 (BRCC3) deubiquitinase complex interacts with NLRP3 and removes the K63-linked ubiquitin chain from the LRR domain of NLRP3, allowing its oligomerization and activation . By contPhosphorylation events control NLRP3 inflammasome assembly and activation, as exemplified by several cases. During the priming, c-Jun N-terminal kinase 1 (JNK1) directly phosphorylates human NLRP3 at Ser198 (mouse Ser194), which is critical for NLRP3 inflammasome assembly and function . The phoPhosphorylation also plays a negative role in regulating NLRP3 activation. For instance, the phosphorylation of human NLRP3 at Ser5 (mouse Ser3) by AKT inhibits NLRP3 inflammasome activation by disrupting the PYD–PYD interaction , while pIn recent years, besides ubiquitination and phosphorylation, PTMs have also been shown to emerge in regulating the NLRP3 inflammasome. These NLRP3 modifications include SUMOylation ,164,165,+ efflux caused by GSDMD pores activates NLRP3 and initiates caspase1-dependent IL-1β and IL-18 maturation. Galectin-3 can augment caspase-4/11 oligomerization and promote non-canonical inflammasome activation through LPS binding [In addition to the canonical pathway, the NLRP3 inflammasome can be activated via the direct sensing of cytosolic LPS by human caspase-4/5 or mouse caspase-11, the process of which is defined as the non-canonical pathway ,42,174.  binding . Notably binding . Besides binding ,179,180. binding .Acute inflammation is beneficial for pathogen clearance and tissue repair, while chronic inflammation is a pathological condition leading to tissue damage. A gain-of-function mutations study on the NLRP3 gene linked its functions to some inherited autoinflammatory diseases . MutatioBesides monocytes and macrophages, the NLRP3 inflammasome can also be activated in a wide range of endothelial, epithelial, and mesenchymal cells, thus, related to various inflammatory diseases in different organs such as the skin, brain, and liver. Thus, the NLRP3 inflammasome has been implicated in central nervous system (CNS) diseases, such as multiple sclerosis (MS), Alzheimer’s disease (AD), and Parkinson’s disease (PD) ,186, metNLRP3 is a drug target of significant interest in the pharmaceutical industry, with the potential for treating various inflammatory diseases. Small molecules directly targeting NLRP3 are developing rapidly . The mosBesides disrupting the NLRP3 inflammasome assembly, many inhibitors are developed to target its ATPase activity . RecentlN-acetyl-Phe-Leu-Thr-Asp-chloromethylketone (Ac-FLTD-CMK), was designed to target inflammatory caspase, such as caspase-1, -4, -5, and -11, but not the apoptotic caspases such as caspase-3. It was shown to inhibit GSDMD cleavage and suppress the pyroptosis downstream of both canonical and non-canonical inflammasomes [Other alternative strategies have also been attempted to inhibit the NLRP3 inflammasome, such as the blockade of ATP receptor P2X7, NF-κB, caspase-1, IL-1β/IL-1R, and IL-18 . Avastinmmasomes . Notablymmasomes  and the mmasomes  and rilommasomes . Howevermmasomes  , was shown to disrupt the assembly of NLRP3 and NEK7 and subsequent NLRP3 oligomerization [In addition to synthetic compounds, herb-based medicine shows excellent potential for inflammatory disease treatment . An alkarization . Licocharization . Androgrrization ,230. Othrization , rpistimrization , pterostrization , and berrization , which aInflammasomes are dynamic protein complexes that multiple pathogenic and sterile inflammatory signals can trigger and induce infectious and non-infectious insults. Unlike other innate immune signalosomes that are generally membrane-anchored and less systemic in structure, inflammasomes appear unique. Given the large number of mutually unrelated upstream signals documented, inflammasome sensors seem to respond to general homeostasis stress, but are not a direct agonist. Characterizing the molecular mechanisms underlying inflammasome organization and cellular compartmentation would also be intriguing and critical to understanding this exquisite molecular machinery. Is there a key factor that integrates all the signals? How do the inflammasomes communicate with metabolism and nutrients and form special cellular compartments? Evidently, inhibitors targeting the inflammasome signaling components, such as those developed by studying cGAS-STING signaling , provide