The artemisinin analog SM934 alleviates dry eye disease in rodent models by regulating TLR4/NF-κB/NLRP3 signaling

Yang, Fayu; Fan, Di; Yang, Xiaoqian; Zhu, Fenghua; Shao, Mei-juan; Li, Qian; Liu, Yuting; Lin, Zheng; Cao, Shougen; Tang, Wei; He, Shijun; Zuo, Jian‐Ping

doi:10.1038/s41401-020-0484-5

Cited by 38 publications

(22 citation statements)

References 46 publications

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“…5 Protection of CEC in the pathological status would help in the management of DED and this research approach provided us various potential therapies for DED. 6,7 Macrophage was a key immune cell recruited to the cornea during the incidence of ocular surface disorders 8,9 and thus the interaction between CEC and macrophage would be an important progress in DED. As macrophage is a key source of inflammatory factors, the up-regulated inflammatory factors during pathological condition would injure the normal function of CEC.…”

Section: Introductionmentioning

confidence: 99%

Nicotinamide Mononucleotide Alleviates Hyperosmolarity-Induced IL-17a Secretion and Macrophage Activation in Corneal Epithelial Cells/Macrophage Co-Culture System

Yu¹,

Pu²,

Dai³

et al. 2021

JIR

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Background Hyperosmosis stress (HS) was a key pathological factor in the development of dry eye disease (DED). Nicotinamide mononucleotide (NMN) demonstrated protective effects in the corneal damage, however, its role in the HS-induced DED remained unclear. Methods A NaCl based HS in-vitro model (500 mOsm) was generated and used in a co-culture system including corneal epithelial cells (CEC) and macrophage cell line RAW264.7. The effect of NMN on NAD+ metabolism and the expression of HS biomarker, tonicity-responsive element binding protein (TonEBP), was studied in the CEC. The cellular activity, including cell viability, apoptosis status and lactate dehydrogenase (LDH) release through trypan blue staining, flow cytometry and LDH assay, respectively. The mitochondrial membrane potential (MMP) assay would be conducted using the JC1 kit. The expression of IL-17a were detected using RT-PCR, ELISA and Western blot. After co-culture with the CEC in different group for 24 h, the phagocytosis ability and macrophage polarization were assessed in RAW264.7 cells co-cultured with CEC with or without HS or NMN treatment. Besides, the involvement of Notch pathway in the RAW264.7 would be analyzed. The potential involvement of Sirtuin 1 (SIRT1) and IL-17a in the crosstalk between CEC and macrophage was studied with SIRT1 inhibitor EX 527 and anti-IL-17a monoclonal antibody, respectively. Results NMN treatment increased NAD+ concentration and thus improved cell viability, reduced apoptotic rate and decreased the LDH release in HS-treated CEC. Besides, NMN alleviated HS-induced MMP, intracellular ROS and LDH release. Besides, it was confirmed NMN improve SIRT1 function and decreased the HS related IL-17a expression in CEC and then alleviated macrophage phagocytosis ability and M1 polarization based on a CEC-macrophage co-culture system. Moreover, NMN treatment of CEC in the CEC could moderate the subsequent macrophage activation through Notch pathway. SIRT1 activation and IL-17a inhibition was regarded as key progress in the function of NMN based on the application of EX 527 and anti-IL-17a antibody in the CEC-macrophage co-culture system. Conclusion The findings demonstrated that NMN could alleviated HS-induced DED status through regulating the CEC/macrophage interaction. Our data pointed to the role of SIRT1, IL-17a and Notch pathway in the function of NMN and then provided updated knowledge of potential NMN application in the management of DED.

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Section: Introductionmentioning

confidence: 99%

Nicotinamide Mononucleotide Alleviates Hyperosmolarity-Induced IL-17a Secretion and Macrophage Activation in Corneal Epithelial Cells/Macrophage Co-Culture System

Yu¹,

Pu²,

Dai³

et al. 2021

JIR

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“… 69–71 The effects of SM934 on DED were investigated in two animal model of DED: scopolamine hydrobromide-induced rodent model, an aqueous-deficient dry eye animal models, and benzalkonium chloride (BAC)-induced rat model, in which BAC induces instability of tear film and excessive evaporation, characteristic features of DED. 72 Topical instillation of SM934 significantly improved signs of DED, leading to an increased tear secretion and reduced corneal damage; this latter effect could be mediated by a reduction of MMP-9 levels in the corneal epithelium. SM934 significantly reduced the levels of inflammatory mediator (IL-1β, TNF-α, IL-6, IL-10) and diminished monocyte accumulation in the conjunctival tissues.…”

Section: Novel Emerging Therapies For Ded With Anti-inflammatory Propmentioning

confidence: 90%

“…At molecular levels it has been proposed that SM934 blocks the inflammatory process by down-regulating Toll-like receptor 4 (TLR4) and therefore inhibiting the inflammasome activation. 72 …”

Section: Novel Emerging Therapies For Ded With Anti-inflammatory Propmentioning

confidence: 99%

Experimental Pharmacotherapy for Dry Eye Disease: A Review

Baiula¹,

Spampinato²

2021

JEP

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Dry eye disease (DED) is a complex multifactorial disease showing heterogenous symptoms, including dryness, photophobia, ocular discomfort, irritation and burning but also pain. These symptoms can affect visual function leading to restrictions in daily life activities and reduction in work productivity with a consequently high impact on quality of life. Several pathological mechanisms contribute to the disease: evaporative water loss leads to impairment and loss of tear homeostasis inducing either directly or indirectly to inflammation, in a self-perpetuating vicious cycle. Dysregulated ocular immune responses result in ocular surface damage, which further contributes to DED pathogenesis. Currently, DED treatment is based on a flexible stepwise approach to identify the most beneficial intervention. Although most of the available treatments may control to a certain extent some signs and symptoms of DED, they show significant limitations and do not completely address the needs of patients suffering from DED. This review provides an overview of the emerging experimental therapies for DED. Several promising therapeutic strategies are under development with the aim of dampening inflammation and restoring the homeostasis of the ocular surface microenvironment. Results from early phase clinical trials, testing the effects of EnaC blockers, TRPM8 agonist or mesenchymal stem cells in DED patients, are especially awaited to demonstrate their therapeutic value for the treatment of DED. Moreover, the most advanced experimental strategies in the pipeline for DED, tivanisiran, IL-1R antagonist EBI-005 and SkQ1, are being tested in Phase III clinical trials, still ongoing. Nevertheless, although promising results, further studies are still needed to confirm efficacy and safety of the new emerging therapies for DED.

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“…In LPS-treated RAW 264.7 cells, it was established that preadministration with SM934 (10 μM) thwarted the upregulation of TLR4 and downstream NF-κB/NLRP3 signaling protein cascade. Taken together, artemisinin derivative SM934 produced therapeutic usefulness in DED by concomitantly preserving the structural rectitude of ocular surface and obviating corneal and conjunctival inflammation, hinting towards a subsequent application of SM934 in ophthalmic therapy, specifically for DED [ 154 ].…”

Section: Inhibitors Of Nlrp3 Inflammasome-driven In Vivo Disease Modelsmentioning

confidence: 99%

Promise of the NLRP3 Inflammasome Inhibitors in In Vivo Disease Models

et al. 2021

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Nucleotide-binding oligomerization domain NOD-like receptors (NLRs) are conserved cytosolic pattern recognition receptors (PRRs) that track the intracellular milieu for the existence of infection, disease-causing microbes, as well as metabolic distresses. The NLRP3 inflammasome agglomerates are consequent to sensing a wide spectrum of pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). Certain members of the NLR family have been documented to lump into multimolecular conglomerates called inflammasomes, which are inherently linked to stimulation of the cysteine protease caspase-1. Following activation, caspase-1 severs the proinflammatory cytokines interleukin (IL)-1β and IL-18 to their biologically active forms, with consequent commencement of caspase-1-associated pyroptosis. This type of cell death by pyroptosis epitomizes a leading pathway of inflammation. Accumulating scientific documentation has recorded overstimulation of NLRP3 (NOD-like receptor protein 3) inflammasome involvement in a wide array of inflammatory conditions. IL-1β is an archetypic inflammatory cytokine implicated in multiple types of inflammatory maladies. Approaches to impede IL-1β’s actions are possible, and their therapeutic effects have been clinically demonstrated; nevertheless, such strategies are associated with certain constraints. For instance, treatments that focus on systemically negating IL-1β (i.e., anakinra, rilonacept, and canakinumab) have been reported to result in an escalated peril of infections. Therefore, given the therapeutic promise of an NLRP3 inhibitor, the concerted escalated venture of the scientific sorority in the advancement of small molecules focusing on direct NLRP3 inflammasome inhibition is quite predictable.

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The artemisinin analog SM934 alleviates dry eye disease in rodent models by regulating TLR4/NF-κB/NLRP3 signaling

Cited by 38 publications

References 46 publications

Nicotinamide Mononucleotide Alleviates Hyperosmolarity-Induced IL-17a Secretion and Macrophage Activation in Corneal Epithelial Cells/Macrophage Co-Culture System

Nicotinamide Mononucleotide Alleviates Hyperosmolarity-Induced IL-17a Secretion and Macrophage Activation in Corneal Epithelial Cells/Macrophage Co-Culture System

Experimental Pharmacotherapy for Dry Eye Disease: A Review

Promise of the NLRP3 Inflammasome Inhibitors in In Vivo Disease Models

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