Periplaneta americana extract promotes infectious diabetic ulcers wound healing by downregulation of LINC01133/SLAMF9

Abstract

Wound healing in diabetic ulcers remains a significant clinical challenge, primarily due to bacterial infection and impaired angiogenesis. Periplaneta americana extract (PAE) has been widely used to treat diabetic wounds, yet its underlying mechanisms are not fully understood. This study aimed to elucidate these mechanisms by analyzing long non-coding RNA (lncRNA) expressions in the wound tissues from diabetic anal fistula patients treated with or without PAE, using high-throughput sequencing. Peripheral blood monocytes from patients were differentiated into M0 macrophages with human macrophage colony-stimulating factor (hM-CSF) and subsequently polarized into M1 macrophages with lipopolysaccharide. The results indicated that LINC01133 and SLAMF9 were downregulated in wound tissues of patients treated with PAE. Furthermore, PAE suppressed M1 macrophage polarization and enhanced human umbilical vein endothelial cell (HUVEC) proliferation, migration, and angiogenesis. These effects were diminished when LINC01133 or SLAMF9 were overexpressed. Mechanistically, LINC01133 was shown to upregulate SLAMF9 through interaction with ELAVL1. Overexpression of SLAMF9 reversed the effects of LINC01133 silencing on macrophage polarization and HUVEC functions. In conclusion, PAE facilitates the healing of infected diabetic ulcers by downregulating the LINC01133/SLAMF9 pathway.

Keywords

Periplaneta americana extract / Infectious diabetic ulcers / M1 macrophage polarization / LINC01133 / SLAMF9

References

[1] Golledge J, Thanigaimani S. Novel therapeutic targets for diabetes-related wounds or ulcers: an update on preclinical and clinical research[J]. Expert Opin Ther Targets, 2021, 25(12): 1061-1075.

[2] Everett E, Mathioudakis N. Update on management of diabetic foot ulcers[J]. Ann N Y Acad Sci, 2018, 1411(1): 153-165.

[3] El-Ashram S, El-Samad LM, Basha AA, et al. Naturally-derived targeted therapy for wound healing: beyond classical strategies[J]. Pharmacol Res, 2021, 170: 105749.

[4] Aitcheson SM, Frentiu FD, Hurn SE, et al. Normal macrophage function and macrophage dysfunction in diabetic wounds[J]. Molecules, 2021, 26(16): 4917.

[5] Chang M, Nguyen TT. Strategy for treatment of infected diabetic foot ulcers[J]. Acc Chem Res, 2021, 54(5): 1080-1093.

[6] Louiselle AE, Niemiec SM, Zgheib C, et al. Macrophage polarization and diabetic wound healing[J]. Transl Res, 2021, 236: 109-116.

[7] Pang L, Liao Q, Zou L, et al. Two glycoproteins from medicinal insect Periplaneta americana (L.) promote diabetic wound healing via macrophage polarization modulation[J]. Int J Biol Macromol, 2022, 209: 2130-2141.

[8] Liao Q, Pang L, Li JJ, et al. Characterization and diabetic wound healing benefits of protein-polysaccharide complexes isolated from an animal ethno-medicine Periplaneta americana L.[J]. Int J Biol Macromol, 2022, 195: 466-474.

[9] Yuan H, Su J, Tan J, et al. Efficacy of Kangfuxin Liquid on radiotherapy-induced oral mucositis for patients with head and neck squamous cell carcinoma and its effect on salivary glands and immune function[J]. Am J Transl Res, 2022, 14(9): 6792-6804.

[10] Wan X, Gen F, Sheng Y, et al. Meta-analysis of the effect of Kangfuxin Liquid on diabetic patients with skin ulcers[J]. Evid Based Complement Alternat Med, 2021, 2021: 1334255.

[11] Lu S, Wu D, Sun G, et al. Gastroprotective effects of Kangfuxin against water-immersion and restraint stress-induced gastric ulcer in rats: roles of antioxidation, anti-inflammation, and pro-survival[J]. Pharm Biol, 2019, 57(1): 770-777.

[12] Chen P, Shen Y, Shi H, et al. Gastroprotective effects of Kangfuxin-against ethanol-induced gastric ulcer via attenuating oxidative stress and ER stress in mice[J]. Chem Biol Interact, 2016, 28: S0009-2797(16)30509-9.

[13] Kuai L, Jiang JS, Li W, et al. Long non-coding RNAs in diabetic wound healing: current research and clinical relevance[J]. Int Wound J, 2022, 19(3): 583-600.

[14] Hu J, Zhang L, Liechty C, et al. Long non-coding RNA GAS5 regulates macrophage polarization and diabetic wound healing[J]. J Invest Dermatol, 2020, 140(8): 1629-1638.

[15] Li B, Zhou Y, Chen J, et al. Long non-coding RNA H19 contributes to wound healing of diabetic foot ulcer[J]. J Mol Endocrinol, 2020, 1: JME-19-0242.R1.

[16] Li Z, Xu D, Chen X, et al. LINC01133: an emerging tumor-associated long non-coding RNA in tumor and osteosarcoma[J]. Environ Sci Pollut Res Int, 2020, 27(26): 32467-32473.

[17] Yang XZ, Cheng TT, He QJ, et al. LINC01133 as ceRNA inhibits gastric cancer progression by sponging miR-106a-3p to regulate APC expression and the Wnt/beta-catenin pathway[J]. Mol Cancer, 2018, 17(1): 126.

[18] Zhang W, Du M, Wang T, et al. Long non-coding RNA LINC01133 mediates nasopharyngeal carcinoma tumorigenesis by binding to YBX1[J]. Am J Cancer Res, 2019, 9(4): 779-790.

[19] Cannons JL, Tangye SG, Schwartzberg PL. SLAM family receptors and SAP adaptors in immunity[J]. Annu Rev Immunol, 2011, 29: 665-705.

[20] Dragovich MA, Mor A. The SLAM family receptors: potential therapeutic targets for inflammatory and autoimmune diseases[J]. Autoimmun Rev, 2018, 17(7): 674-682.

[21] Wilson TJ, Clare S, Mikulin J, et al. Signalling lymphocyte activation molecule family member 9 is found on select subsets of antigen-presenting cells and promotes resistance to Salmonella infection[J]. Immunology, 2020, 159(4): 393-403.

[22] Zeng X, Liu G, Peng W, et al. Combined deficiency of SLAMF8 and SLAMF9 prevents endotoxin-induced liver inflammation by downregulating TLR4 expression on macrophages[J]. Cell Mol Immunol, 2020, 17(2): 153-162.

[23] Dollt C, Michel J, Kloss L, et al. The novel immunoglobulin super family receptor SLAMF9 identified in TAM of murine and human melanoma influences pro-inflammatory cytokine secretion and migration[J]. Cell Death Dis, 2018, 9(10): 939.

[24] Ren Y, Yang M, Wang X, et al. ELAV-like RNA binding protein 1 regulates osteogenesis in diabetic osteoporosis: involvement of divalent metal transporter 1[J]. Mol Cell Endocrinol, 2022, 546: 111559.

[25] Jeyabal P, Thandavarayan RA, Joladarashi D, et al. MicroRNA-9 inhibits hyperglycemia-induced pyroptosis in human ventricular cardiomyocytes by targeting ELAVL1[J]. Biochem Biophys Res Commun, 2016, 471(4): 423-429.

[26] Li X, Zeng L, Cao C, et al. Long noncoding RNA MALAT1 regulates renal tubular epithelial pyroptosis by modulated miR-23c targeting of ELAVL1 in diabetic nephropathy[J]. Exp Cell Res, 2017, 350(2): 327-335.

[27] Zhang L, Feng H, Jin Y, et al. Long non-coding RNA LINC01119 promotes neuropathic pain by stabilizing BDNF transcript[J]. Front Mol Neurosci, 2021, 14: 673669.

[28] Wang Z, Wang X, Zhang T, et al. LncRNA MALAT1 promotes gastric cancer progression via inhibiting autophagic flux and inducing fibroblast activation[J]. Cell Death Dis, 2021, 12(4): 368.

[29] Kang J, Liu Y, Peng S, et al. Efficacy and safety of traditional Chinese medicine external washing in the treatment of postoperative wound of diabetes complicated with anal fistula: study protocol of a randomized, double-blind, placebo-controlled, multi-center clinical trial[J]. Front Pharmacol, 2022, 13: 938270.

[30] Lotfollahi Z, Dawson J, Fitridge R, et al. The anti-inflammatory and proangiogenic properties of high-density lipoproteins: an emerging role in diabetic wound healing[J]. Adv Wound Care (New Rochelle), 2021, 10(7): 370-380.

[31] Zhang JJ, Zhou R, Deng LJ, et al. Huangbai liniment and berberine promoted wound healing in high-fat diet/streptozotocin-induced diabetic rats[J]. Biomed Pharmacother, 2022, 150: 112948.

[32] Patel S, Srivastava S, Singh MR, et al. Mechanistic insight into diabetic wounds: pathogenesis, molecular targets and treatment strategies to pace wound healing[J]. Biomed Pharmacother, 2019, 112: 108615.

[33] Ni L, Lu Q, Tang M, et al. Periplaneta americana extract ameliorates dextran sulfate sodium-induced ulcerative colitis via immunoregulatory and PI3K/AKT/NF-kappaB signaling pathways[J]. Inflammopharmacology, 2022, 30(3): 907-918.

[34] Zhao B, Xu J, Wang Y, et al. Periplaneta americana extract promotes hard palate mucosal wound healing via the PI3K/AKT signaling pathway in male mice[J]. Arch Oral Biol, 2024, 158: 105856.

[35] Li J, Wei M, Liu X, et al. The progress, prospects, and challenges of the use of non-coding RNA for diabetic wounds[J]. Mol Ther Nucleic Acids, 2021, 24: 554-578.

[36] Li X, Li N, Li B, et al. Noncoding RNAs and RNA-binding proteins in diabetic wound healing[J]. Bioorg Med Chem Lett, 2021, 50: 128311.

[37] Jiang S, Zhang Q, Li J, et al. New sights into long non-coding RNA LINC01133 in cancer[J]. Front Oncol, 2022, 12: 908162.

[38] Feng Y, Qu L, Wang X, et al. LINC01133 promotes the progression of cervical cancer by sponging miR-4784 to up-regulate AHDC1[J]. Cancer Biol Ther, 2019, 20(12): 1453-1461.

[39] Wang WJ, Wang D, Zhao M, et al. Serum lncRNAs (CCAT2, LINC01133, LINC00511) with squamous cell carcinoma antigen panel as novel non-invasive biomarkers for detection of cervical squamous carcinoma[J]. Cancer Manag Res, 2020, 12: 9495-9502.

[40] Chambers SE, O'Neill CL, O'Doherty TM, et al. The role of immune-related myeloid cells in angiogenesis[J]. Immunobiology, 2013, 218(11): 1370-1375.

[41] Wolf SJ, Melvin WJ, Gallagher K. Macrophage-mediated inflammation in diabetic wound repair[J]. Semin Cell Dev Biol, 2021, 119: 111-118.

[42] Christensen SM, Belew AT, El-Sayed NM, et al. Host and parasite responses in human diffuse cutaneous leishmaniasis caused by L. amazonensis[J]. PLoS Negl Trop Dis, 2019, 13(3): e0007152.

[43] Liu R, Wu K, Li Y, et al. Human antigen R: a potential therapeutic target for liver diseases[J]. Pharmacol Res, 2020, 155: 104684.

[44] Chen R, Zhang X, Wang C. LncRNA HOXB-AS1 promotes cell growth in multiple myeloma via FUT4 mRNA stability by ELAVL1[J]. J Cell Biochem, 2020, 121(10): 4043-4051.

[45] Li Z, Wang Y, Hu R, et al. LncRNA B4GALT1-AS1 recruits HuR to promote osteosarcoma cells stemness and migration via enhancing YAP transcriptional activity[J]. Cell Prolif, 2018, 51(6): e12504.

[46] Krishnamurthy P, Lambers E, Verma S, et al. Myocardial knockdown of mRNA-stabilizing protein HuR attenuates post-MI inflammatory response and left ventricular dysfunction in IL-10-null mice[J]. FASEB J, 2010, 24(7): 2484-2494.

[47] Nagai N, Kawashima H, Toda E, et al. Renin-angiotensin system impairs macrophage lipid metabolism to promote age-related macular degeneration in mouse models[J]. Commun Biol, 2020, 3(1): 767.

Funding

Natural Science Foundation of Hunan Province(2021JJ30516)