Host Defense Peptide RNase 7 Is Down-regulated in the Skin of Diabetic Patients with or without Chronic Ulcers, and its Expression is Altered with Metformin

Rodríguez-Carlos, Adrián; Trujillo, Valentín; González-Curiel, Irma; Marín-Luevano, Sara Paulina; Torres-Juárez, Flor; Santos-Mena, Alan; Rivas‐Santiago, César; Enciso-Moreno, José Antonio; Zaga‐Clavellina, Veronica; Rivas-Santiago, Bruno

doi:10.1016/j.arcmed.2020.03.006

Cited by 13 publications

(9 citation statements)

References 37 publications

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“…Previous studies have demonstrated downregulated expression of AMPs in patients with diabetes, which explains why diabetic wounds show frequent bacterial infections that contribute to tissue destruction and delayed wound healing 18,34 . In this study, we also confirmed that the expression of IGFBP5, the parent protein of AMP‐IBP5, was decreased under in vivo and in vitro diabetic conditions, suggesting that the absence of AMP‐IBP5 could contribute to the impairment of diabetic wound healing.…”

Section: Discussionsupporting

confidence: 86%

Antimicrobial peptide derived from insulin‐like growth factor‐binding protein 5 improves diabetic wound healing

Yue

Song

Sutthammikorn

et al. 2022

Wound Repair Regeneration

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Impaired keratinocyte functions are major factors that are responsible for delayed diabetic wound healing. In addition to its antimicrobial activity, the antimicrobial peptide derived from insulin‐like growth factor‐binding protein 5 (AMP‐IBP5) activates mast cells and promotes keratinocyte and fibroblast proliferation and migration. However, its effects on diabetic wound healing remain unclear. Human keratinocytes were cultured in normal or high glucose milieus. The production of angiogenic growth factor and cell proliferation and migration were evaluated. Wounds in normal and streptozotocin‐induced diabetic mice were monitored and histologically examined. We found that AMP‐IBP5 rescued the high glucose‐induced attenuation of proliferation and migration as well as the production of angiogenin and vascular endothelial growth factors in keratinocytes. The AMP‐IBP5‐induced activity was mediated by the epidermal growth factor receptor, signal transducer and activator of transcription 1 and 3, and mitogen‐activated protein kinase pathways, as indicated by the inhibitory effects of pathway‐specific inhibitors. In vivo, AMP‐IBP5 markedly accelerated wound healing, increased the expression of angiogenic factors and promoted vessel formation in both normal and diabetic mice. Overall, the finding that AMP‐IBP5 accelerated diabetic wound healing by protecting against glucotoxicity and promoting angiogenesis suggests that AMP‐IBP5 might be a potential therapeutic target for treating chronic diabetic wounds.

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Section: Discussionsupporting

confidence: 86%

Antimicrobial peptide derived from insulin‐like growth factor‐binding protein 5 improves diabetic wound healing

Yue

Song

Sutthammikorn

et al. 2022

Wound Repair Regeneration

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“…However, there is little to no production of cathelicidin in DFUs [ 68 ], which contributes to the impaired wound healing phenotype. Expression of other AMPs, such as human β-defensins, have been shown to be upregulated in DFUs, but subsequent AMP production has been proposed to be insufficient for microbial regulation [ 68 , 69 ]. To further complicate matters, AMP production has been shown to be influenced by common drugs used in diabetes treatment, such as in the case of RNase 7 downregulation by metformin [ 69 ].…”

Section: Pathophysiology Associated With Diabetic Wound Healingmentioning

confidence: 99%

“…Expression of other AMPs, such as human β-defensins, have been shown to be upregulated in DFUs, but subsequent AMP production has been proposed to be insufficient for microbial regulation [ 68 , 69 ]. To further complicate matters, AMP production has been shown to be influenced by common drugs used in diabetes treatment, such as in the case of RNase 7 downregulation by metformin [ 69 ]. Low AMP production combined with evidence of increased AGEs, impaired lamellar body production, and decreased stratum corneum lipid content in the setting of diabetes sets the stage for an impaired wound healing environment [ 14 ].…”

Section: Pathophysiology Associated With Diabetic Wound Healingmentioning

confidence: 99%

Diabetic Wound-Healing Science

et al. 2021

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Diabetes mellitus is an increasingly prevalent chronic metabolic disease characterized by prolonged hyperglycemia that leads to long-term health consequences. It is estimated that impaired healing of diabetic wounds affects approximately 25% of all patients with diabetes mellitus, often resulting in lower limb amputation, with subsequent high economic and psychosocial costs. The hyperglycemic environment promotes the formation of biofilms and makes diabetic wounds difficult to treat. In this review, we present updates regarding recent advances in our understanding of the pathophysiology of diabetic wounds focusing on impaired angiogenesis, neuropathy, sub-optimal chronic inflammatory response, barrier disruption, and subsequent polymicrobial infection, followed by current and future treatment strategies designed to tackle the various pathologies associated with diabetic wounds. Given the alarming increase in the prevalence of diabetes, and subsequently diabetic wounds, it is imperative that future treatment strategies target multiple causes of impaired healing in diabetic wounds.

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“…In humans, RNASE7 is highly expressed in most epithelia including skin, urothelium and respiratory tract epithelium 48,133 . The gene is significantly downregulated in the skin and urinary tract of diabetic patients (potentially because RNASE7 expression can be induced by insulin signaling), which reduces innate immune defense capacities and likely contributes to the much higher incidence of bacterial skin and urinary tract infections in diabetic patients 134,135 . The exclusive loss of RNASE7 in vampire bats, which might also be related to their reduced insulin secretory capacities, predicts that vampire bats have a reduced capacity for secreting bactericidal peptides.…”

Section: Loss Of the Immune-related Rnase7 And A Different Pathogen Profile Of Bloodmentioning

confidence: 99%

Gene losses in the common vampire bat illuminate molecular adaptations to blood feeding

Blumer

Brown

Freitas

et al. 2021

Preprint

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Feeding exclusively on blood, vampire bats represent the only obligate sanguivorous lineage among mammals. To uncover genomic changes associated with adaptations to this unique dietary specialization, we generated a new haplotype-resolved reference-quality genome of the common vampire bat (Desmodus rotundus) and screened 26 bat species for genes that were specifically lost in the vampire bat lineage. We discovered previously-unknown gene losses that relate to metabolic and physiological changes, such as reduced insulin secretion (FFAR1, SLC30A8), limited glycogen stores (PPP1R3E), and a distinct gastric physiology (CTSE). Other gene losses likely reflect the biased nutrient composition (ERN2, CTRL) and distinct pathogen diversity of blood (RNASE7). Interestingly, the loss of REP15 likely helped vampire bats to adapt to high dietary iron levels by enhancing iron excretion and the loss of the 24S-hydroxycholesterol metabolizing enzyme CYP39A1 could contribute to their exceptional cognitive abilities. Finally, losses of key cone phototransduction genes (PDE6H, PDE6C) suggest that these strictly-nocturnal bats completely lack cone-based vision. These findings enhance our understanding of vampire bat biology and the genomic underpinnings of adaptations to sanguivory.

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Host Defense Peptide RNase 7 Is Down-regulated in the Skin of Diabetic Patients with or without Chronic Ulcers, and its Expression is Altered with Metformin

Cited by 13 publications

References 37 publications

Antimicrobial peptide derived from insulin‐like growth factor‐binding protein 5 improves diabetic wound healing

Antimicrobial peptide derived from insulin‐like growth factor‐binding protein 5 improves diabetic wound healing

Diabetic Wound-Healing Science

Gene losses in the common vampire bat illuminate molecular adaptations to blood feeding

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