The Role of MicroRNAs in Impaired Diabetic Wound Healing

Diabetes mellitus is a worldwide pandemic, affecting 29 million Americans, resulting in substantial morbidity and mortality, and accounting for an annual healthcare expenditure exceeding $176 billion in the US alone. This burden of disease is the result of a progressive disease associated with numerous complications and the development of chronic wounds, which remain the leading cause of hospital admissions and nontraumatic lower extremity amputations in diabetic patients. Despite clinical strategies aimed at prevention and early detection, patients with diabetes continue to remain at risk of developing chronic diabetic wounds due to poor patient compliance and progression of the diabetic phenotype. Development of the diabetic phenotype and wound healing impairment is associated with dysregulation of microRNAs that regulate inflammation, extracellular matrix composition, and angiogenesis; here we present evidence from the studies that demonstrate correction of microRNA dysregulation expedites wound healing and reverses the diabetic skin phenotype

Inhibition of stromal cell-derived factor-1α further impairs diabetic wound healing

ObjectiveImpaired diabetic wound healing is associated with abnormal stromal cell-derived factor (SDF)-1α production, decreased angiogenesis, and chronic inflammation. Lentiviral-mediated overexpression of SDF-1α can correct the impairments in angiogenesis and healing in diabetic wounds. We hypothesized that SDF-1α is a critical component of the normal wound-healing response and that inhibition of SDF-1α would further delay the wound-healing process.MethodsdB/Db diabetic mice and Db/+ nondiabetic mice were wounded with an 8-mm punch biopsy and the wounds treated with a lentiviral vector containing either the green fluorescent protein (GFP) or SDF-1α inhibitor transgene. The inhibitor transgene is a mutant form of SDF-1α that binds, but does not activate, the CXCR4 receptor. Computerized planimetry was used to measure wound size daily. Wounds were analyzed at 3 and 7 days by histology and for production of inflammatory markers using real-time polymerase chain reaction. The effect of the SDF-1α inhibitor on cellular migration was also assessed.ResultsInhibition of SDF-1α resulted in a significant decrease in the rate of diabetic wound healing, (3.8 vs 6.5 cm2/day in GFP-treated wounds; P = .04), and also impaired the early phase of nondiabetic wound healing. SDF-1α inhibition resulted in fewer small-caliber vessels, less granulation tissue formation, and increased proinflammatory gene expression of interleukin-6 and macrophage inflammatory protein-2 in the diabetic wounds.ConclusionsThe relative level of SDF-1α in the wound plays a key role in the wound-healing response. Alterations in the wound level of SDF-1α, as seen in diabetes or by SDF-1α inhibition, impair healing by decreasing cellular migration and angiogenesis, leading to increased production of inflammatory cytokines and inflammation. Inhibition of SDF-1α further impairs diabetic wound healing.Clinical RelevanceDiabetes results in a significant impairment in wound healing, leading to significant morbidity and health care expenditures. The pathophysiology that underlies this process is multifactorial, including abnormal growth factor production, cellular migration, and cellular function. Stromal cell-derived factor (SDF)-1α is a key chemokine involved in the wound-healing process and is involved in cellular recruitment and angiogenesis. SDF-1α is decreased in diabetic individuals. This study showed that inhibition of SDF-1α results in an even more dramatic delay in the diabetic wound-healing process and even results in a delay in the early phases of wound healing in normal mice, further supporting its role in wound healing. Inhibition of this chemokine promotes greater inflammatory cytokine production, inflammatory cell migration, and less vasculogenesis after dermal wounding. This study identifies SDF-1α as an essential component of normal wound healing and provides a potential therapeutic target to improve the diabetic wound-healing impairment

Effects of microRNAs on angiogenesis in diabetic wounds

Diabetes mellitus is a morbid condition affecting a growing number of the world population, and approximately one third of diabetic patients are afflicted with diabetic foot ulcers (DFU), which are chronic non-healing wounds that frequently progress to require amputation. The treatments currently used for DFU focus on reducing pressure on the wound, staving off infection, and maintaining a moist environment, but the impaired wound healing that occurs in diabetes is a constant obstacle that must be faced. Aberrant angiogenesis is a major contributor to poor wound healing in diabetes and surgical intervention is often necessary to establish peripheral blood flow necessary for healing wounds. Over recent years, microRNAs (miRNAs) have been implicated in the dysregulation of angiogenesis in multiple pathologies including diabetes. This review explores the pathways of angiogenesis that become dysregulated in diabetes, focusing on miRNAs that have been identified and the mechanisms by which they affect angiogenesis

Cost-Effectiveness of HIV Testing Referral Strategies among Tuberculosis Patients in India

Background: Indian guidelines recommend routine referral for HIV testing of all tuberculosis (TB) patients in the nine states with the highest HIV prevalence, and selective referral for testing elsewhere. We assessed the clinical impact and cost-effectiveness of alternative HIV testing referral strategies among TB patients in India. Methods and Findings: We utilized a computer model of HIV and TB disease to project outcomes for patients with active TB in India. We compared life expectancy, cost, and cost-effectiveness for three HIV testing referral strategies: 1) selective referral for HIV testing of those with increased HIV risk, 2) routine referral of patients in the nine highest HIV prevalence states with selective referral elsewhere (current standard), and 3) routine referral of all patients for HIV testing. TB-related data were from the World Health Organization. HIV prevalence among TB patients was 9.0% in the highest prevalence states, 2.9% in the other states, and 4.9% overall. The selective referral strategy, beginning from age 33.50 years, had a projected discounted life expectancy of 16.88 years and a mean lifetime HIV/TB treatment cost of US$100. The current standard increased mean life expectancy to 16.90 years with additional per-person cost of US$10; the incremental cost-effectiveness ratio was US$650/year of life saved (YLS) compared to selective referral. Routine referral of all patients for HIV testing increased life expectancy to 16.91 years, with an incremental cost-effectiveness ratio of US$730/YLS compared to the current standard. For HIV-infected patients cured of TB, receiving antiretroviral therapy increased survival from 4.71 to 13.87 years. Results were most sensitive to the HIV prevalence and the cost of second-line antiretroviral therapy. Conclusions: Referral of all patients with active TB in India for HIV testing will be both effective and cost-effective. While effective implementation of this strategy would require investment, routine, voluntary HIV testing of TB patients in India should be recommended

SARS-CoV-2 receptor ACE2 gene expression in small intestine correlates with age

Gastrointestinal symptoms are common in COVID-19 patients, especially in younger patients. Our hypothesis was that intestinal SARS-CoV-2 receptor ACE2 expression depends on patients' age. We examined duodenal biopsies from 43 healthy human adults. ACE2 gene expression was directly correlated with age (Spearman's r = 0.317, p = 0.039). With each year, duodenal ACE2 expression increased by 0.083 RU. The higher intestinal ACE2 mRNA expression in older patients may impact on their susceptibility to develop intestinal symptoms

Role of microRNAs in Pressure Ulcer Immune Response, Pathogenesis, and Treatment

Pressure ulcers are preventable, yet highly prevalent, chronic wounds that have significant patient morbidity and high healthcare costs. Like other chronic wounds, they are characterized by impaired wound healing due to dysregulated immune processes. This review will highlight key biochemical pathways in the pathogenesis of pressure injury and how this signaling leads to impaired wound healing. This review is the first to comprehensively describe the current literature on microRNA (miRNA, miR) regulation of pressure ulcer pathophysiology

Long non-coding RNA Lethe regulates hyperglycemia-induced reactive oxygen species production in macrophages.

Type 2 diabetes mellitus is a complex, systemic metabolic disease characterized by insulin resistance and resulting hyperglycemia, which is associated with impaired wound healing. The clinical complications associated with hyperglycemia are attributed, in part, to the increased production of reactive oxygen species (ROS). Recent studies revealed that long non-coding RNAs (lncRNAs) play important regulatory roles in many biological processes. Specifically, lncRNA Lethe has been described as exhibiting an anti-inflammatory effect by binding to the p65 subunit of NFκB and blocking its binding to DNA and the subsequent activation of downstream genes. We therefore hypothesize that dysregulation of Lethe's expression plays a role in hyperglycemia-induced ROS production. To test our hypothesis, we treated RAW264.7 macrophages with low glucose (5 mM) or high glucose (25 mM) for 24h. High glucose conditions significantly induced ROS production and NOX2 gene expression in RAW cells, while significantly decreasing Lethe gene expression. Overexpression of Lethe in RAW cells eliminated the increased ROS production induced by high glucose conditions, while also attenuating the upregulation of NOX2 expression. Similar results was found also in non-diabetic and diabetic primary macrophage, bone marrow derived macrophage (BMM). Furthermore, overexpression of Lethe in RAW cells treated with high glucose significantly reduced the translocation of p65-NFkB to the nucleus, which resulted in decreased NOX2 expression and ROS production. Interestingly, these findings are consistent with the decreased Lethe gene expression and increased NOX2 gene expression observed in a mouse model of diabetic wound healing. These findings provide the first evidence that lncRNA Lethe is involved in the regulation of ROS production in macrophages through modulation of NOX2 gene expression via NFκB signaling. Moreover, this is the first report to describe a role of lncRNAs, in particular Lethe, in impaired diabetic wound healing. Further studies are warranted to determine if correction of Lethe expression in diabetic wounds could improve healing