Role of sirtuins in attenuating plaque vulnerability in atherosclerosis.

Atherosclerosis is characterized by the development of intimal plaque, thrombosis, and stenosis of the vessel lumen causing decreased blood flow and hypoxia precipitating angina. Chronic inflammation in the stable plaque renders it unstable and rupture of unstable plaques results in the formation of emboli leading to hypoxia/ischemia to the organs by occluding the terminal branches and precipitate myocardial infarction and stroke. Such delibitating events could be controlled by the strategies that prevent plaque development or plaque stabilization. Despite the use of statins to stabilize plaques, there is a need for novel targets due to continuously increasing cases of cardiovascular events. Sirtuins (SIRTs), a family of signaling proteins, are involved in sustaining genome integrity, DNA damage response and repair, modulating oxidative stress, aging, inflammation, and energy metabolism. SIRTs play a critical role in modulating inflammation and involves in the development and progression of atherosclerosis. The role of SIRTs in relation to atherosclerosis and plaque vulnerability is scarcely discussed in the literature. Since SIRTs regulate oxidative stress, inflammation, and aging, they may also regulate plaque progression and vulnerability as these molecular mechanisms underlie the pathogenesis of plaque development, progression, and vulnerability. This review critically discusses the role of SIRTs in plaque progression and vulnerability and the possibility of targeting SIRTs to attenuate plaque rupture, focusing on the highlights in genomics, molecular pathways, and cell types involved in the underlying pathophysiology.

Cholesterol crystal formation is a unifying pathogenic mechanism in the development of diabetic retinopathy.

AIMS/HYPOTHESIS: Hyper-reflective crystalline deposits found in retinal lesions have been suggested to predict the progression of diabetic retinopathy, but the nature of these structures remains unknown. METHODS: Scanning electron microscopy and immunohistochemistry were used to identify cholesterol crystals (CCs) in human donor, pig and mouse tissue. The effects of CCs were analysed in bovine retinal endothelial cells in vitro and in db/db mice in vivo using quantitative RT-PCR, bulk RNA sequencing, and cell death and permeability assays. Cholesterol homeostasis was determined using 2H2O and 2H7-cholesterol. RESULTS: We identified hyper-reflective crystalline deposits in human diabetic retina as CCs. Similarly, CCs were found in the retina of a diabetic mouse model and a high-cholesterol diet-fed pig model. Cell culture studies demonstrated that treatment of retinal cells with CCs can recapitulate all major pathogenic mechanisms leading to diabetic retinopathy, including inflammation, cell death and breakdown of the blood-retinal barrier. Fibrates, statins and α-cyclodextrin effectively dissolved CCs present in in vitro models of diabetic retinopathy, and prevented CC-induced endothelial pathology. Treatment of a diabetic mouse model with α-cyclodextrin reduced cholesterol levels and CC formation in the retina, and prevented diabetic retinopathy. CONCLUSIONS/INTERPRETATION: We established that cholesterol accumulation and CC formation are a unifying pathogenic mechanism in the development of diabetic retinopathy.

Single-cell genomics illustrates heterogeneous phenotypes of myocardial fibroblasts under ischemic insults.

Myocardial regenerative strategies are promising where the choice of ideal cell population is crucial for successful translational applications. Herein, we explored the regenerative/repair responses of infarct zone cardiac fibroblast(s) (CF) by unveiling their phenotype heterogeneity at single-cell resolution. CF were isolated from the infarct zone of Yucatan miniswine that suffered myocardial infarction, cultured under simulated ischemic and reperfusion, and grouped into control, ischemia, and ischemia/reperfusion. The single-cell RNA sequencing analysis revealed 19 unique cell clusters suggesting distinct subpopulations. The status of gene expression (log2 fold change (log2 FC) > 2 and log2 FC < -2) was used to define the characteristics of each cluster unveiling with diverse features, including the pro-survival/cardioprotective (Clusters 1, 3, 5, 9, and 18), vasculoprotective (Clusters 2 and 5), anti-inflammatory (Clusters 4 and 17), proliferative (Clusters 4 and 5), nonproliferative (Clusters 6, 8, 11, 16, 17, and 18), proinflammatory (Cluster 6), profibrotic/pathologic (Clusters 8 and 19), antihypertrophic (Clusters 8 and 10), extracellular matrix restorative (Clusters 9 and 12), angiogenic (Cluster 16), and normal (Clusters 7 and 15) phenotypes. Further understanding of these unique phenotypes of CF will provide significant translational opportunities for myocardial regeneration and cardiac management.

Hyperlipidemia in tendon injury: chronicles of low-density lipoproteins.

Hyperlipidemia impacts millions of people globally and has been the major risk factor for developing atherosclerosis and cardiovascular disease. Interestingly, hyperlipidemic subjects exhibit increased incidence of rotator cuff tendon injury (RCTI) and disorganization of tendon matrix. Low-density lipoproteins (LDL) and its oxidized form (ox-LDL) play a crucial role in hyperlipidemia-driven pro-inflammatory responses in multiple tissues including the tendon. The signaling of oxLDL upregulates the inflammatory cytokines, chemokines, adhesion molecules, and the activation of monocytes/macrophages/resident tendon cells and matrix metalloproteinases impairing the tendon homeostasis resulting in the alteration of extracellular matrix. In addition, the hyperlipidemia-driven immune response and subsequent oxidative stress promote degenerative responses in the tendon tissue. However, the pathological mechanisms underlying the occurrence of RCTI in hyperlipidemia and the effect of ox-LDL in tendon matrix are currently unknown. The present review focuses on the implications and perspectives of LDL/oxLDL on the increased incidence of RCTI.

Carboxymethyl cellulose-alginate interpenetrating hydroxy ethyl methacrylate crosslinked polyvinyl alcohol reinforced hybrid hydrogel templates with improved biological performance for cardiac tissue engineering.

Cardiac tissue engineering is an emerging approach for cardiac regeneration utilizing the inherent healing responses elicited by the surviving heart using biomaterial templates. In this study, we aimed to develop hydrogel scaffolds for cardiac tissue regeneration following myocardial infarction (MI). Two superabsorbent hydrogels, CAHA2A and CAHA2AP, were developed employing interpenetration chemistry. CAHA2A was constituted with alginate, carboxymethyl cellulose, (hydroxyethyl) methacrylate, and acrylic acid, where CAHA2AP was prepared by interpenetrated CAHA2A with polyvinyl alcohol. Both hydrogels displayed superior physiochemical characteristics, as determined by attenuated total reflection infrared spectroscopy spectral analysis, differential scanning calorimetry measurements, tensile testing, contact angle, water profiling, dye release, and conductivity. In vitro degradation of the hydrogels displayed acceptable weight composure and pH changes. Both hydrogels were hemocompatible, and biocompatible as evidenced by direct contact and MTT assays. The hydrogels promoted anterograde and retrograde migration as determined by the z-stack analysis using H9c2 cells grown with both gels. Additionally, the coculture of the hydrogels with swine epicardial adipose tissue cells and cardiac fibroblasts resulted in synchronous growth without any toxicity. Also, both hydrogels facilitated the production of extracellular matrix by the H9c2 cells. Overall, the findings support an appreciable in vitro performance of both hydrogels for cardiac tissue engineering applications.

Male or female sex: considerations and translational aspects in diabetic foot ulcer research using rodent models.

Treatment of nonhealing diabetic foot ulcers (DFUs) is a major clinical concern and challenge for clinicians. Despite the advancement in treatment strategies, there is no definitive treatment for complicated nonhealing DFUs. Animal models are crucial for understanding pathogenesis and investigating novel therapeutic small molecules and the rodent model is commonly used for research related to cutaneous wound healing. Sexual dimorphism and its effect on the efficacy of sex hormones in enhancing healing in cutaneous wounds using a rodent model have been discussed, however, there is a lack of data related to diabetic foot ulcers. Further, the effects of sexual dimorphism on the issues related to induction of diabetes, differential immune response, type and size of the wound, the effectiveness of topical versus systemic treatment, and molecular mechanisms involved in wound healing like hemostasis, granulation tissue formation, the response of keratinocytes and fibroblasts, inflammation, and skin anatomy are scarcely discussed. Understanding these aspects is of significance and will help in choosing the correct sex, species, and strain of rodents while investigating therapeutic small molecules for DFUs. This review critically summarized these issues and their translational aspects followed by highlighting the effect of sexual dimorphism on these important aspects.

Role of oncostatin-M in ECM remodeling and plaque vulnerability.

Atherosclerosis is a multifactorial inflammatory disease characterized by the development of plaque formation leading to occlusion of the vessel and hypoxia of the tissue supplied by the vessel. Chronic inflammation and altered collagen expression render stable plaque to unstable and increase plaque vulnerability. Thinned and weakened fibrous cap results in plaque rupture and formation of thrombosis and emboli formation leading to acute ischemic events such as stroke and myocardial infarction. Inflammatory mediators including TREM-1, TLRs, MMPs, and immune cells play a critical role in plaque vulnerability. Among the other inflammatory mediators, oncostatin-M (OSM), a pro-inflammatory cytokine, play an important role in the development and progression of atherosclerosis, however, the role of OSM in plaque vulnerability and extracellular matrix remodeling (ECM) is not well understood and studied. Since ECM remodeling plays an important role in atherosclerosis and plaque vulnerability, a detailed investigation on the role of OSM in ECM remodeling and plaque vulnerability is critical. This is important because the role of OSM has been discussed in the context of proliferation of vascular smooth muscle cells and regulation of cytokine expression but the role of OSM is scarcely discussed in relation to ECM remodeling and plaque vulnerability. This review focuses on critically discussing the role of OSM in ECM remodeling and plaque vulnerability.

Residual risks and evolving atherosclerotic plaques.

Atherosclerotic disease of the coronary and carotid arteries is the primary global cause of significant mortality and morbidity. The chronic occlusive diseases have changed the epidemiological landscape of health problems both in developed and the developing countries. Despite the enormous benefit of advanced revascularization techniques, use of statins, and successful attempts of targeting modifiable risk factors, like smoking and exercise in the last four decades, there is still a definite "residual risk" in the population, as evidenced by many prevalent and new cases every year. Here, we highlight the burden of the atherosclerotic diseases and provide substantial clinical evidence of the residual risks in these diseases despite advanced management settings, with emphasis on strokes and cardiovascular risks. We critically discussed the concepts and potential underlying mechanisms of the evolving atherosclerotic plaques in the coronary and carotid arteries. This has changed our understanding of the plaque biology, the progression of unstable vs stable plaques, and the evolution of plaque prior to the occurrence of a major adverse atherothrombotic event. This has been facilitated using intravascular ultrasound, optical coherence tomography, and near-infrared spectroscopy in the clinical settings to achieve surrogate end points. These techniques are now providing exquisite information on plaque size, composition, lipid volume, fibrous cap thickness and other features that were previously not possible with conventional angiography.

Pathological alterations in the expression status of rotator cuff tendon matrix components in hyperlipidemia.

Hyperlipidemia is an important risk factor in the development and progression of tendon pathology, however its role in aggravating rotator cuff tendon injury (RCTI) is largely unknown. We aimed to assess the expression status of key extracellular matrix (ECM) components in the tendon tissues and tenocytes under hyperlipidemia. Shoulder rotator cuff (RC) tendon tissues harvested from the swine model of hyperlipidemia displayed alterations in histomorphometry and the expression status of major ECM component proteins including COL-I, COL-III, COL-IV, COL-V, COL-VI, MMP2, and MMP9. Similarly, the LDL- and oxLDL-challenged tenocytes displayed altered expression of the same proteins at both transcriptional and translational levels. In addition, the lipid uptake and cellular reactive oxygen radicals predominated in the lipid-challenged tenocytes compared to the control. Overall, the LDL-treated cells displayed predominant pathological alterations compared to the ox-LDL-treated cells. Further understanding regarding the underlying molecular mechanisms driving the tendon matrisome alteration and subsequent aggravated RCTI pathology in hyperlipidemia could open novel translational avenues in the management of RCTI.

Role of fibroblast plasticity and heterogeneity in modulating angiogenesis and healing in the diabetic foot ulcer.

Chronic diabetic foot ulcers (DFUs) are an important clinical issue faced by clinicians despite the advanced treatment strategies consisting of wound debridement, off-loading, medication, wound dressings, and keeping the ulcer clean. Non-healing DFUs are associated with the risk of amputation, increased morbidity and mortality, and economic stress. Neo-angiogenesis and granulation tissue formation are necessary for physiological DFU healing and acute inflammation play a key role in healing. However, chronic inflammation in association with diabetic complications holds the ulcer in the inflammatory phase without progressing to the resolution phase contributing to non-healing. Fibroblasts acquiring myofibroblasts phenotype contribute to granulation tissue formation and angiogenesis. However, recent studies suggest the presence of five subtypes of fibroblast population and of changing density in non-healing DFUs. Further, the association of fibroblast plasticity and heterogeneity with wound healing suggests that the switch in fibroblast phenotype may affect wound healing. The fibroblast phenotype shift and altered function may be due to the presence of chronic inflammation or a diabetic wound microenvironment. This review focuses on the role of fibroblast plasticity and heterogeneity, the effect of hyperglycemia and inflammatory cytokines on fibroblasts, and the interaction of fibroblasts with other cells in diabetic wound microenvironment in the perspective of DFU healing. Next, we summarize secretory, angiogenic, and angiostatic phenotypes of fibroblast which have been discussed in other organ systems but not in relation to DFUs followed by the perspective on the role of their phenotypes in promoting angiogenesis in DFUs.

Novel mediators regulating angiogenesis in diabetic foot ulcer healing.

A non-healing diabetic foot ulcer (DFU) is a debilitating clinical problem amounting to socioeconomic and psychosocial burdens. DFUs increase morbidity due to prolonged treatment and mortality in the case of non-treatable ulcers resulting in gangrene and septicemia. The overall amputation rate of the lower extremity with DFU ranges from 3.34% to 42.83%. Wound debridement, antibiotics, applying growth factors, negative pressure wound therapy, hyperbaric oxygen therapy, topical oxygen, and skin grafts are common therapies for DFU. However, recurrence and nonhealing ulcers are still major issues. Chronicity of inflammation, hypoxic environment, poor angiogenesis, and decreased formation of the extracellular matrix (ECM) are common impediments leading to nonhealing patterns of DFUs. Angiogenesis is crucial for wound healing since proper vessel formation facilitates nutrients, oxygen, and immune cells to the ulcer tissue to help in clearing out debris and facilitate healing. However, poor angiogenesis due to decreased expression of angiogenic mediators and matrix formation results in nonhealing and ultimately amputation. Multiple proangiogenic mediators and vascular endothelial growth factor (VEGF) therapy exist to enhance angiogenesis, but the results are not satisfactory. Thus, there is a need to investigate novel pro-angiogenic mediators that can either alone or in combination enhance the angiogenesis and healing of DFUs. In this article, we critically reviewed the existing pro-angiogenic mediators followed by potentially novel factors that might play a regulatory role in promoting angiogenesis and wound healing in DFUs.

Biomarkers for Early Detection, Prognosis, and Therapeutics of Esophageal Cancers.

Esophageal cancer (EC) is the deadliest cancer worldwide, with a 92% annual mortality rate per incidence. Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are the two major types of ECs, with EAC having one of the worst prognoses in oncology. Limited screening techniques and a lack of molecular analysis of diseased tissues have led to late-stage presentation and very low survival durations. The five-year survival rate of EC is less than 20%. Thus, early diagnosis of EC may prolong survival and improve clinical outcomes. Cellular and molecular biomarkers are used for diagnosis. At present, esophageal biopsy during upper endoscopy and histopathological analysis is the standard screening modality for both ESCC and EAC. However, this is an invasive method that fails to yield a molecular profile of the diseased compartment. To decrease the invasiveness of the procedures for diagnosis, researchers are proposing non-invasive biomarkers for early diagnosis and point-of-care screening options. Liquid biopsy involves the collection of body fluids (blood, urine, and saliva) non-invasively or with minimal invasiveness. In this review, we have critically discussed various biomarkers and specimen retrieval techniques for ESCC and EAC.

Bioactive extracellular matrix fragments in tendon repair.

Tendinopathy is a common tendon disorder that causes pain, loss of strength and function, and local inflammation mainly characterized by hypoxia, collagen degradation, and extracellular matrix (ECM) disorganization. Generally, ECM degradation and remodeling is tightly regulated; however, hyperactivation of matrix metalloproteases (MMPs) contributes to excessive collagenolysis under pathologic conditions resulting in tendon ECM degradation. This review article focuses on the production, function, and signaling of matrikines for tendon regeneration following injury with insights into the expression, tissue compliance, and cell proliferation exhibited by various matrikines. Furthermore, the regenerative properties suggest translational significance of matrikines to improve the outcomes post-injury by assisting with tendon healing.

Toll-like receptors and damage-associated molecular patterns in the pathogenesis of heart transplant rejection.

Significant strides have been made in our understanding of the immune system and its role in cardiac transplant rejection. Despite the growing knowledge of immune responses, the mortality rate following cardiac transplantation remains grim. Related to procedural and pathological complications, toll-like receptor (TLR) and damage-associated molecular pattern (DAMP) signaling is the most direct and earliest interface between tissue integration and the innate immune response. This in turn can activate an adaptive immune response that further damages myocardial tissue. Furthermore, relevant literature on the status of DAMPs in the context of heart-transplantation remains limited, warranting further attention in clinical and translational research. This review aims to critically appraise the perspectives, advances, and challenges on DAMP-mediated innate immune response in the immune-mediated rejection of cardiac transplantation. Detailed analysis of the influence of TLR and DAMP signaling in mounting the immune response against the transplanted heart holds promise for improving outcomes through early detection and prevention of varied forms of organ rejection.

Clinically relevant experimental rodent models of diabetic foot ulcer.

Chronic wounds are a substantial clinical problem in diabetes and nearly 6% of diabetics suffer from foot disease including ulceration, infection, and tissue necrosis. Wound healing in diabetes is impaired and delayed and is augmented by diabetic complications. Wound healing involves complex cellular, molecular, and biochemical processes and animal models are the most suitable prototype to investigate and understand the underlying pathological changes in the process of wound healing. Animal models are also useful in evaluating the safety and efficacy of newer therapeutic agents and improving the clinical approaches for human patients with chronic ulcers. The wound healing strategies get more complicated in the presence of diabetes and its associated complication. Despite the advancement in methods of wound healing, the healing of the chronic diabetic foot ulcer (DFU) remains an important clinical problem resulting in costly and prolonged treatment and poses a risk for major amputation. Saying that it is important to elucidate the newer therapeutic targets and strategies via an in-depth understanding of the complicated cascade of the chronic DFU. A major challenge in translating lab findings to clinics is the lack of an optimal preclinical model capable of properly recapitulating human wounds. Both small and large animal models of wound healing involving rodents, rabbits, and pigs have been discussed. Mouse and rats as small animal models and pig as large animal models have been discussed in association with the diabetic wound but there are advantages and limitations for each model. In this review, we critically reviewed the pros and cons of experimental models of diabetic wound healing with a focus on type II diabetes rodent models.

Ocular transmissibility of COVID-19: possibilities and perspectives.

Since the initial outbreak of coronavirus disease 2019 (COVID-19), extensive research has emerged from across the globe to understand the pathophysiology of this novel coronavirus. Transmission of this virus is a subject of particular interest as researchers work to understand which protective and preventative measures are most effective. Despite the well understood model of aerosol-respiratory mediated transmission, the exact mechanism underlying the inoculation, infection and spread of COVID-19 is currently unknown. Given anatomical positioning and near constant exposure to aerosolized pathogens, the eye may be a possible gateway for COVID-19 infection. This critical review explores the possibility of an ocular-systemic or ocular-nasal-pulmonic pathway of COVID-19 infection and includes novel insights into the possible immunological mechanisms leading to cytokine surge.

Design of the lentivirus-driven sustained LR12 delivery system for TREM-1 inhibition for palliating atherosclerosis.

Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) has been a potential target in the management of pathophysiology and clinical sequelae of atherosclerosis. LR12 peptide effectively blocks ligand-TREM-1 interaction; however, the short half-life of LR12 is a major hurdle in its translational application in atherosclerosis management warranting new methods for sustained bioavailability in clinical applications. The present study reports a novel method of packing the coding sequence of LR12 in a lentiviral system to ensure a sustained expression and bioavailability for effective TREM-1 inhibition. Lentivirus vector systems (LV-LR12 and LV-SP) for the expression of LR12 peptide and SP (scrambled peptide) were successfully designed, constructed, and tested in vitro in smooth muscle cells (SMCs). Viral amounts obtained were 703.6 ± 145.12 and 609.3 ± 145.93 ng/ml p24 for LV-LR12 and LV-SP, respectively which correspond to ~ 107 IFU/ml for both vectors. Dot blot assay revealed significantly increased expression of LR12-FLAG and SP-FLAG in 125 µg total protein which was doubled in 250 µg protein with respect to un-transduced SMCs suggesting the sustained release of LR12/SP as confirmed by ELISA. Cellular expression of LR12-FLAG and SP-FLAG displayed 8.44-fold and 7.55-fold increase, respectively compared to the control SMCs. The findings demonstrated a promising strategy for packing the LR12 coding sequence in lentiviral vector for TREM-1 inhibition for the management of atherosclerosis and other inflammatory diseases.

Recent advances in the development of active hybrid molecules in the treatment of cardiovascular diseases.

Multifactorial nature of the underlying pathophysiology of chronic disorders hinders in the effective treatment and management of many complex diseases. The conventional targeted therapies have limited applications due to highly complicated disease etiology. Cardiovascular diseases (CVDs) are the group of disorders of the heart and blood vessels. Currently, there is limited knowledge on the underlying cellular and molecular mechanisms of many of the CVDs due to their complex pathophysiology and co-morbidities. Their management with conventional medications results in failure due to adverse drug reactions and clinical specificity of solo-targeting drug therapy. Therefore, it is critical to introduce an alternative strategy to treat multi-factorial diseases. In the past few years, discovery and use of multi-targeted drug therapy with hybrid molecules have shown promising results with minimal side effects, and thus considered a most effective approach. In this review article, prominent hybrid molecules combining with different active moieties are reported to synergistically and simultaneously block different pathways involved in CVDs. Here, we provide a critical evaluation and discussion on their pharmacology with mechanistic insights and the structure activity relationship. The timely information provided in this article reveals the recent trends of molecular hybridization to the scientific community interested in CVDs and help them in designing the next generation of multi-targeting drug therapeutics.

LPS and oxLDL-induced S100A12 and RAGE expression in carotid arteries of atherosclerotic Yucatan microswine.

BACKGROUND: S100A12, also known as Calgranulin C, is a ligand for the receptor for advanced glycation end products (RAGE) and plays key roles in cardiovascular and other inflammatory diseases. Interactions between S100A12 and RAGE initiate downstream signaling activating extracellular signal-regulated kinases (ERK1/2), mitogen activated protein kinases (MAPK), and transcription factor NF-κB. This increases the expression of pro-inflammatory cytokines to induce the inflammatory response. S100A12, and RAGE play a critical role in the development and progression of atherosclerosis. There is a well-known relationship between the bacterial endotoxin lipopolysaccharide (LPS) and the lipid antigens oxidized low-density lipoprotein (oxLDL) in driving the immune response in atherosclerosis. METHODS AND RESULTS: Our study aimed to compare the potential of LPS and oxLDL in regulating the expression of S100A12 and RAGE in atherosclerosis. The expression of these proteins was assessed in the harvested carotid arteries from LPS- and oxLDL-treated atherosclerotic Yucatan microswine. Tissues were collected from five different treatment groups: (i) angioplasty alone, (ii) LPS alone, (iii) oxLDL alone, (iv) angioplasty with LPS, and (v) angioplasty with oxLDL. Immunohistochemical findings revealed that angioplasty with LPS induced higher expression of S100A12 and RAGE compared to other treatment groups. The results were further corroborated by testing their gene expression through qPCR in cultured vascular smooth muscle cells (VSMCs) isolated from control carotid arteries and LPS- and oxLDL-treated arteries. CONCLUSIONS: The results of this study suggest that LPS induces the expression of S100A12 and RAGE more than oxLDL in atherosclerotic artery and both S100A12 and RAGE could be therapeutic targets.

The role of CXCL8 in chronic nonhealing diabetic foot ulcers and phenotypic changes in fibroblasts: a molecular perspective.

INTRODUCTION: A persistent inflammation is perpetuated by infiltrating immune cells and cytokines secreted from these immune cells. Additionally, apoptotic keratinocytes and adipocytes in diabetes causes diabetic foot ulcer (DFU) to arrest in an inflammatory phase without progressing to the resolution phase. This leads to a nonhealing DFU and, despite advanced treatments consisting of wound debridement, off-loading the ulcer of necrotic tissue, wound dressings to keep it moist and control exudate, medication, and preventing infection, DFUs remain a clinical problem. Nonhealing DFUs pose not only an economic burden but also increased morbidity and mortality in the form of psychological stress with and increased chance of amputation, and even death. Thus, investigating the complicated underlying molecular mechanism responsible for nonhealing patterns and designing better therapeutics is warranted. This review article focuses on the role of IL-8-mediated persistent inflammation and phenotypic change of fibroblasts due to this inflammatory cascade. We have discussed various sources of interleukin (IL)-8 secretion and the possible association of IL8-fibroblast plasticity as a cause of nonhealing DFUs. MATERIAL AND METHODS: A literature search on PubMed, Google Scholar, and PMC was done including the terms diabetic foot ulcer, diabetes, diabetic ulcer, chronic inflammation, interleukin 8, diabetic wound, and nonhealing diabetic foot ulcers. The articles in the English language and published in last 10 years were selected. From the pool of these, the articles describing the relationship between IL-8 and nonhealing diabetic foot ulcer and diabetic ulcer were used sorted out and used for this review article following PRISMA guidelines. CONCLUSION: Increased infiltration of inflammatory immune cells, secretion of pro-inflammatory cytokines, altered keratinocyte-fibroblast function, and phenotypic changes of fibroblasts in DFUs seem to be critical to the nonhealing of DFUs. Thus, inhibiting IL-8 secretion and downstream signaling seems to be a goal of potential therapeutics.