IL-17 in wound repair: bridging acute and chronic responses.

Chronic wounds, resulting from persistent inflammation, can trigger a cascade of detrimental effects including exacerbating inflammatory cytokines, compromised blood circulation at the wound site, elevation of white blood cell count, increased reactive oxygen species, and the potential risk of bacterial infection. The interleukin-17 (IL-17) signaling pathway, which plays a crucial role in regulating immune responses, has been identified as a promising target for treating inflammatory skin diseases. This review aims to delve deeper into the potential pathological role and molecular mechanisms of the IL-17 family and its pathways in wound repair. The intricate interactions between IL-17 and other cytokines will be discussed in detail, along with the activation of various signaling pathways, to provide a comprehensive understanding of IL-17's involvement in chronic wound inflammation and repair.

The cGAS-STING pathway: a therapeutic target in diabetes and its complications.

Diabetic wound healing (DWH) represents a major complication of diabetes where inflammation is a key impediment to proper healing. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway has emerged as a central mediator of inflammatory responses to cell stress and damage. However, the contribution of cGAS-STING activation to impaired healing in DWH remains understudied. In this review, we examine the evidence that cGAS-STING-driven inflammation is a critical factor underlying defective DWH. We summarize studies revealing upregulation of the cGAS-STING pathway in diabetic wounds and discuss how this exacerbates inflammation and senescence and disrupts cellular metabolism to block healing. Partial pharmaceutical inhibition of cGAS-STING has shown promise in damping inflammation and improving DWH in preclinical models. We highlight key knowledge gaps regarding cGAS-STING in DWH, including its relationships with endoplasmic reticulum stress and metal-ion signaling. Elucidating these mechanisms may unveil new therapeutic targets within the cGAS-STING pathway to improve healing outcomes in DWH. This review synthesizes current understanding of how cGAS-STING activation contributes to DWH pathology and proposes future research directions to exploit modulation of this pathway for therapeutic benefit.

The Role of p53 in Regulating Chronic Inflammation and PANoptosis in Diabetic Wounds.

Diabetic wounds represent a formidable challenge in the clinical management of diabetes mellitus, markedly diminishing the patient's quality of life. These wounds arise from a multifaceted etiology, with the pathophysiological underpinnings remaining elusive and complex. Diabetes precipitates neuropathies and vasculopathies in the lower extremities, culminating in infections, ulcerations, and extensive tissue damage. The hallmarks of non-healing diabetic wounds include senescence, persistent inflammation, heightened apoptosis, and attenuated cellular proliferation. The TP53 gene, a pivotal tumor suppressor frequently silenced in human malignancies, orchestrates cellular proliferation, senescence, DNA repair, and apoptosis. While p53 is integral in cell cycle regulation, its role in initial tissue repair appears to be deleterious. In typical cutaneous wounds, p53 levels transiently dip, swiftly reverting to baseline. Yet in diabetic wounds, protracted p53 activation impedes healing via two distinct pathways: i) activating the p53-p21-Retinoblastoma (RB) axis, which halts the cell cycle, and ii) upregulating the cGAS-STING and nuclear factor-kappaB (NF-κB) cascades, instigating ferroptosis and pyroptosis. Furthermore, p53 intersects with various metabolic pathways, including glycolysis, gluconeogenesis, oxidative phosphorylation, and autophagy. In diabetic wounds, p53 may drive metabolic reprogramming, thus potentially derailing macrophage polarization. This review synthesizes case studies investigating the therapeutic modulation of p53 in diabetic wounds care. In summation, p53 modulates chronic inflammation and cellular aging within diabetic cutaneous wounds and is implicated in a novel cell death modality, encompassing ferroptosis and pyroptosis, which hinders the reparative process.

Protective effect of solanesol in glucose-induced hepatocyte injury: Mechanistic insights on oxidative stress and mitochondrial preservation.

Solanesol is a tetra sesquiterpene enol with various biological activities. Modern medical studies have confirmed that solanesol has the function of lipid antioxidation and scavenges free radicals. This study aimed to investigate the protective effect of solanesol against oxidative damage induced by high glucose on human normal hepatocytes (L-02 cells) and its possible mechanism. The results showed that solanesol could effectively improve the decrease of cell viability induced by high glucose, decrease the contents of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) in the extracellular medium, increased the enzyme activities of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), catalase (CAT), balanced the level of reactive oxygen species (ROS) in cells, inhibited lipid peroxidation of all kinds of biological membranes, and restored mitochondrial membrane potential (MMP). In addition, Solanesol also inhibited the expression of Keap1, promoted the nuclear translocation of Nrf2 by hydrogen bonding with Nrf2, and activated the expression of downstream antioxidant factors NQO1 and HO-1. Altogether, these findings suggest that solanesol may be a potential protectant against diabetic liver injury.

Piezo1 in skin wound healing and related diseases: Mechanotransduction and therapeutic implications.

Skin wound healing is a multifaceted and intricate process involving inflammation, tissue proliferation, and scar formation, all of which are accompanied by the continuous application of mechanical forces. Mechanotransduction is the mechanism by which the skin receives and reacts to physical signals from the internal and external environment, converting them into intracellular biochemical signals. This intricate process relies on specialized proteins known as mechanotransducers, with Piezo1 being a critical mechanosensitive ion channel that plays a central role in this process. This article provides an overview of the structural characteristics of Piezo1 and summarizes its effects on corresponding cells or tissues at different stages of skin trauma, including how it regulates skin sensation and skin-related diseases. The aim is to reveal the potential diagnostic and therapeutic value of Piezo1 in skin trauma and skin-related diseases. Piezo1 has been reported to be a vital mediator of mechanosensation and transduction in various organs and tissues. Given its high expression in the skin, Piezo1, as a significant cell membrane ion channel, is essential in activating intracellular signaling cascades that trigger several cellular physiological functions, including cell migration and muscle contraction. These functions contribute to the regulation and improvement of wound healing.

Neuropeptide substance P: A promising regulator of wound healing in diabetic foot ulcers.

In the past, neuropeptide substance P (SP) was predominantly recognized as a neuroinflammatory factor, while its potent healing activity was overlooked. This paper aims to review the regulatory characteristics of neuropeptide SP in both normal and diabetic wound healing. SP actively in the regulation of wound healing-related cells directly and indirectly, exhibiting robust inflammatory properties, promoting cell proliferation and migration and restoring the activity and paracrine ability of skin cells under diabetic conditions. Furthermore, SP not only regulates healing-related cells but also orchestrates the immune environment, thereby presenting unique and promising application prospects in wound intervention. As new SP-based preparations are being explored, SP-related drugs are poised to become an effective therapeutic intervention for diabetic foot ulcers (DFU).

Targeting DNA methylation and demethylation in diabetic foot ulcers.

BACKGROUND: Poor wound healing is a significant complication of diabetes, which is commonly caused by neuropathy, trauma, deformities, plantar hypertension and peripheral arterial disease. Diabetic foot ulcers (DFU) are difficult to heal, which makes patients susceptible to infections and can ultimately conduce to limb amputation or even death in severe cases. An increasing number of studies have found that epigenetic alterations are strongly associated with poor wound healing in diabetes. AIM OF REVIEW: This work provides significant insights into the development of therapeutics for improving chronic diabetic wound healing, particularly by targeting and regulating DNA methylation and demethylation in DFU. Key scientific concepts of review: DNA methylation and demethylation play an important part in diabetic wound healing, via regulating corresponding signaling pathways in different breeds of cells, including macrophages, vascular endothelial cells and keratinocytes. In this review, we describe the four main phases of wound healing and their abnormality in diabetic patients. Furthermore, we provided an in-depth summary and discussion on how DNA methylation and demethylation regulate diabetic wound healing in different types of cells; and gave a brief summary on recent advances in applying cellular reprogramming techniques for improving diabetic wound healing.

Fibroblasts: Immunomodulatory factors in refractory diabetic wound healing.

Diabetes is a systemic disease in which patients with diabetes may develop peripheral neuropathy of the lower extremities and peripheral vascular disease due to long-term continuous exposure to high glucose. Delayed wound healing in diabetes is one of the major complications of diabetes. Slow wound healing in diabetic patients is associated with high glucose toxicity. When the condition deteriorates, the patient needs to be amputated, which seriously affects the quality of life and even endangers the life of the patient. In general, the delayed healing of diabetes wound is due to the lack of chemokines, abnormal inflammatory response, lack of angiogenesis and epithelial formation, and fibroblast dysfunction. The incidence of several chronic debilitating conditions is increasing in patients with diabetes, such as chronic renal insufficiency, heart failure, and hepatic insufficiency. Fibrosis is an inappropriate deposition of extracellular matrix (ECM) proteins. It is common in diabetic patients causing organ dysfunction. The fibrotic mechanism of diabetic fibroblasts may involve direct activation of permanent fibroblasts. It may also involve the degeneration of fibers after hyperglycemia stimulates immune cells, vascular cells, or organ-specific parenchymal cells. Numerous studies confirm that fibroblasts play an essential role in treating diabetes and its complications. The primary function of fibroblasts in wound healing is to construct and reshape the ECM. Nowadays, with the widespread use of single-cell RNA sequencing (scRNA-seq), an increasing number of studies have found that fibroblasts have become the critical immune sentinel cells, which can detect not only the activation and regulation of immune response but also the molecular pattern related to the injury. By exploring the heterogeneity and functional changes of fibroblasts in diabetes, the manuscript discusses that fibroblasts may be used as immunomodulatory factors in refractory diabetic wound healing, providing new ideas for the treatment of refractory diabetic wound healing.

Pyroptosis and inflammasomes in diabetic wound healing.

Diabetic wound is one of the complications of diabetes and is not easy to heal. It often evolves into chronic ulcers, and severe patients will face amputation. Compared with normal wounds, diabetic wounds have an increased proportion of pro-inflammatory cytokines that are detrimental to the normal healing response. The burden of this disease on patients and healthcare providers is overwhelming, and practical solutions for managing and treating diabetic wounds are urgently needed. Pyroptosis, an inflammatory type of programmed cell death, is usually triggered by the inflammasome. The pyroptosis-driven cell death process is primarily mediated by the traditional signaling pathway caused by caspase -1 and the non-classical signaling pathways induced by caspase -4/5/11. Growing evidence that pyroptosis promotes diabetic complications, including diabetic wounds. In addition, inflammation is thought to be detrimental to wound healing. It is worth noting that the activation of the NLRP3 inflammasome plays a crucial role in the recovery of diabetic wounds. This review has described the mechanisms of pyroptosis-related signaling pathways and their impact on diabetic wounds. It has discussed new theories and approaches to promote diabetic wound healing, as well as some potential compounds targeting pyroptosis and inflammasome signaling pathways that could be new approaches to treating diabetic wounds.

Molecular mechanisms of Marine-Derived Natural Compounds as photoprotective strategies.

Excessive exposure of the skin to ultraviolet radiation (UVR) causes oxidative stress, inflammation, immunosuppression, apoptosis, and changes in the extracellular matrix, which lead to the development of photoaging and photodamage of skin. At the molecular level, these pathological changes are mainly caused by the activation of related protein kinases and downstream transcription pathways, the increase of matrix metalloproteinase, the formation of reactive oxygen species, and the combined action of cytokines and inflammatory mediators. At present, the photostability, toxicity, and damage to marine ecosystems of most sun protection products in the market have affected their efficacy and safety. Another way is to use natural products produced by various marine species. Marine organisms have evolved a variety of molecular strategies to protect themselves from the harmful effects of ultraviolet radiation, and their unique chemicals have attracted more and more attention in the research of photoprotection and photoaging resistance. This article provides an extensive description of the recent literature on the potential of Marine-Derived Natural Compounds (MDNCs) as photoprotective and photoprotective agents. It reviews the positive effects of MDNCs in counteracting UV-induced oxidative stress, inflammation, DNA damage, apoptosis, immunosuppression, and extracellular matrix degradation. Some MDNCs have the potential to develop feasible solutions for related phenomena, such as photoaging and photodamage caused by UVR.

Dendrobium nobile Lindl. Polysaccharides protect fibroblasts against UVA-induced photoaging via JNK/c-Jun/MMPs pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Dendrobium nobile Lindl. is an orchid species that is found throughout Asia, including Thailand, Laos, Vietnam, and China. It has been used to treat tumors, hyperglycemia, hyperlipidemia, and neurological disorders caused by aging in recent decades. AIM OF THE STUDY: To investigate the antagonistic effect of Dendrobium nobile Lindl. Polysaccharides (DNLP) on UVA-induced photoaging of Human foreskin fibroblasts (HFF-1) and explore its possible anti-aging mechanisms. MATERIALS AND METHODS: An in vitro photoaging model of dermal fibroblasts was established with multiple UVA irradiations. Fibroblasts were treated with 0.06 mg/ml, 0.18 mg/ml, 0.54 mg/ml of DNLP one day before photodamage induction. The levels of reactive oxygen species (ROS), Malondialdehyde (MDA), cell viability and longevity, Superoxide Dismutase (SOD), Catalase (CAT), and Glutathione peroxidase (GSH-Px) enzymatic activities were determined. We examined how DNLP ameliorates the effects of photoaging, the JNK/c-Fos/c-Jun pathway, senescence-associated ß-galactosidase (SA-ß-Gal), and MMP expression levels were measured. RESULTS: UVA irradiation reduced the viability, lifespan, and proliferation of HFF-1 cells, increased ROS and lipid peroxidation and decreased the activities of free radical scavenging enzyme systems SOD, CAT, and GSH-Px. DNLP treatment can reverse UVA damage, reduce SA-ß-Gal expression, reduce phosphorylation activation of the JNK/c-Fos/c-Jun pathway and inhibit MMP-1, MMP-2 MMP-3, and MMP-9 protein expression. CONCLUSIONS: DNLP can effectively inhibit UVA damage to HFF-1 and prevent cell senescence. Its mechanism of action may increase antioxidant enzyme activity while inhibiting JNK pathway activation and MMPs expression.

Macrophage polarization in diabetic wound healing.

Impaired wound healing is one of the severe complications of diabetes. Macrophages have been shown to play a vital role in wound healing. In different wound environments, macrophages are classified into two phenotypes: classically activated macrophages and alternatively activated macrophages. Dysregulation of macrophage phenotypes leads to severely impaired wound healing in diabetes. Particularly, uncontrolled inflammation and abnormal macrophage phenotype are important reasons hindering the closure of diabetic wounds. This article reviews the functions of macrophages at various stages of wound healing, the relationship between macrophage phenotypic dysregulation and diabetic wound healing and the mechanism of macrophage polarization in diabetic wound healing. New therapeutic drugs targeting phagocyte polarization to promote the healing of diabetic wounds might provide a new strategy for treating chronic diabetic wound healing.