Diabetes is a metabolic disorder that significantly impacts human health, with 25% of patients suffering from diabetic ulcers. Chronic persistent inflammation is one of the primary factors impeding wound healing in diabetes. As a recently identified adipocytokine, omentin-1 (also known as intelectin-1, ITLN1) demonstrates significant expression levels in the omentum, subcutaneous adipose tissue, and vascular endothelium, exhibiting potent anti-inflammatory characteristics. Emerging evidence indicates that this adipokine plays a crucial protective role in multiple inflammatory disorders, particularly in the pathogenesis of atherosclerosis, osteoarthritis, and inflammatory bowel disease. However, its therapeutic potential in diabetic wound healing remains unclear. Our experimental data demonstrated a marked downregulation of omentin-1 expression in cutaneous tissues obtained from the Streptozotocin (STZ)-induced diabetic murine model. Local administration of recombinant omentin-1 improved efferocytosis in impaired macrophages within the wound bed and promoted macrophage phenotypic switching to the reparative M2 phenotype, thereby attenuating inflammatory responses and accelerating wound healing in diabetic mice. Further mechanistic studies revealed that omentin-1 enhanced the expression of the key efferocytosis receptor MERTK (mer proto-oncogene tyrosine kinase) in diabetic wounds and facilitated macrophage efferocytosis through modulation of the downstream SRC/PI3K/Akt signaling cascade. Additionally, omentin-1 facilitated the polarization of macrophages toward the M2 phenotype and attenuated the inflammatory responses induced by lipopolysaccharide (LPS). The findings of this study indicate that omentin-1 suggests its potential as a candidate for developing novel adjunctive therapies for chronic non-healing diabetic wounds.

Introduction Ferroptosis significantly compromises diabetic wound healing and represents a promising therapeutic target for clinical intervention. Baicalein (Bai), a natural flavonoid, has been considered to own ferroptosis-regulating properties, while the underlying mechanisms remain understood. Objectives The study aims to investigate potential mechanisms by which Bai inhibits ferroptosis in endothelial cells and validate the therapeutic efficacy of Bai-loaded hydrogel on diabetic wounds. Methods High-glucose-cultured human umbilical vein endothelial cells (HUVECs) were chosen to study Bai’s molecular mechanisms inhibiting ferroptosis. Subsequently, a Bai@GA/Gel/Zn2+ supramolecular nanofibrous hydrogel was developed for active Bai delivery. Its wound-healing efficacy and underlying mechanisms were further evaluated in a diabetic rat model. Results In vitro experiments, HUVECs were observed to exhibit characteristic ferroptosis, which were induced by high-glucose (HG) microenvironment, leading to compromised cellular functions. Through the inhibition of ferroptosis in HUVECs, Bai effectively promoted cell growth, migration, and angiogenesis. Herein, we further reveal that Bai inhibits HG-induced ferroptosis by modulating the Keap1/NRF2/HIF-1α signaling axis. To optimize therapeutic delivery, Bai was encapsulated into supramolecular nanofibers self-assembled from glycyrrhizic acid (GA), followed by cross-linking with gelatin (Gel) and zinc ions (Zn2+) to form a hydrogel (Bai@GA/Gel/Zn2+), thereby enabling sustained release of Bai at the wound-healing interface. Bai@GA/Gel/Zn2+ nanofiber-incorporated hydrogel demonstrated favorable mechanical and biological properties, markedly reducing ferroptosis levels and accelerating diabetic wound healing. Conclusion In summary, our findings reveal the ferroptosis-inhibiting mechanism of Bai and develop a Bai@GA/Gel/Zn2+ supramolecular nanofibrous hydrogel that synergistically enhances diabetic wound healing with proven therapeutic efficacy.

Diabetes is a metabolic disease that affects global human health, with 25% of diabetic patients suffering from chronic non-healing ulcers. Omentin-1, also referred to as intelectin-1 and encoded by the itln1 gene, is a recently discovered adipokine that modulates inflammation, cellular activities, and vascular tone. Research indicates that omentin-1 provides protective benefits in several conditions, including atherosclerosis and diabetic retinopathy. Nevertheless, the therapeutic potential of omentin-1 in promoting diabetic wound healing is still not well understood. Our results revealed a significant decrease in ITLN1 levels in the cutaneous tissues of diabetic mice. Subcutaneous injection of omentin-1 reduced endothelial cell apoptosis, enhanced angiogenesis, and accelerated wound repair in diabetic mice. In vitro studies demonstrated that omentin-1 upregulated VEGF expression in endothelial cells, improved endothelial function under high-glucose conditions, reduced high glucose-induced endothelial apoptosis, and promoted endothelial tube formation. Further mechanistic studies revealed that omentin-1 improved endothelial function and promoted angiogenesis under high-glucose conditions by mediating the PI3K/AKT/FOXO1 pathway. Our results suggest that omentin-1 is a potential adjunct or therapeutic agent for treating chronic non-healing diabetic wounds by enhancing endothelial cell function and promoting vascularization.

Eucommia ulmoides Oliv (EUO) is a traditional therapeutic drug that tonifies the liver and kidney and may improve depression. However, the mechanism of action of the main component, aucubin (AU), is unknown. To study the therapeutic effect of AU, we constructed a chronic unpredictable mild stress (CUMS) depression model in mice. Depression-like behaviors, pathological damage, hormonal changes, inflammation, intranuclear expression of glucocorticoid receptor (GR), and hippocampal protein expression were assessed. Immunofluorescence staining of the hippocampus showed that CUMS decreased neuronal regeneration, and axons were observed to be reduced and broken. Intracellular GR expression decreased in the hippocampus and hypothalamus, and serum levels of stress hormones increased. Furthermore, molecular changes indicative of pyroptosis were observed. AU administration reversed these changes and significantly improved the depression-like behavior induced by CUMS. Our results suggested that AU improves depression by promoting the intranuclear expression of GR and inhibiting nuclear factor-kappa B-mediated inflammatory activation-driven cell pyroptosis.

Fibroblast activation disorder is one of the main pathogenic characteristics of diabetic wounds. Orchestrated fibroblast functions and myofibroblast differentiation are crucial for wound contracture and extracellular matrix (ECM) formation. Pyruvate dehydrogenase kinase 4 (PDK4), a key enzyme regulating energy metabolism, has been implicated in modulating fibroblast function, but its specific role in diabetic wounds remains poorly understood. In this study, we investigated the impact of PDK4 on diabetic wounds and its underlying mechanisms. To assess the effect of PDK4 on human dermal fibroblasts (HDFs), we conducted CCK-8, EdU proliferation assay, wound healing assay, transwell assay, flow cytometry, and western blot analyses. Metabolic shifts were analyzed using the Seahorse XF analyzer, while changes in metabolite expression were measured through LC-MS. Local recombinant PDK4 administration was implemented to evaluate its influence on wound healing in diabetic mice. Finally, we found that sufficient PDK4 expression is essential for a normal wound-healing process, while PDK4 is low expressed in diabetic wound tissues and fibroblasts. PDK4 promotes proliferation, migration, and myofibroblast differentiation of HDFs and accelerates wound healing in diabetic mice. Mechanistically, PDK4-induced metabolic reprogramming increases the level of succinate that inhibits PHD2 enzyme activity, thus leading to the stability of the HIF-1α protein, during which process the elevated HIF-1α mRNA by PDK4 is also indispensable. In conclusion, PDK4 promotes fibroblast functions through regulation of HIF-1α protein stability and gene expression. Local recombinant PDK4 administration accelerates wound healing in diabetic mice.

Patients with diabetic wounds may end with lower extremity amputation or death. Leucine-rich α-2-glycoprotein 1 (LRG1) is an effective regulator of angiogenesis and essential for timely wound healing. However, its role in regulating angiogenesis in diabetic wounds remains unclear. This study aimed to investigate the pro-angiogenic function of exogenous LRG1 in diabetic wound healing and explore possible mechanisms. LRG1 expression patterns following injury in normal and diabetic wounds were determined by western blotting. Local injection of LRG1 was used to verify the effects on angiogenesis and wound healing in diabetic rats. Immunohistochemical staining for CD31 was used to analyze the vessel density. Human umbilical vein endothelial cells (HUVECs) cultured in hyperglycemia were used to explore how LRG1 promotes angiogenesis in diabetic wound healing. We found that the expression peak of LRG1 around the wounds was delayed in diabetic rats compared with that in normal rats. Exogenous administration of LRG1 significantly accelerated the wound closure rate and promoted angiogenesis in diabetic rats. In addition, exogenous LRG1 effectively restored the proliferation, migration, and tube formation ability of HUVECs under hyperglycemia. Mechanistically, LRG1 promoted angiogenesis and diabetic wound healing mainly by activating the Wnt/β-catenin pathway, which is inhibited in diabetic wounds. This research suggests that LRG1 promotes angiogenesis and wound closure in diabetic rats by improving angiogenesis via activation of the Wnt/β-catenin pathway. Hence, LRG1 may be a possible therapeutic strategy for diabetic foot treatment.

Abstract Background Skin wound healing depends on the progress of different but overlapping stages of healing, including hemostasis, inflammatory, proliferative and remodeling. Failure of these stages to occur in a timely and gradual manner may result in non-healing pathological wounds. Macrophages and neutrophils have been shown to play an essential role in the inflammatory responses of wound tissue, and their active plasticity allows them to modulate tissue damage and repair functions. The ability of macrophages and neutrophils to regulate the occurrence and resolution of inflammatory processes is essential for the treatment of pathological wound healing. Methods Mice were categorized into negative control, streptozotocin, streptozotocin + puerarin and puerarin groups. The traditional Chinese medicine extract puerarin was selected to treat different groups of mice with a full-thickness skin defect wound. Cells of the RAW264.7 cell line were stimulated under different puerarin conditions. Then, real time quantitative polymerase chain reaction (RT-qPCR), western blot, immunofluorescence and other assays were carried out to explore the effect of puerarin on wound healing and its molecular mechanism. Results Animal experiments found that the wound healing of diabetic mice treated with puerarin was significantly accelerated, and histological analysis found that puerarin treatment markedly decreased the infiltration of macrophages and neutrophils in wound tissue. Through western blot, RT-qPCR and immunofluorescence experiments, it was observed that puerarin treatment remarkably inhibited nuclear factor kinase B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, downregulated the expression of inflammatory cytokines and induced the M2 polarization of macrophages. At the cellular level, we also observed that puerarin improved M2 macrophage polarization and inhibited inflammatory pathway activation in a high-glucose culture. Conclusion Puerarin has a significant therapeutic effect on wound healing in diabetic mice. The therapeutic effect is achieved by regulating macrophage polarization through suppressing NF-κB and MAPK signaling cascades.

Context Aucubin (AU), an iridoid glycoside that is one of the active constituents of Eucommia ulmoides Oliv. (EUO) (Eucommiaceae), a traditional Chinese medicine, has been extensively studied in the management of neurological diseases (NDs). However, a comprehensive review of its effects and mechanisms in this regard is currently not available.Objective To compile the protective effects and mechanisms of AU in NDs and provide a basis for further research.Methods We used ‘aucubin’ as the ‘All Fields’ or ‘MeSH’ in PubMed, Web of Science and China National Knowledge Infrastructure without any limitation to search all relevant articles as comprehensively as possible; we selected the articles on AU treatment of NDs for summary.Results Studies reviewed herein reported that AU improved the symptoms or prognosis of Parkinson’s disease, Alzheimer's disease, intracerebral haemorrhage, diabetic encephalopathy, epilepsy, anxiety and depression, and traumatic brain injury. The pharmacological mechanisms involved in repairing neuronal loss were postulated to include increasing γ-aminobutyric acid (GABA) content in the synapse, promoting differentiation of neural precursor cells into GABAergic neurons, providing antioxidant and anti-neuroinflammation activities, as well as enhancing autophagy and anti-apoptotic actions.Discussion and conclusions The protective effects of AU on some NDs have been confirmed. According to the pharmacological effects, AU is also highly likely to have protective effects on other NDs, which can be realized by further in vivo and in vitro basic research, and clinical trials. In the future, AU may be used for clinical prevention or treatment of patients with neurological diseases.

Wound healing is a major secondary complication in type 2 diabetes, which results in significant disability and mortality, imposing a significant clinical and social burden. Sustained activation of the Nod-like receptor protein (NLRP) inflammasome in wounds is responsible for excessive inflammatory responses and aggravates wound damage. The activation of the NLRP3 inflammasome is regulated by a two-step process: the priming/licensing (signal 1) step involved in transcription and posttranslation and the protein complex assembly (signal 2) step triggered by danger molecules. This review focuses on the advances made in understanding the pathophysiological mechanisms underlying wound healing in the diabetic microenvironment. Simultaneously, this review summarizes the molecular mechanisms of the main regulatory pathways associated with signal 1 and signal 2, which trigger the NLRP3 inflammasome complex assembly in the development of diabetic wounds (DW). Activation of the NLRP3 inflammasome-related pathway, involving the disturbance in Nrf2 and the NF-κB/NLRP3 inflammasome, TLR receptor-mediated activation of the NF-κB/NLRP3 inflammasome, and various stimuli inducing NLRP3 inflammasome assembly play a pivotal role in DW healing. Furthermore, therapeutics targeting the NLRP3 inflammasome-related pathways may promote angiogenesis, reprogram immune cells, and improve DW healing.

Context The reduction in M2 macrophage polarisation plays a major role during diabetic wound healing. Resveratrol (RSV) can promote the polarisation of M2 macrophages and accelerate diabetic wound healing. However, the specific mechanism by which RSV regulates M2 macrophage polarisation to promote diabetic wound healing is unclear. Objective This study evaluated the effectiveness of RSV on diabetic wound healing and analysed the underlying mechanisms. Materials and methods STZ-induced C57/B6 mice were used as a diabetic mice model for a period of 15 days. RSV (10 mu mol/L) was injected around the wound to evaluate the effect of RSV on the healing process of diabetic wounds. The human monocyte line THP-1 was used to evaluate the effects of RSV (10 mu mol/L) on polarisation of M2 macrophages and the secretion of pro-inflammatory factors. Results In vivo, RSV significantly increased diabetic wound healing (p < 0.05) and make the regenerated skin structure more complete. And it promoted the expression of alpha-SMA and Collagen I (p < 0.05). Moreover, RSV reduced the secretion of inflammatory factors (TNF-alpha, iNOS and IL-1 beta) (p < 0.05) and promoted M2 macrophage polarisation by increasing Arg-1 and CD206 expression (p < 0.01). In vitro, RSV promoted the polarisation of M2 macrophages (p < 0.001) and reduced the secretion of pro-inflammatory factors (TNF-alpha, IL-6 and IL-1 beta) (p < 0.05). The therapeutic effects of RSV were all significantly reversed with LY294002 (p < 0.01). Discussion and conclusions RSV has the positive effects on promoting the acceleration and quality of skin wound healing, which provides a scientific basis for clinical treatment in diabetic wound.

Diabetic wounds have been a serious concern for human health owing to their long chronic inflammation and reduced vascularization. Herein, we report novel oil-in-water (o/w) nanoemulsions (NEs) containing Poria cocos triterpenes extract (PTE) to fabricate hyaluronic acid hydrogels (PTE-NEs) for the treatment of diabetic wounds. The size and morphology of NEs are analyzed by transmission electron microscope (TEM) and Zeta potential, respectively. Furthermore, the rheological behavior and morphology of synthesized hydrogels are also determined. It is found that PTE-NEs gel has a homogeneous and porous structure with good elastic properties. In addition, in vitro experiments show that the cell viability of PTE-NEs gel is >85 % without cytotoxicity. In vivo experiments of diabetic rats demonstrate that the PTE-NEs gel can not only significantly accelerate diabetic wound healing, collagen deposition, M2 macrophage polarization, and angiogenesis, but also inhibit inflammation. In conclusion, PTE plays a significant role in wound healing and exhibits anti-inflammatory effects, demonstrating its great potential in treating diabetic wounds.

Objective Hua-Feng-Dan (HFD) is a Chinese medicine for stroke. This study is to predict and verify potential molecular targets and pathways of HFD against stroke using network pharmacology. Methods The TCMSP database and TCMID were used to search for the active ingredients of HFD, and GeneCards and DrugBank databases were used to search for stroke-related target genes to construct the “component-target-disease” by Cytoscape 3.7.1, which was further filtered by MCODE to build a core network. The STRING database was used to obtain interrelationships by topology and to construct a protein-protein interaction network. GO and KEGG were carried out through DAVID Bioinformatics. Autodock 4.2 was used for molecular docking. BaseSpace was used to correlate target genes with the GEO database. Results Based on OB ≥ 30% and DL ≥ 0.18, 42 active ingredients were extracted from HFD, and 107 associated targets were obtained. PPI network and Cytoscape analysis identified 22 key targets. GO analysis suggested 51 cellular biological processes, and KEGG suggested that 60 pathways were related to the antistroke mechanism of HFD, with p53, PI3K-Akt, and apoptosis signaling pathways being most important for HFD effects. Molecular docking verified interactions between the core target (CASP8, CASP9, MDM2, CYCS, RELA, and CCND1) and the active ingredients (beta-sitosterol, luteolin, baicalein, and wogonin). The identified gene targets were highly correlated with the GEO biosets, and the stroke-protection effects of Xuesaitong in the database were verified by identified targets. Conclusion HFD could regulate the symptoms of stroke through signaling pathways with core targets. This work provided a bioinformatic method to clarify the antistroke mechanism of HFD, and the identified core targets could be valuable to evaluate the antistroke effects of traditional Chinese medicines.

Background. Although the traditional Chinese medicine Shan-Zhu-Yu may be efficacious against depression, its mechanism of action is unknown. In this study, we aimed to explore the possible mechanisms of action of Shan-Zhu-Yu in the treatment of depression using network pharmacology. Methods. The active ingredients and targets of Shan-Zhu-Yu were obtained from the Traditional Chinese Medicine System Pharmacology Database (TCMSP) database and converted into gene names using UniProt. Then, the target genes of depression were collected using GeneCards and OMIM. Drug disease intersection genes were obtained using a Venn tool, and a protein-protein interaction network was constructed using STRING. Cytoscape was used to construct an active ingredients-targets-drug-disease network. GO and KEGG pathway enrichment analyses were performed using DAVID. Furthermore, Autodock was used to evaluate drug and target binding and explore possible molecular mechanisms. Results. We identified 9721 disease genes, 13 active ingredients, 50 target genes, and 48 drug disease intersecting genes. The results of the GO enrichment analysis suggested that Shan-Zhu-Yu affects the activity of G protein-coupled amine, neurotransmitter, steroid hormone, nuclear, and G protein-coupled neurotransmitter receptors in the treatment of depression by acting on hormone and nuclear receptor binding. The main signaling pathways were associated with neuroactive ligand-receptor interaction, calcium, cGMP-PKG, apoptosis, estrogen, p53, and AGE-RAGE. Molecular docking confirmed that the active components of Shan-Zhu-Yu (e.g., telocinobufagin and β-sitosterol) docked suitably with NR3C1, Bax, Bcl-2, and caspase-3. Shan-Zhu-Yu may exert its therapeutic effects on depression via multiple targets and pathways. Conclusions. The present study elucidates that Shan-Zhu-Yu suppresses the expression of Bax and caspase-3 and promotes that of NR3C1 and Bcl-2 through neuroactive ligand-receptor interaction and apoptosis signaling pathways. Therefore, Shan-Zhu-Yu is a potential treatment option for depression, and the results of this study will provide new reference points for future experimental research and a scientific basis for its widespread clinical application.

Objective. Hua-Feng-Dan (HFD) is a Chinese medicine for stroke. ,is study is to predict and verify potential molecular targets and pathways of HFD against stroke using network pharmacology. Methods. ,e TCMSP database and TCMID were used to search for the active ingredients of HFD, and GeneCards and DrugBank databases were used to search for stroke-related target genes to construct the “component-target-disease” by Cytoscape 3.7.1, which was further filtered by MCODE to build a core network. ,e STRING database was used to obtain interrelationships by topology and to construct a protein-protein interaction network. GO and KEGG were carried out through DAVID Bioinformatics. Autodock 4.2 was used for molecular docking. BaseSpace was used to correlate target genes with the GEO database. Results. Based on OB≥ 30% and DL≥ 0.18, 42 active ingredients were extracted fromHFD, and 107 associated targets were obtained. PPI network and Cytoscape analysis identified 22 key targets. GO analysis suggested 51 cellular biological processes, and KEGG suggested that 60 pathways were related to the antistroke mechanism of HFD, with p53, PI3K-Akt, and apoptosis signaling pathways being most important for HFD effects. Molecular docking verified interactions between the core target (CASP8, CASP9, MDM2, CYCS, RELA, and CCND1) and the active ingredients (beta-sitosterol, luteolin, baicalein, and wogonin). ,e identified gene targets were highly correlated with the GEO biosets, and the stroke-protection effects of Xuesaitong in the database were verified by identified targets. Conclusion. HFD could regulate the symptoms of stroke through signaling pathways with core targets. ,is work provided a bioinformatic method to clarify the antistroke mechanism of HFD, and the identified core targets could be valuable to evaluate the antistroke effects of traditional Chinese medicines.