Targeting the sirtuin 6-NF-κB p65 axis by 6-hydroxyhyoscyamine hydrobromide: a deacetylation-driven new therapy for diabetic wounds.

Aims: Cold atmospheric plasma (CAP) interacted with tissue and had potential effects on wound healing and tissue regeneration. The aim of this study is to investigate the efficacy and safety of CAP as a novel therapy for diabetic wounds in vitro and in vivo. Methods: The plasma consists of ionized helium gas that is produced by a high-voltage (8.5kV) and high-frequency (17kHz) power supply. Eight-week-old male db/db mice were treated with conventional wound dressing only (control group), additional 90’s CAP (low-dose group) or 180’s CAP (high-dose group) for 2 weeks, respectively. Skin samples around wound in 3, 7, 14 days and blood samples were collected and analyzed in three groups. We carried out in vitro analysis included scratch wound healing assays in immortalized human epidermal HaCaT cells. Results: After 14 days of treatment, CAP could obviously promote diabetic wound healing because of inflammation inhibition and angiogenesis increase. Wound- closure rates of two CAP groups were significantly faster than that of control group. The protein expression of IL-6, TNF-α, iNOS and SOD significantly decreased while the protein level of VEGF, TGF-β in two CAP groups significantly increased compared to those in control group (all p < 0.05). And such changes showed a good consistency with the change in mRNA level (all p < 0.05). In vitro, scratch wound healing assays showed that plasma treatment could effectively accelerate the wound healing within 3 minutes exposure (all p < 0.05). Additionally, there were no significant differences in histological observation and the level of serum ALT, AST, BUN, CREA and WBC among the three groups. Conclusions: CAP treatment for 3 min daily improves diabetic wound healing by inhibiting inflammation, reducing oxidative stress and enhancing angiogenesis without toxicity to liver and kidney. Disclosure R. He: None. Q. Li: None. M. Yu: None. T. Wang: None. H. Lu: None. J. Lu: None. W. Zhu: None. M. Luo: None. J. Zhang: None. H. Gao: None. W. Xing: None. D. Wang: None. F. Liu: None. Funding National Natural Science Fund of China; Shanghai Science & Technology; Shanghai Municipal Education Commission

Cold atmospheric plasma (CAP) is a group of various chemical active species, such as ozone and nitric oxide, generated by working gas. CAP was demonstrated to have an effect on tissue regeneration and wound healing. We conducted this study to evaluate the efficacy and safety of CAP as a novel therapy for diabetic wounds in vitro and in vivo. The plasma consists of ionised helium gas that is produced by a high-voltage and high-frequency power supply. Eight-week-old male db/db mice and C57BL mice were treated with helium gas (control group), 90s' CAP (low-dose group), and 180s' CAP (high-dose group). Mice were treated and observed for 2 weeks. Skin samples from around the wound and blood samples were collected. Our in vitro analysis included scratch wound-healing assays by using human HaCaT immortalised human epidermal cells. After 14 days of treatment, CAP could obviously promote diabetic wound healing. Wound closure rates were significantly higher in the low-dose group and high-dose groups compared with the control group. Meanwhile, compared with the control group, the protein expression of IL-6, tumour necrosis factor-α, inducible nitric oxide synthase, and superoxide dismutase in two CAP groups significantly decreased, while the protein expression of vascular endothelial growth factor and transforming growth factor-β in two CAP groups significantly increased (all P < .05); these data show good agreement with the change in mRNA level (all P < .05). In vitro, scratch wound-healing assays showed that plasma treatment could effectively ensure healing within 3 minutes of exposure (all P < .05). In addition, no difference was found in histological observations of normal skin and the level of serum alanine transaminase, aspartate aminotransferase, blood urea nitrogen, creatinine, and white blood cells among the CAP groups and control group. CAP treatment for 3 minutes every day improves wound healing in diabetic mice by suppressing inflammation, reducing oxidative stress, and enhancing angiogenesis, involving several proteins signalling, and it is safe for the liver and kidney.

Diabetic wounds are considered one of the most frequent and severe complications of diabetes mellitus. Recently, the omentum has been used in diabetic wound healing because of its tissue repair properties. The activated omentum is richer in growth factors than the inactivated, thereby contributing to the wound healing process. To further investigate the effect of activated omentum conditioned medium (aOCM) on diabetic wound healing, we injected supernatant from aOCM, saline-OCM (sOCM), inactivated-OCM (iOCM), and medium (M) subcutaneously upon creation of a cutaneous wound healing model in diabetic mice. Wound area (%) was evaluated on days 0, 3, 5, 7, 9, 11, 14, 21, and 28 post-operation. At 9 and 28 d post-operation, skin tissue was harvested and assessed for gross observation, neovascularization, peripheral nerve fiber regeneration, and collagen deposition. We observed that aOCM enhanced the wound repair process, with significant acceleration of epidermal and collagen deposition in the surgical lesion on day 9. Additionally, aOCM displayed marked efficiency in neovascularization and peripheral nerve regeneration during wound healing. Thus, aOCM administration exerts a positive influence on the diabetic mouse model, which can be employed as a new therapy for diabetic wounds.

It is estimated that 15 percent of individuals with diabetes mellitus suffer from diabetic ulcers worldwide. The aim of this study is to present a non-thermal atmospheric plasma treatment as a novel therapy for diabetic wounds. The plasma consists of ionized helium gas that is produced by a high-voltage (8 kV) and high-frequency (6 kHz) power supply. Diabetes was induced in rats via an intravascular injection of streptozotocin. The plasma was then introduced to artificial xerograph wounds in the rats for 10 minutes. Immunohistochemistry assays was performed to determine the level of transforming growth factor (TGF-β1) cytokine. The results showed a low healing rate in the diabetic wounds compared with the wound-healing rate in non-diabetic animals (P < 0.05). Moreover, the results noted that plasma enhanced the wound-healing rate in the non-diabetic rats (P < 0.05), and significant wound contraction occurred after the plasma treatment compared with untreated diabetic wounds (P < 0.05). Histological analyses revealed the formation of an epidermis layer, neovascularization and cell proliferation. The plasma treatment also resulted in the release of TGF-β1 cytokine from cells in the tissue medium. The findings of this study demonstrate the effect of plasma treatment for wound healing in diabetic rats.

Jurnal Biologi Indonesia diterbitkan oleh Perhimpunan Biologi Indonesia. Jurnal ini memuat hasil penelitian ataupun kajian yang berkaitan dengan masalah biologi yang diterbitkan secara berkala dua kali setahun.

Near-infrared light-activatable, analgesic nanocomposite delivery system for comprehensive therapy of diabetic wounds in rats

An ionic liquid-functionalized near-infrared fluorescent hydrogel dressing for promoting wound healing and real-time monitoring hypochlorous acid at the diabetic wound site

Diabetic wounds remain a formidable clinical challenge due to excessive reactive oxygen species (ROS) accumulation, impaired immune regulation, and compromised tissue regeneration. Herein, we report a multifunctional thermosensitive smart hydrogel integrating hollow mesoporous MnO2 nanozymes and transforming growth factor-β1 (TGF-β1) into an adhesive thermosensitive hydrogel (TGF-β1@MATH) for synergistic diabetic wound therapy. The MnO2 nanozymes efficiently scavenge ROS in the diabetic wound microenvironment, suppressing the Nrf2-HO-1-NQO-1 pathway to alleviate oxidative stress and restore the cell migration capacity. Triggered by body temperature, TGF-β1@MATH undergoes stiffness enhancement and controlled TGF-β1 release: the increased stiffness upregulates integrin β2 (ITGB2) expression in T cells, while TGF-β1 synergizes with ITGB2 to activate the Smad2/3 pathway, promoting regulatory T cell (Tregs) aggregation and secretion of growth factors. In vitro studies confirm that TGF-β1@MATH accelerates fibroblast migration, induces myofibroblast differentiation, and modulates the immune microenvironment. In diabetic mice, TGF-β1@MATH achieves a 95% wound healing rate within 14 days, significantly enhancing re-epithelialization, collagen deposition, angiogenesis, and Tregs recruitment. This integrated design addresses multiple pathological barriers of diabetic wound areas (WA) through ROS scavenging, thermosensitive regulation and immune-modulated regeneration, offering a promising translational strategy for clinical diabetic wound management.

Currently, diabetic wound dressings continue to exhibit various limitations, hindering their ability to effectively respond to the dynamic and complex microenvironment of diabetic wounds. Particularly, significant challenges remain in developing multifunctional dressings capable of effective multicomponent integration and precise, controlled release of each component. Herein, the novel electrospun nanofiber composite membranes (NCMs) are developed that hierarchically incorporate zeolitic imidazolate framework (ZIF)-based nanoplatforms for spatiotemporally controlled and continuous release of multiple bioactive components, enabling the effective regulation of key factors involved in diabetic wound healing. Specifically, platelet-derived growth factor-BB (PDGF-BB)-loaded ZIF-8 (PZ) nanoparticles (NPs) are embedded within poly(ε-caprolactone)/gelatin (PCL/GT) nanofibers, while ZIF-67 NPs are in situ grown on the nanofiber surface, yielding multifunctional ZIF-67/PZ/PCL/GT (ZPZPG) NCMs. The hierarchical structures facilitate a staged pH-responsive release, wherein initially released Co2+ from ZIF-67 NPs rapidly exerts antibacterial effects and promotes early angiogenesis, followed by the prolonged release of Zn2+ and PDGF-BB from embedded ZIF-8 NPs, further enhancing antimicrobial activity, neovascularization, fibroblast proliferation, and tissue regeneration. Both in vitro and in vivo studies demonstrate effective infection control, improved vascularization, and accelerated wound healing, underscoring the potential of hierarchical metal-organic framework (MOF)-integrated NCMs as an attractive way to overcome current limitations in diabetic wound therapy.

Diabetic wounds (DWs) are considered chronic complications observed in patients suffering from type 2 diabetes mellitus (DM). Usually, DWs originate from the interplay of inflammation, oxidation, impaired tissue re-epithelialization, vasculopathy, nephropathy, and neuropathy, all of which are related to insulin resistance and sensitivity. The conventional approaches available for the treatment of DWs are mainly confined to the relief of wound pressure, debridement of the wound, and management of infection. In this paper, we speculate that treatment of DWs with 5-aminosalicylic acid (5-ASA) and subsequent activation of peroxisome proliferator-activated receptor gamma (PPAR-γ) and transforming growth factor beta (TGF-β) via the AhR pathway might be highly beneficial for DW patients. This estimation is based on several lines of evidence showing that 5-ASA and PPAR-γ activation are involved in the restoration of insulin sensitivity, re-epithelialization, and microcirculation. Additionally, 5-ASA and TGF-β activate inflammation and the production of pro-inflammatory mediators. Suitable stabilized formulations of 5-ASA with high absorption rates are indispensable for scrutinizing its probable pharmacological benefits since 5-ASA is known to possess lower solubility profiles because of its reduced permeability through skin tissue. In vitro and in vivo studies with stabilized formulations and a control (placebo) are mandatory to determine whether 5-ASA indeed holds promise for the curative treatment of DWs.

A growing body of evidence suggests that the interaction between immune and metabolic responses is essential for maintaining tissue and organ homeostasis. These interacting disorders contribute to the development of chronic diseases associated with immune-aging such as diabetes, obesity, atherosclerosis, and nonalcoholic fatty liver disease. In Diabetic wound (DW), innate immune cells respond to the Pathogen-associated molecular patterns (PAMAs) and/or Damage-associated molecular patterns (DAMPs), changes from resting to an active phenotype, and play an important role in the triggering and maintenance of inflammation. Furthermore, the abnormal activation of innate immune pathways secondary to immune-aging also plays a key role in DW healing. Here, we review studies of innate immune cellular molecular events that identify metabolic disorders in the local microenvironment of DW and provide a historical perspective. At the same time, we describe some of the recent progress, such as TLR receptor-mediated intracellular signaling pathways that lead to the activation of NF-κB and the production of various pro-inflammatory mediators, NLRP3 inflammatory via pyroptosis, induction of IL-1β and IL-18, cGAS-STING responds to mitochondrial injury and endoplasmic reticulum stress, links sensing of metabolic stress to activation of pro-inflammatory cascades. Besides, JAK-STAT is also involved in DW healing by mediating the action of various innate immune effectors. Finally, we discuss the great potential of targeting these innate immune pathways and reprogramming innate immune cell phenotypes in DW therapy.

Diabetic wounds are refractory and recurrent diseases that necessitate the development of multifunctional dressings. Inspired by the structure and function of the skin, we herein delicately design a novel swollen hydrophobic hydrogel (QL@MAB) composed of hydrophobic methyl acrylate (MA) and (3-acrylamidophenyl)boronic acid (AAPBA) network and co-loaded with antioxidant quercetin (Q) and antibiotic levofloxacin (L) for efficient diabetic wound therapy. The hydrophobic MA segments undergo phase separation to form a dense "epidermis", ensuring prolonged drug diffusion, long-term water retention, and high water content. Meanwhile, the AAPBA segments generate glucose-labile "sweat pores" via borate ester bonds with the polyphenol drug Q. Upon encountering the hyperglycemic wound microenvironment, the "sweat pores" are dilated due to the cleavage of the borate ester bonds and exposure of the diffusion channel, facilitating drug release for accelerated wound healing. In the infected diabetic rats, QL@MAB achieves rapid wound debridement and re-epithelization while promoting angiogenesis, hair follicle regeneration, and extracellular matrix remodeling. Taken together, this study not only represents a multipronged dressing for effective interventions of diabetic wounds but also contributes to the rational design of smart hydrogels tailored for biomedical applications.

Silver nanoparticles: Advanced and promising technology in diabetic wound therapy.

Diabetic wound healing is a global biomedical challenge. Bacterial infection and microenvironmental modulation are major factors in the refractory healing of diabetic wounds. Conventional therapeutic approaches are often hindered by limitations, such as inadequate drug penetration, the rise of antimicrobial resistance, and restricted depth of drug delivery. Nanomedicine is emerging as a prospective drug delivery and anti-infective therapeutic approach in the field of wound management. Herein, all-trans retinoic acid (ATRA) was loaded into a zeolite imidazolate framework-91 salt+ (ZIF-91 salt+). A gelatin methacryloyl (GelMA) hydrogel microneedles (MNs) patch based on this multifunctional ZIFs (denoted as GelMA-ZIF-91 salt+@ATRA MNs patch) was developed, which makes transdermal drug delivery and combinatory treatment for diabetic wound healing feasible. Significantly, ATRA-containing ZIF-91 salt+ provides nanocomposites with anti-inflammatory activity through their modulation of macrophage polarization. Crucially, the prepared ZIF-91 salt+ showed efficient antibacterial activity against Staphylococcus aureus and Escherichia coli in vitro. Therapeutic effects of the GelMA-ZIF-91 salt+@ATRA MNs patch were verified in a diabetic mouse model with full-thickness cutaneous wounds. A unique MNs patch with antimicrobial, angiogenesis-inducing, and anti-inflammatory properties was designed in accordance with the physiological characteristics of wounds. Collectively, the designed MNs patch based on this multifunctional ZIF-91 salt+ provides new insights into diabetic wound therapy.

Diabetic wounds are characterized by persistent inflammation, impaired angiogenesis, and susceptibility to infection, posing significant clinical challenges. Here, we report an intelligent shape-memory sponge (P1A3@B-MOF) engineered for the programmable modulation of the diabetic wound microenvironment. The dressing consists of an interpenetrating network of oxidized pullulan and acellular dermal matrix, incorporating zeolitic imidazolate framework-8 (ZIF-8) metal-organic frameworks encapsulated with salvianolic acid B (SalB) via in situ self-assembly. This design enables exudate-triggered shape recovery and pH-responsive drug release, targeting the acidic pathological environment. We demonstrate that the released Zn2+ and SalB exert synergistic effects: conferring broad-spectrum antibacterial activity, orchestrating macrophage repolarization from proinflammatory M1 to regenerative M2 phenotypes, and activating the hypoxia-inducible factor 1-alpha (Hif-1α)/vascular endothelial growth factor (VEGF) pathway to restore vascularization. In a diabetic rat model, the sponge accelerated wound closure with a 98.5% healing rate by day 14 and modulated collagen deposition via the transforming growth factor-β (TGF-β)/Smad signaling axis, thereby effectively mitigating scar formation. This integrated strategy offers a promising modality for restoring immune homeostasis and promoting functional skin regeneration.