Objective
To investigate whether electroacupuncture induction promotes polarized NGF to M2 type.
Methods
Twenty-four Beagle dogs aged 6 months according to random number table method were randomly divided into sham operation group, nerve injury group, electroacupuncture group and AM1241 group, with 6 dogs in each group. Sham operation group: only the abducent nerve was exposed and separated, the incision skin was sutured without nerve injury during operation, and the abducent nerve injury model was made, and the abducent nerve injury model was bound by electroacupuncture. Nerve injury group: abducent nerve injury model was made and restrained by electroacupuncture ; electroacupuncture group: electroacupuncture stimulation was lasted for 2 weeks after beagle dog abducent nerve injury model established. Abducent nerve injury + CB2R agonist AM1241 was injected intraperitoneally with a solvent of 3 mL/kg for 2 weeks after abducent nerve injury and restrained by electroacupuncture. The expression levels of M1-specific marker proteins iNOS and IL-1 beta, M2-specific marker proteins Arginase and BDNF were detected by western blot on the 7th and 14th day after 2 weeks of intervention. The Kruskal-Wallis H test was used between the 4 groups, and Mann-Whitney U test was used to compare the two groups.
Results
(1) on the seventh day after operation, the median expression of iNOS in the 4 groups was 1.370, 1.610, 0.190 and 0.105 respectively. The expression of iNOS in the four groups had statistical significance (χ2=21.64, P<0.05). The expression of iNOS in the electro-acupuncture treatment group and AM1241 group was lower than that in the nerve injury group (Z=-2.89, -2.89, all P< 0.05). On the 14th day after operation, the expression of iNOS in the four groups was 1.430, 1.990, 0.165 and 0.150, respectively. The expression of iNOS in four groups had statistical significance (χ2=20.99, P<0.05). The expression of iNOS in electro-acupuncture treatment group and AM1241 group was lower than that in nerve injury group (Z=-2.89, -2.94, all P< 0.05). (2) on the seventh day after operation, the median of IL-1βin the 4 groups was 1.255, 1.575, 0.180 and 0.160 respectively. The expression of IL-1β in the four groups had statistical significance (χ2=21.34, P<0.05). The expression of IL-1βin electro-acupuncture treatment group and AM1241 group was lower than that in nerve injury group (Z=-2.90, -2.91, all P<0.05). On the fourteenth day after operation, the expression of IL-1β in the 4 groups was 1.245, 1.485, 0.255 and 0.185 respectively. There was significant difference in the expression of IL-1β between the four groups (χ2=21.69, P<0.05). The expression of IL-1β in electroacupuncture group and AM1241 group was lower than that in nerve injury group (Z=-2.91, -2.93, all P<0.05). (3) M2 specific marker proteins (Arginase, BDNF) were detected in the 4 groups. Seventh days after operation, the expression of Arginase in 4 groups was 0.090, 0.420, 1.795 and 1.820 respectively. The expression of Arginase in the four groups had statistical significance (χ2=21.44, P<0.05), and the expression of Arginase in the electro-acupuncture treatment group and AM1241 group was higher than that in the nerve injury group (Z=-2.92, -2.93, all P<0.05). On the fourteenth day after operation, the expression of Arginase in the 4 groups was 0.165, 0.545, 1.850 and 1.930 respectively. There was a significant difference in Arginase expression between the four groups (χ2=20.52, P<0.05). The expression of Arginase in electro-acupuncture group and AM1241 group was higher than that in nerve injury group (Z=-2.90, -2.91, all P<0.05). (4) on the seventh day after operation, the expression of BDNF in the 4 groups was 0.075, 0.385, 1.715 and 1.770 respectively. The expression of BDNF in four groups had statistical significance (χ2=21.69, P<0.05). The expression of BDNF in electro-acupuncture treatment group and AM1241 group was higher than that in nerve injury group (Z=-2.91, -2.92, all P<0.05). On the fourteenth day after operation, the expression of BDNF in the 4 groups was 0.140, 0.485, 1.810 and 1.870 respectively. There was a significant difference in the expression of BDNF between the four groups (χ2=21.72, P<0.05). The expression of BDNF in electro-acupuncture group and AM1241 group was higher than that in nerve injury group (Z=-2.93, -2.92, all P<0.05).
Conclusion
Electroacupuncture can induce the polarization of M2 microglial cells in Beagle dogs and promote nerve repair. At the same time, AM1241, a CB2R receptor agonist, can exert a good electroacupuncture synergistic effect, but AM1241 does not affect the upregulation of M2 type marker protein expression in microglia.
Key words:
Electroacupuncture; Abducens nerve injury; Microglia cell; Beagle dogs
Diabetic foot ulcers, pressure ulcers, and bedsores can easily develop into chronic wounds with bacterial infections, complicating wound healing. This work reports a two-step strategy for treating infected chronic wounds. Firstly, LL37 mimetic peptide-W379 peptides were rapidly released to eliminate the bacterial biofilm on the wound. Then, 3D radially aligned nanofiber scaffolds loaded with W379 antimicrobial peptide and PDGF-BB were used to treat the wound to prevent bacterial infection recurrence and promote angiogenesis and granulation tissue regeneration, thereby accelerating wound healing. In the presented study, we found that the combined use of burst and controlled release of W379 antimicrobial peptide effectively clears the bacterial biofilm and prevents the recurrence of bacterial infection. Additionally, we found that the removal of the bacterial biofilm contributed to modulating the local inflammatory response from a pro-inflammatory type to a pro-regenerative type. Furthermore, the use of PDGF-BB significantly promotes neovascularization and granulation tissue regeneration in the wound bed, resulting in accelerating re-epithelialization and wound closure. Our study provides a promising treatment method for the repair of infected chronic wounds.
Keloids are abnormal fibrous hyperplasias that are difficult to treat. Melatonin can be used to inhibit the development of certain fibrotic diseases but has never been used to treat keloids. We aimed to discover the effects and mechanisms of melatonin in keloid fibroblasts (KFs).Flow cytometry, CCK-8 assays, western blotting, wound-healing assays, transwell assays, collagen gel contraction assays and immunofluorescence assays were applied to demonstrate the effects and mechanisms of melatonin in fibroblasts derived from normal skin, hypertrophic scars and keloids. The therapeutic potential of the combination of melatonin and 5-fluorouracil (5-FU) was investigated in KFs.Melatonin significantly promoted cell apoptosis and inhibited cell proliferation, migration and invasion, contractile capability and collagen production in KFs. Further mechanistic studies demonstrated that melatonin could inhibit the cAMP/PKA/Erk and Smad pathways through the membrane receptor MT2 to alter the biological characteristics of KFs. Moreover, the combination of melatonin and 5-FU remarkably promoted cell apoptosis and inhibited cell migration and invasion, contractile capability and collagen production in KFs. Furthermore, 5-FU suppressed the phosphorylation of Akt, mTOR, Smad3 and Erk, and melatonin in combination with 5-FU markedly suppressed the activation of the Akt, Erk and Smad pathways.Collectively, melatonin may inhibit the Erk and Smad pathways through the membrane receptor MT2 to alter the cell functions of KFs, while combination with 5-FU could exert even more inhibitory effects in KFs through simultaneous suppression of multiple signalling pathways.
The wound healing process is divided into four phases of hemostasis, inflammation, proliferation, and remodeling that each wound needs to go through to heal normally. Each phase is crucial to the healing of the wound. Herein, for the first time, we describe an emerging bifunctional hybrid fiber membrane of ZnO–Fe2O3/kaolinite nanoclay/poly-(3-caprolactone)-gelatin (ZnO–Fe2O3/Kaol/PG) that concurrently controls bleeding, prevents bacterial colonization, reduces excessive inflammation, and facilitates wound healing for the early emergency self-rescue. Topical treatment with the fiber membrane in bacteria-infected mice models could accelerate wound healing through reducing bacterial growth, and promote cell proliferation and neovascularization, which is attributed to the antibacterial and anti-inflammatory activity of ZnO–Fe2O3/Kaol. Kaolin can activate the intrinsic coagulation cascade, in addition, it can concentrate on blood platelets, RBCs, and clotting factors by absorbing fluid. Fe2O3 can facilitate RBC aggregation and clotting, while ZnO can mediate the inhibition of the release of pro-inflammatory cytokines and antibacterial effect. The fibrous architecture of PG electrostatically spun fibers can provide an appropriate environment for wound healing. Here, for the first time, we found that ZnO–Fe2O3/Kaol can control bleeding quickly for wound injury and protect the wound from external bacterial infection and reduces inflammation. The versatility and portability of the as-prepared hybrid fiber membrane make it an effective strategy for hemorrhage control and wound healing.
Diabetic ulcer is a challenging complication of diabetes mellitus but current treatments cannot achieve satisfactory results. In this study, the effect of Huangbai liniment (HB) and berberine on the wound healing in high fat diet/streptozotocin injection induced diabetic rats was investigated by RNA-seq technology. HB topical treatment promoted wound healing in the diabetic patients and diabetic rats, and it affected multiple processes, of which IL-17 signalling pathway was of importance. Inhibiting IL-17a by its inhibitor or antibody remarkably facilitated wound healing and HB significantly repressed the high IL-17 expression and its downstream targets, including Cxcl1, Ccl2, Mmp3, Mmp9, G-CSF, IL1B and IL6, in diabetic wounds, promoted T-AOC, SOD activity and GSH levels; decreased the levels of nitrotyrosine and 8-OHdG; enhanced angiogenesis-related CD31, PDGF-BB and ANG1 expression; inhibited cleaved caspase-3 levels and promoted TIMP1 and TGFB1. Moreover, berberine (a major component in HB) repressed the IL-17 signalling pathway, and promoted wound healing in diabetes mellitus. This study highlights the strategy of targeting IL-17a in diabetic wounds, deepens the understanding of wound healing in diabetes mellitus in a dynamic way and reveals the characteristics of HB and berberine in promoting wound healing of type 2 diabetes mellitus.
Objective To systematically evaluate the efficacy and safety of butylphthalide combined with donepezil versus butylphthalide monotherapy for the treatment of vascular dementia. Methods Randomized controlled trials were searched in electronic databases, including PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure, Chinese Science and Technology Periodical Database (VIP), Wan Fang, and China Biology Medicine from inception to 29 November 2022. Two reviewers independently screened the papers and extracted data from the included studies. The data were processed using RevMan5.4 statistical software. Results Nine randomized controlled trials (n = 1024) were included in this meta-analysis. Regarding the primary outcomes, compared with butylphthalide monotherapy, combined butylphthalide and donepezil treatment exhibited significantly greater total clinical efficacy (relative risk = 1.24, 95% confidence interval [1.17, 1.31]) and did not increase the adverse event rate (relative risk = 1.39, 95% confidence interval [0.91, 2.14]). Regarding the secondary outcomes, the meta-analysis results for the Mini-Mental State Examination, abilities of daily living, and Montreal Cognitive Assessment scores and the interleukin-6, tumor necrosis factor-α, and superoxide dismutase blood levels all supported combined butylphthalide and donepezil treatment. Conclusion Butylphthalide combined with donepezil may be a better treatment strategy than donepezil alone for the treatment of vascular dementia in clinical practice.
The aim of this study is to examine the factors that contribute to anxiety and depression in individuals undergoing maintenance hemodialysis (MHD), as well as their association with serum levels of brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and serotonin (5-HT).In May 2020 and June 2022, 120 MHD patients who received MDH treatment at our hospital were enrolled. The control group was composed of 60 healthy adults (>18) who completed the physical examination at the same time. The serum levels of BDNF, NT-3, and 5-HT in patients and clinical data of MHD patients with different degrees of anxiety and depression were compared. The Pearson correlation was used to evaluate the correlation between anxiety and depression scores and serum BDNF, NT-3,5-HT levels in patients with MHD. Multivariate analysis was employed to analyze the risk factors of anxiety and depression in MHD patients.The incidence of anxiety and depression in 120 MHD patients was 34.17% (41/120) and 64.17% (77/120), respectively. The levels of serum NT-3 and 5-HT in the anxiety group were higher than those in the non-anxiety and control group, and the levels of serum NT-3 in the non-anxiety group were higher than those in the control group (P < 0.05). The levels of serum BDNF, NT-3 and 5-HT in the depressed group were higher than those in the non-depressed group and control group, and the levels of serum NT-3 in the non-depressed group were higher than those in the control group (P < 0.05). SAS score was positively correlated with serum NT-3 and 5-HT levels, while the SDS score was negatively correlated with serum BDNF and positively correlated with serum NT-3 and 5-HT levels. Female, rural household registration, and restless leg syndrome were independent risk variables for anxiety in patients with MHD (P < 0.05). Rural household registration, economic deterioration, fatigue, insomnia, and vascular pain were independent variables of depression risk in patients with MHD.Anxiety and depression in patients with MHD are closely related to the levels of serum BDNF, NT-3, and 5-HT. Female, rural household registration, more than eight dialysis times/month, insomnia, and restless leg syndrome are the risk factors for anxiety in patients with MHD. Rural household registration, economic deterioration, fatigue, insomnia, and vascular pain are the risk factors for depression in patients with MHD. The clinical implication of these findings suggests that these indexes may perhaps serve as biological indicators of anxiety and depression amongst patients undergoing MHD. Such investigation can hence contribute to early detection, monitoring, and potentially enable the depiction of novel therapeutic strategies for managing these adverse states.
Abstract Effective regulation and reconstruction of the microenvironment are critical for the regeneration of chronic wounds. Diabetic wounds, in particular, pose a significant clinical challenge due to increased oxidative stress and dysfunctional healing processes. In this study, a novel therapeutic strategy is developed using 3D copper‐magnesium bimetallic antioxidant nano‐enzymes (Cu/Mg‐MOF) to mitigate reactive oxygen species (ROS) and restore redox balance through electron transfer. To optimize delivery, a thermo‐sensitive hydrogel composed of chitosan (CS) and ε ‐polylysine (PL) is designed, serving as an efficient carrier for the nano‐enzymes. This Cu/Mg‐MOF@CS/PL hydrogel exhibits excellent physical properties, including injectability, softness, and biocompatibility, making it ideal for application in diabetic wounds. In a diabetic wound model, treatment with Cu/Mg‐MOF@CS/PL hydrogel significantly accelerated wound healing, with a closure rate of 90.6% by day 14, compared to just 55.4% in the untreated group. The hydrogel effectively promoted key aspects of wound healing, such as collagen deposition, re‐epithelialization, angiogenesis, and immunomodulation. These findings underscore the potential of the Cu/Mg‐MOF@CS/PL hydrogel as a promising therapeutic system for enhancing the healing of diabetic wounds.
Despite advances in wound treatments, chronic diabetic wounds remain a significant medical challenge. Exosomes from mesenchymal stem cells (MSCs) and small molecule activators of nuclear factor erythroid 2-related factor 2 (Nrf2) have emerged as potential therapies for nonhealing diabetic wounds. This study aimed to evaluate the effects of exosomes from bone marrow-derived MSCs (BMSCs) alone, or in combination with a small molecule activator of Nrf2 on diabetic wound healing.BMSCs and endothelial progenitor cells (EPCs) were isolated from the femur and tibia bone marrow of Sprague-Dawley (SD) rats and culture-expanded. Exosomes were harvested from the BMSC culture supernatants through ultracentrifugation. The effects of the exosomes and Nrf2 knockdown, alone or in combination, on EPC tube formation were evaluated. Streptozotocin-induced diabetic rats bearing a fresh full-thickness round wound were treated with the exosomes alone, or in combination with a lentiviral shRNA targeting Nrf2 (Lenti-sh-Nrf2) or tert-butylhydroquinone (tBHQ), a small molecule activator of Nrf2. Two weeks later, wound closure, re-epithelization, collagen deposition, neovascularization, and local inflammation were evaluated. BMSC exosomes promoted while Nrf2 knockdown inhibited EPC tube formation. BMSC exosomes accelerated wound closure, re-epithelization, collagen deposition, and neovascularization, and reduced wound inflammation in diabetic rats. These regenerative and anti-inflammatory effects of the exosomes were inhibited by Lenti-sh-Nrf2 but enhanced by tBHQ administration.BMSC exosomes in combination with a small molecule Nrf2 activator hold promise as a new therapeutic option for chronic diabetic wounds.
Importance Peceleganan spray is a novel topical antimicrobial agent targeted for the treatment of skin wound infections. However, its efficacy and safety remain unclear. Objective To assess the safety and efficacy of peceleganan spray for the treatment of wound infections. Design, Setting, and Participants This multicenter, open-label, phase 3 randomized clinical trial recruited and followed up 570 adult patients diagnosed with secondary open wound infections from 37 hospitals in China from August 23, 2021, to July 16, 2022. Interventions Patients were randomized to 2 groups with a 2:1 allocation. One group received treatment with 2‰ peceleganan spray (n = 381) and the other with 1% silver sulfadiazine (SSD) cream (n = 189). Main Outcomes and Measures The primary efficacy outcome was the clinical efficacy rate (the number of patients fulfilling the criteria for efficacy of the number of patients receiving the treatment) on the first day following the end of treatment (day 8). The secondary outcomes included the clinical efficacy rate on day 5 and the bacterial clearance rate (cases achieving negative bacteria cultures after treatment of all cases with positive bacteria cultures before treatment) on days 5 and 8. The safety outcomes included patients’ vital signs, physical examination results, electrocardiographic findings, blood test results, and adverse reactions. Results Among the 570 patients randomized to 1 of the 2 groups, 375 (98.4%) in the 2‰ peceleganan treatment group and 183 (96.8%) in the 1% SSD control group completed the trial (n = 558). Of these, 361 (64.7%) were men, and the mean (SD) age was 48.6 (15.3) years. The demographic characteristics were similar between groups. On day 8, clinical efficacy was achieved by 339 patients (90.4%) in the treatment group and 144 (78.7%) in the control group ( P &lt; .001). On day 5, clinical efficacy was achieved by 222 patients (59.2%) in the treatment group and 90 (49.2%) in the control group ( P = .03). On day 8, bacterial clearance was achieved by 80 of 334 patients (24.0%) in the treatment group and in 75 of 163 (46.0%) in the control group ( P &lt; .001). On day 5, bacterial clearance was achieved by 55 of 334 patients (16.5%) in the treatment group and 50 of 163 (30.7%) in the control group ( P &lt; .001). The adverse events related to the application of peceleganan spray and SSD cream were similar. Conclusions and Relevance This randomized clinical trial found that peceleganan spray is a safe topical antimicrobial agent with a satisfactory clinical efficacy rate for the treatment of skin wound infections, while the effectiveness of bacterial clearance remains uncertain. Trial Registration Chinese Clinical Trial Registry Identifier: ChiCTR2100047202
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