Therapeutic downregulation of neuronal PAS domain 2 (Npas2) promotes surgical skin wound healing.

Attempts to minimize scarring remain among the most difficult challenges facing surgeons, despite the use of optimal wound closure techniques. Previously, we reported improved healing of dermal excisional wounds in circadian clock neuronal PAS domain 2 (Npas2)-null mice. In this study, we performed high-throughput drug screening to identify a compound that downregulates Npas2 activity. The hit compound (Dwn1) suppressed circadian Npas2 expression, increased murine dermal fibroblast cell migration, and decreased collagen synthesis in vitro. Based on the in vitro results, Dwn1 was topically applied to iatrogenic full-thickness dorsal cutaneous wounds in a murine model. The Dwn1-treated dermal wounds healed faster with favorable mechanical strength and developed less granulation tissue than the controls. The expression of type I collagen, Tgfß1, and α-smooth muscle actin was significantly decreased in Dwn1-treated wounds, suggesting that hypertrophic scarring and myofibroblast differentiation are attenuated by Dwn1 treatment. NPAS2 may represent an important target for therapeutic approaches to optimal surgical wound management.

Comparison of three kinds of self-expandable metallic stents induced granulation tissue hyperplasia in the rabbit trachea.

To compare stent-induced granulation tissue hyperplasia of bare (SEMS), polyurethane-covered (PU-SEMS) and electrospun nanofibre-covered (EN-SEMS) self-expandable metallic stents in the rabbit trachea. Twenty-seven rabbits were randomly assigned to 3 groups that received SEMS, PU-SEMS or EN-SEMS. Computed tomography and sacrifice were performed as scheduled. Haematoxylin-eosin and Masson's trichrome staining protocols were performed for pathological analysis. The data for tracheal ventilation area ratio, qualitative histological scoring, number of epithelial layers, and thicknesses of papillary projection and submucosa were documented and statistically analysed. All stents were successfully placed under the guidance of fluoroscopy without complications. Post-stenting 3 and 7 days, computed tomography revealed that the fully expandable EN-SEMS was similar to the SEMS and PU-SEMS. The mean stented tissue score in the SEMS group was higher than those of both the PU-SEMS and EN-SEMS groups at 3 days post-stenting. The pathological findings suggested that there was no papillary projection formation 3 days after stent placement. The thickness of papillary projection in the SEMS group was significantly higher than those of the PU-SEMS and EN-SEMS groups at 7 days post-stenting. After stenting 4 weeks, the tracheal ventilation area ratio of SEMS, PU-SEMS and EN-SEMS was 0.214 ± 0.021, 0.453 ± 0.028 and 0.619 ± 0.033, respectively. There were significant between-group differences. In conclusion, the stent-induced granulation tissue formation in EN-SEMS is less severe than that of PU-SEMS and SEMS. EN-SEMS has smaller radial force, and the tracheal ventilation ratio after stent placement better than that of PU-SEMS.

Insulin Topical Application for Wound Healing in Nondiabetic Patients.

BACKGROUND: Low-cost and safe strategies to improve wound healing will be of great social and economic value. The goal of this pilot clinical trial is aimed at analyzing how effective insulin therapy is at healing wounds in nondiabetic people. METHODS: In this protocol research, 346 individuals were included. Patients were divided as 2 groups at random: experimental patients were given a ten-unit answer. For each 10 cm2 of wound, insulin was injected in solution with 1 mL 0.9 percent saline, whereas the control group got a standard dressing with normal saline. RESULTS: During the therapy period, no adverse effects were reported. After insulin therapy, no substantial insulin-related side effects were reduced. After 10 days of therapy, the experimental group's granulation tissue coverage rate and thickness were considerably improved as compared to control. Furthermore, a momentous difference in the occurrence of wound bleeding and suppurative wounds between the two groups (P = 0.05). CONCLUSION: The results of this pilot research suggest that insulin injections could harmless and effective alternative therapy for wound healing in nondiabetic individuals and that larger, placebo-controlled trials are needed to evaluate effectiveness and safety of insulin treatment in wound healing patients.

The Role of Allium subhirsutum L. in the Attenuation of Dermal Wounds by Modulating Oxidative Stress and Inflammation in Wistar Albino Rats.

In our study, Allium subhirsutum L. (AS) was investigated to assess its phenolic profile and bioactive molecules including flavonoids and organosulfur compounds. The antioxidant potential of AS and wound healing activity were addressed using skin wound healing and oxidative stress and inflammation marker estimation in rat models. Phytochemical and antiradical activities of AS extract (ASE) and oil (ASO) were studied. The rats were randomly assigned to four groups: group I served as a control and was treated with simple ointment base, group II was treated with ASE ointment, group III was treated with ASO ointment and group IV (reference group; Ref) was treated with a reference drug "Cytolcentella® cream". Phytochemical screening showed that total phenols (215 ± 3.5 mg GAE/g) and flavonoids (172.4 ± 3.1 mg QE/g) were higher in the ASO than the ASE group. The results of the antioxidant properties showed that ASO exhibited the highest DPPH free radical scavenging potential (IC50 = 0.136 ± 0.07 mg/mL), FRAP test (IC50 = 0.013 ± 0.006 mg/mL), ABTS test (IC50 = 0.52 ± 0.03 mg/mL) and total antioxidant capacity (IC50 = 0.34 ± 0.06 mg/mL). In the wound healing study, topical application of ASO performed the fastest wound-repairing process estimated by a chromatic study, percentage wound closure, fibrinogen level and oxidative damage status, as compared to ASE, the Cytolcentella reference drug and the untreated rats. The use of AS extract and oil were also associated with the attenuation of oxidative stress damage in the wound-healing treated rats. Overall, the results provided that AS, particularly ASO, has a potential medicinal value to act as effective skin wound healing agent.

Application and Clinical Effectiveness of Antibiotic-Loaded Bone Cement to Promote Soft Tissue Granulation in the Treatment of Neuropathic Diabetic Foot Ulcers Complicated by Osteomyelitis: A Randomized Controlled Trial.

This study explored the clinical effectiveness of antibiotic-loaded bone cement on primary treatment of diabetic foot infection. This is a randomized controlled study, including thirty-six patients with diabetic foot ulcer complicated by osteomyelitis who had undergone treatment between May 2018 and December 2019. Patients were randomly divided into control group (group A) and study group (group B). Patients in the intervention group received antibiotic-loaded bone cement repair as primary treatment, while patients in the control group received conventional vacuum sealing draining treatment. Clinical endpoints were assessed and compared between the two groups, including wound healing time, wound bacterial conversion, NRS pain score, number of wound dressing changes, and average hospitalization time. All patients were followed up for a period of 12 months after discharge. Results show that compared with the control group, patients in the study group had significant difference in the number of patients for baseline pathogens eradication, short NRS pain score, hospital length of stay and cost, wound surface reduction, healing time, low rate of complications, and infection recurrence. Based on the findings, we conclude that antibiotic-loaded bone cement can be used for treatment of wound in patient with diabetic foot infection. It can help to control wound infections, shorten hospital length of stay, reduce medical cost, and relieve both doctors' and patients' burden. The application of antibiotic-loaded bone cement is suitable for diabetic wound with soft tissue infection or osteomyelitis.

Molecular Effects of Topical Estrogen on Vaginal Granulation Tissue in Postpartum Women.

OBJECTIVE: The aims of this study were to evaluate the biomolecular properties of vaginal and perineal granulation tissue in postpartum women and assess the potential impact of vaginal estrogen application. METHODS: We prospectively identified women referred to a subspecialty peripartum clinic between September 2016 and April 2018 who developed symptomatic perineal or vaginal granulation tissue. As part of routine clinical care, granulation tissue was excised from each participant by a urogynecologist and subjected to RNA extraction, real-time quantitative polymerase chain reaction, histologic evaluation, and immunohistochemistry. Serum steroid hormone levels were measured. Comparisons were made between participants who used topical vaginal estradiol (E2) and those who did not (non-E2 controls). RESULTS: Sixteen postpartum women were recruited for this pilot study. More than 30% of patients (n = 5, 31%) had used topical vaginal estradiol (E2) during their postpartum recovery. Histological appearance of granulation tissue evaluated by hematoxylin and eosin staining was similar in women treated with vaginal E2 and non-E2 controls. Both estrogen receptor α (ERα) and ERß mRNA and ERα protein were readily detectable in the granulation tissue of E2-treated women. Although not statistically significant, participants who used topical E2 developed granulation tissue that exhibited local estrogen-responsive gene upregulation. Serum levels of estrone, E2, dehydroepiandrosterone, progesterone, and testosterone did not differ between vaginal E2-treated patients and controls. CONCLUSIONS: Estrogen receptor α seems to be the predominant receptor mediating estrogen action in postpartum perineal and vaginal granulation tissue. Vaginal E2 use does not seem to affect serum levels of estrone, E2, dehydroepiandrosterone, progesterone, and testosterone in postpartum women.

Protective effects of different anti­inflammatory drugs on tracheal stenosis following injury and potential mechanisms.

Tracheal stenosis following injury cannot be effectively treated. The current study compared the protective effects of different anti­inflammatory drugs on tracheal stenosis and investigated their possible mechanisms. Rabbit tracheal stenosis models following injury were constructed and confirmed using hematoxylin and eosin (H&E) staining. A total of 30 rabbits were divided into the control (CON), penicillin (PEN), erythromycin (ERY), budesonide (BUD) and PEN + ERY + BUD groups (n=6). Stenotic tracheal tissue, serum and bronchoalveolar lavage fluid (BALF) were collected 10 days after continuous treatment. Pathological changes in the tracheas were observed by H&E staining. Histone deacetylase 2 (HDAC2) expression in tracheal tissues was detected by immunofluorescence. Immunohistochemistry was performed to detect collagen I (Col­I) and collagen III (Col­III) levels in tracheal tissues. Transforming growth factor ß1 (TGF­ß1), vascular endothelial growth factor (VEGF) and interleukin 8 (IL­8) levels in serum and BALF samples were determined using ELISA kits. Western blotting detected HDAC2, IL­8, TGF­ß1 and VEGF levels in tracheal tissues. H&E staining demonstrated that tracheal epithelial hyperplasia and fibroblast proliferation in the ERY and PEN + ERY + BUD groups markedly improved compared with the CON group. Furthermore, in tracheal tissues, HDAC2 expression was significantly increased and IL­8, TGF­ß1, VEGF, Col­I and Col­III levels were significantly decreased in the ERY and PEN + ERY + BUD groups compared with the CON group. Additionally, the results for the PEN + ERY + BUD were more significant compared with the ERY group. In serum and BALF samples, IL­8, TGF­ß1 and VEGF levels in the ERY and PEN + ERY + BUD groups were significantly lower compared with the CON group, with the results of the PEN + ERY + BUD group being more significant compared with the ERY group. There were no significant differences between the PEN, BUD and CON groups. ERY inhibited tracheal granulation tissue proliferation and improved tracheal stenosis following injury and synergistic effects with PEN and BUD further enhanced these protective effects. The mechanism may involve HDAC2 upregulation and inhibition of local airway and systemic inflammatory responses.

Therapeutic effect of local photothermal heating of gold nanoparticle-coated self-expandable metallic stents for suppressing granulation tissue formation in the mouse colon.

PURPOSE: To investigate the therapeutic effect of local photothermal (PT) heating on suppression of stent-induced granulation tissue formation in mouse colon. MATERIALS AND METHODS: A gold nanoparticle (GNP)-coated self-expandable metallic stent (SEMS) was prepared using a two-step synthesis process for local PT heating under near-infrared laser irradiation. Twenty-four mice were randomly divided into two groups of 12 and subjected to SEMS placement in the colon. Group A received a GNP-coated SEMS without local heating and Group B received a GNP-coated SEMS and underwent local heating at 55°C after SEMS placement. The therapeutic effect of local heating was assessed by comparing the histopathological, immunohistochemical, and endoscopic results. RESULTS: Four mice were excluded because of stent migration (n = 3, group B) or death (n = 1, group A). Stent-induced granulation tissue-related variables were significantly lower in group B than in group A (p < 0.001). In vivo endoscopic images, 4 weeks after stent placement, showed granulation tissue formation over the wire mesh in group A and relatively good patency of the stented colon with no definite irregularities in group B. There was more vascular endothelial growth factor (VEGF) positivity in group A than in group B. CONCLUSION: Local PT heating suppresses granulation tissue formation after stent placement in mouse colon.

Healing potential of Spirulina platensis for skin wounds by modulating bFGF, VEGF, TGF-ß1 and α-SMA genes expression targeting angiogenesis and scar tissue formation in the rat model.

Blue-green microalga Spirulina platensis (SP) gained more attention for its antioxidant and/or anti-inflammatory properties magnifying its beneficial effects as a feed additive and for cosmetic and biomedical applications. This study was performed to examine the impact of SP on the cutaneous wound and burn healing and to develop an understanding of the correlation between the sequelae of wound healing and the molecular expression patterns of wound healing-related genes as angiogenic basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) and fibrosis-related genes as transforming growth factor-ß (TGF-ß) and α-smooth muscle actin (α-SMA) in rat wound models. To achieve these goals, two experiments were performed on 32 Wister male rats that were divided into 4 groups of 8 rats each. Each experiment was represented by 2 groups; the control group (CG) and the Spirulina group (SG). A full-thickness wound (1.5 × 1.5 cm) and burn wound (2 × 2 cm) were made on the back of each generally anaesthetized rat and the areas of wound and burn were measured on days of 0, 3, 6, 9, 12, and 15 and 0, 3, 6, 9, 12, 15, 18, and 21 post-wound and post-burn respectively. In both experiments, SP was topically applied on the backs of wounded and burned rats in Spirulina treated groups. The phases of wound granulation tissues were detected histopathologically. Immunohistochemistry was used to determine the expressions of (TGF-B1) and (VEGF). Furthermore, the relative quantification of gene expression was implemented using the (bFGF), (VEGF), (TGF-Ɓ1), and (α-SMA) as target genes. Histopathological examination revealed inflammatory cell infiltration, angiogenesis, epithelialization, and extracellular matrix deposition and wound contraction in SG as compared to CG in both experiments. Immunohistochemistry results showed a significant improvement in the VEGF and TGF-ß1 expression levels of SG in both experiments. Interestingly, SG in both experiments revealed upregulation of angiogenic genes (bFGF and VEGF) and downregulation of fibrotic genes (TGF-ß1 and α-SMA). In conclusion, our findings suggest that the topically applied Spirulina promoted wound healing. Thus, SP can be used as a biomedical application to treat various skin wounds and may reveal a potential molecular basis for future promising antifibrotic agents against scar formation.

Histamine augments collagen content via H1 receptor stimulation in cultures of myofibroblasts taken from wound granulation tissue.

The inflammatory reaction influences the deposition of collagen within wound granulation tissue. The aim of the present study is to determine whether histamine acting directly on myofibroblasts derived from wound granulation tissue may influence collagen deposition. It also identifies the histamine receptor involved in this process. The experiments were carried out on cells isolated from the granulation tissue of a wound model (a polypropylene net inserted subcutaneously to rats) or intact rat skin. Collagen content was measured following the addition of different concentrations of histamine and treatment with histamine receptor antagonists (ketotifen - H1 inhibitor, ranitidine - H2 inhibitor) and a histamine receptor H1 agonist (2-pyridylethylamine dihydrochloride).The cells were identified as myofibroblasts: alpha-smooth muscle actin, vimentin, and desmin positive in all experimental conditions. Histamine increased the collagen level within both cell cultures, i.e., those isolated from granulation tissue or intact skin. It did not, however, influence the expression of either the collagen type I or III genes within the cultured myofibroblasts. Histamine activity was reduced by ketotifen (the H1 receptor inhibitor) and increased by the H1 receptor agonist, as demonstrated by changes in the levels of collagen in the myofibroblast culture. Histamine increased collagen content within the cultures, acting directly on myofibroblasts via H1 receptor stimulation.

Formulation and evaluation of wound healing activity of Elaeis guineensis Jacq leaves in a Staphylococcus aureus infected Sprague Dawley rat model.

ETHNOPHARMACOLOGICAL RELEVANCE: Medicinal plants are crucial to healing numerous illnesses. Elaeis guineensis Jacq (family Arecaceae) is a medicinal plant traditionally used for the treatment of wounds. AIM OF THE STUDY: However, there are no scientific reports documented on the wound healing activities of this plant against Staphylococcus aureus infections in the Sprague Dawley male rat model. Thus, the present study was conducted to evaluate the wound healing potential of E. guineensis extract leaves. MATERIALS AND METHODS: The crude extract was prepared in 10% (w/w) ointment and evaluated for wound healing activity using excision and infected wound models in Sprague Dawley rats. The wound healing activity was evaluated from wound closure rate, CFU reduction, histological analysis of granulation tissue and matrix metalloprotease expression. RESULTS: The results show that the E. guineensis extract has potent wound healing ability, as manifest from improved wound closure and tissue regeneration supported by histopathological parameters. Assessment of granulation tissue every fourth day showed a significant reduction in the microbial count. The expression of matrix metalloproteinases was well correlated with the other results, hence confirming E. guineensis wound healing activity's effectiveness. CONCLUSIONS: E. guineensis enhanced infected wound healing in rats, thus supporting its traditional use.

GPR43 regulates sodium butyrate-induced angiogenesis and matrix remodeling.

Butyrate is a short-chain fatty acid (SCFA) derived from microbiota and is involved in a range of cell processes in a concentration-dependent manner. Low concentrations of sodium butyrate (NaBu) were shown to be proangiogenic. However, the mechanisms associated with these effects are not yet fully known. Here, we investigated the contribution of the SCFA receptor GPR43 in the proangiogenic effects of local treatment with NaBu and its effects on matrix remodeling using the sponge-induced fibrovascular tissue model in mice lacking the Gpr43 gene (Gpr43-KO) and the wild-type (WT) mice. We demonstrated that NaBu (0.2 mM intraimplant) treatment enhanced the neovascularization process, blood flow, and VEGF levels in a GPR43-dependent manner in the implants. Moreover, NaBu was able to modulate matrix remodeling aspects of the granulation tissue such as proteoglycan production, collagen deposition, and α-smooth muscle actin (α-SMA) expression in vivo, besides increasing transforming growth factor (TGF)-ß1 levels in the fibrovascular tissue, in a GPR43-dependent manner. Interestingly, NaBu directly stimulated L929 murine fibroblast migration and TGF-ß1 and collagen production in vitro. GPR43 was found to be expressed in human dermal fibroblasts, myofibroblasts, and endothelial cells. Overall, our findings evidence that the metabolite-sensing receptor GPR43 contributes to the effects of low dose of NaBu in inducing angiogenesis and matrix remodeling during granulation tissue formation. These data provide important insights for the proposition of new therapeutic approaches based on NaBu, beyond the highly explored intestinal, anti-inflammatory, and anticancer purposes, as a local treatment to improve tissue repair, particularly, by modulating granulation tissue components.NEW & NOTEWORTHY Our data show the contribution of the metabolite-sensing receptor GPR43 in the effects of low dose of sodium butyrate (NaBu) on stimulating angiogenesis and extracellular matrix remodeling in a model of granulation tissue formation in mice. We also show that human dermal fibroblasts, myofibroblasts, and endothelial cells express the receptor GPR43. These data provide important insights for the use of NaBu in local therapeutic approaches applicable to tissue repair in sites other than the intestine.

Substance P enhances the therapeutic effect of MSCs by modulating their angiogenic potential.

Bone marrow mesenchymal stem cell (MSC) therapy acts through multiple differentiations in damaged tissue or via secretion of paracrine factors, as demonstrated in various inflammatory and ischaemic diseases. However, long-term ex vivo culture to obtain a sufficient number of cells in MSC transplantation leads to cellular senescence, deficiency of the paracrine potential, and loss of survival rate post-transplantation. In this study, we evaluated whether supplementation of MSCs with substance P (SP) can improve their therapeutic potential. SP treatment elevated the secretion of paracrine/angiogenic factors, including VEGF, SDF-1a and PDGF-BB, from late passage MSCs in vitro. MSCs supplemented with SP accelerated epidermal/dermal regeneration and neovascularization and suppressed inflammation in vivo, compared to MSCs transplanted alone. Importantly, supplementation with SP enabled the incorporation of transplanted human MSCs into the host vasculature as pericytes via PDGF signalling, leading to the direct engagement of transplanted cells in compact vasculature formation. Our results showed that SP is capable of restoring the cellular potential of senescent stem cells, possibly by modulating the generation of paracrine factors from MSCs, which might accelerate MSC-mediated tissue repair. Thus, SP is anticipated to be a potential beneficial agent in MSC therapy for inflammatory or ischaemic diseases and cutaneous wounds.

Wound Healing Activity of Crassocephalum crepidioides (Benth.) S. Moore. Leaf Hydroethanolic Extract.

Crassocephalum crepidioides (Benth.) S. Moore. has been used to treat small wounds by minority people in Lam Dong, Vietnam. However, there has been no scientific evidences about its wound healing activity. This study is aimed at evaluating the wound healing activity of Crassocephalum crepidioides hydroethanolic extract via its antioxidant and anti-inflammation activities and healing capability on a mouse excision wound model. Crassocephalum crepidioides hydroethanolic extract (CCLE) at a dose of 50 mg/kg/day reduced the wound closure time about 3.5 days, compared to vehicle treatment. The granulation tissue on day 7 after surgery from the treated group showed a 2.8-fold decrease in the density of inflammatory cells, 1.9-fold increase in the fibroblast density, and a higher number of blood vessels. Real-time PCR analysis indicated that the mRNA expression level of NF-κB1 and TNF-α mRNA in CCLE-treated wounds decreased by 4.6 and 3.3 times, respectively, while TGF-ß1 and VEGF were found to increase by 3.3 and 2.4 times, respectively. Our experimental data provided proofs of Crassocephalum crepidioides leaf wound healing activity due to its antioxidant, anti-inflammation, fibroblast proliferation, wound contraction, and angiogenesis effects.

The use of irradiated amnion dressing for the treatment of antibiotic-disinfected skin ulcer.

Skin ulcers are non-healed wounds caused by inflammation of epidermis up to the dermis, which causes pain and limits body movements, significantly reducing quality of life. Amniotic membrane is a placental collagenous biomaterial with many biological and mechanical properties important for tissue engineering and regenerative medicine. The aim of this work is to evaluate the efficacy of topical antibiotic washing followed with irradiated human amniotic membrane (iHAM) dressing for treating five different types of ulcers. The current study included 15 patients who were recruited from the outpatient clinic of the Egyptian Atomic Energy Authority. Follow up of all treated cases that completed the regimen was up to 3 months. The clinical progression of all treated ulcers was quantitatively evaluated by computerized estimation of the wound size reduction based on 3D image analysis. All cases in this study showed great outcomes within several weeks of treatment depending on wound infection, ulcer depth and size, period of healing disorder, age, blood glycemia, and other clinical criteria. Patients' questionnaires revealed that pain was controlled by the first time of treatment. After 1 week post-treatment, granulation tissue was generated and observed in all patients, and all microbial colonies have been eliminated from wounds with previous infection. The current study indicated that the dressing of ulcers with iHAM induces fast healing without complication.

A comparison of the wound healing process after the application of three dermal substitutes with or without basic fibroblast growth factor impregnation in diabetic mice.

Pelnac GplusⓇ, IntegraⓇ, and TerudermisⓇ are approved artificial dermis products in Japan. Previously, we proved that Pelnac GplusⓇ was able to sustain basic fibroblast growth factor (bFGF) and accelerated wound healing by releasing impregnated bFGF. In this study, we impregnated Pelnac GplusⓇ, IntegraⓇ, and TerudermisⓇ with bFGF and compared the binding activity and wound-healing process. We applied bFGF to each material and compared the bFGF concentrations in the surrounding area after 24-h incubation. For the in vivo study, dermal substitutes were impregnated with bFGF and implanted into full-thickness wounds of BKS.Cg-+Leprdb/+Leprdb/Jcl mice. Wounds were evaluated at days 7, 14, and 21 after implantation. The in vitro study showed that bFGF is strongly bound to IntegraⓇ, followed by Pelnac GplusⓇ and TerudermisⓇ. The in vivo study showed that fibroblasts and capillaries had infiltrated into the Pelnac GplusⓇ but not the IntegraⓇ or TerudermisⓇ. Furthermore, long epithelium and wide granulation tissue were formed in the Pelnac GplusⓇ with bFGF group. The TerudermisⓇ with bFGF group had more capillaries than other groups, but only at the base of the wound. The combination of Pelnac GplusⓇ with bFGF may be a novel approach for treating full-thickness skin defects or chronic skin ulcers.

Role of Erythromycin-Regulated Histone Deacetylase-2 in Benign Tracheal Stenosis.

Objective: This study aims to explore the role of erythromycin-regulated histone deacetylase-2 in benign tracheal stenosis. Methods: The rabbit model of tracheal stenosis was established. The rabbits were randomly divided into 8 groups. Histone deacetylase-2 (HDAC2) expression was detected by immunofluorescence. The expression of type I collagen and type III collagen was detected by immunohistochemical method. The expression of TGF-ß1, VEGF and IL-8 in serum and alveolar lavage fluid was detected by ELISA. The expression of HDAC2, TGF-ß1, VEGF and IL-8 in serum and alveolar lavage fluid was detected by ELISA. The expression of HDAC2, TGF. Results: In Erythromycin (ERY) group, ERY + Budesonide group, ERY + Vorinostat group and ERY + Budesonide + Vorinostat group, the degree of bronchial stenosis was alleviated, and the mucosal epithelium was still slightly proliferated. The effect of ERY combined with other drugs was more obvious. The HDAC2 protein expression increased significantly in ERY group, ERY + Budesonide group and ERY + Budesonide + Vorinostat group and decreased significantly in Vorinostat group, the expression of collagen I and III decreased significantly in ERY group, ERY + Budesonide group and ERY + Budesonide + Vorinostat group (P < 0.05). The TGF-ß1, VEGF and IL-8 in serum and alveolar lavage fluid was detected by ELISA. The expression of HDAC2, TGF-P < 0.05). The TGF. Conclusions: Erythromycin inhibited inflammation and excessive proliferation of granulation tissue after tracheobronchial mucosal injury by up-regulating the expression of HDAC2, it promoted wound healing and alleviated tracheobronchial stenosis. When combined with budesonide, penicillin and other glucocorticoids and antibiotics, it had a good synergistic effect. However, vorinostat could attenuate erythromycin's effect by down-regulating the expression of HDAC2. It may have good clinical application prospects in the treatment of tracheal stenosis.

Comparison of metamizole and paracetamol effects on colonic anastomosis and fibroblast activities in Wistar rats.

BACKGROUND: Leakage following colorectal anastomosis surgery causes various complications associated with high morbidity and mortality, especially in pediatric patients. It might be caused by the use of non-steroidal anti-inflammatory drugs (NSAIDs) as postoperative analgesics. This study aimed to compare the effect of metamizole and paracetamol on colonic anastomosis and fibroblast activities, including proliferation, migration, and collagen synthesis, in Wistar rats. METHODS: Rats were divided into control, paracetamol and metamizole groups. The colonic anastomosis was evaluated by determining the integrity of the muscle layers, the formation of granulation tissue, and mucosal anastomosis. Fibroblast activities were analyzed by measuring the proliferation, migration, and collagen synthesis. RESULTS: Metamizole caused more damage to muscle layer integrity, more inhibition of granulation tissue formation in the anastomosis area and lower mucosal anastomosis compared with paracetamol and control groups. Metamizole had a higher cytotoxic effect than paracetamol, which suppressed the proliferation and migration of fibroblasts. Furthermore, both drugs did not affect the synthesis of collagen. CONCLUSION: Metamizole shows worse effects on the integrity of muscle layers, inhibition of granulation tissue formation, mucosal anastomosis, fibroblast proliferation, and migration, but not collagen synthesis, than paracetamol in Wistar rat intestines following colonic anastomosis. These findings might indicate that paracetamol is safer than metamizole as analgesic following colonic anastomosis.

Moist-Retaining, Self-Recoverable, Bioadhesive, and Transparent in Situ Forming Hydrogels To Accelerate Wound Healing.

In the management of accelerating wound healing, moist environments play an important role. Compared with other scaffolds of various forms, hydrogels can maintain a moist environment in the wound area. They are cross-linked hydrophilic polymeric networks that resemble natural soft tissues and extracellular matrices. Among them, injectable hydrogels have attracted great attention in wound repair, as they can be injected into irregular-shaped skin defects and formed in situ to shape the contour of different dimensions. The excellent compliance makes hydrogels easy to adapt to the wound under different conditions of skin movement. Here, we oxidized hydroxyethyl starch (O-HES) and modified carboxymethyl chitosan (M-CMCS) to fabricate an in situ forming hydrogel with excellent self-recoverable extensibility-compressibility, biocompatibility, biodegradability, and transparency for accelerating wound healing. The oxidation degree of O-HES was 74%. The amino modification degree of M-CMCS was 63%. M-CMCS/O-HES hydrogels were formed through the Schiff base reaction. The physicochemical properties of M-CMCS/O-HES hydrogels with various ratios were investigated, and M-CMCS/O-HES hydrogel with a volume ratio of 5:5 exhibited appropriate gelation time, notable water-retaining capacity, self-recoverable conformal deformation, suitable biodegradability, and good biocompatibility for wound-healing application. Then, skin wound-healing experimental studies were carried out in Sprague-Dawley rats with full-thickness skin defects. Significant outcomes were achieved in the M-CMCS/O-HES hydrogel-treated group including higher wound closure percentage, more granulation tissue formation, faster epithelialization, and decreased collagen deposition. These findings demonstrate that using the obtained M-CMCS/O-HES hydrogels is a promising therapeutic strategy for wound healing.

Combined effects of metformin and photobiomodulation improve the proliferation phase of wound healing in type 2 diabetic rats.

We determined the impact of Photobiomodulation (PBM) and metformin administration alone and combined on the inflammation and proliferation steps of wound healing of incisions in type two diabetes mellitus (T2DM) rats. 40 rats were divided into 4 groups (n = 10 each group). A non-genetic model of T2DM was induced in all rats, and an incision was made on each rat. There were 4 groups as follows: Group 1 was control group. Group 2 received PBM alone (890 nm, 80 Hz, 0.324 J/cm2, daily). Group 3 received metformin alone (50 mg/kg, i.p., daily) and the fourth group received combination of PBM + metformin. At inflammation (day 4) and proliferation (day 7) steps, tensiometerical, stereological, and immunohistochemical examinations were performed. PBM and PBM + metformin treatments significantly increased wound strength at inflammation and proliferation steps of wound healing respectively. PBM, metformin, and PBM + metformin groups significantly decreased inflammatory cells at inflammation and proliferation steps of wound healing. PBM, metformin, and PBM + metformin groups significantly improved granulation tissue formation by increasing fibroblasts, and new blood vessel formation at inflammation and proliferation steps of wound healing. Metformin significantly increased M2 macrophages than other treatment groups at inflammation and proliferation steps of wound healing. Simultaneously, PBM significantly decreased M2 macrophages than control group. We concluded PBM and PBM + metformin treatments significantly hastened repair at the inflammation and proliferation steps of repairing skin injury in a non-genetic model of T2 DM. PBM + metformin showed a synergistic impact. There were not a positive relation between M2 macrophage number and wound strength in the studied groups. The details of the molecular mechanisms of PBM, and PBM + metformin treatments of repairing wounds in animals, and treatment of DFUs of patients with T2 DM should be elucidated by further research.