The neuroprotective function of 2-carba-cyclic phosphatidic acid: Implications for tenascin-C via astrocytes in traumatic brain injury.

We examined the mechanism how 2-carba-cyclic phosphatidic acid (2ccPA), a lipid mediator, regulates neuronal apoptosis in traumatic brain injury (TBI). First, we found 2ccPA suppressed neuronal apoptosis after the injury, and increased the immunoreactivity of tenascin-C (TN-C), an extracellular matrix protein by 2ccPA in the vicinity of the wound region. 2ccPA increased the mRNA expression levels of Tnc in primary cultured astrocytes, and the conditioned medium of 2ccPA-treated astrocytes suppressed the apoptosis of cortical neurons. The neuroprotective effect of TN-C was abolished by knockdown of TN-C. These results indicate that 2ccPA contributes to neuroprotection via TN-C from astrocytes in TBI.

Histone deacetylase inhibition promotes regenerative neurogenesis after stab wound injury in the adult zebrafish optic tectum.

The central nervous system (CNS) of adult zebrafish is capable of recovering from injury, unlike the CNS of mammals such as humans or rodents. Previously, we established a stab wound injury model of the optic tectum (OT) in the adult zebrafish and showed that the radial glial cells (RG) proliferation and neuronal differentiation contributes to OT regeneration. In the present study, we analyzed the function of histone deacetylases (HDACs) as potential regulators of OT regeneration. The expression of both hdac1 and hdac3 was found to be significantly decreased in the injured OT. In order to analyze the roles of HDACs in RG proliferation and differentiation after injury, we performed pharmacological experiments using the HDAC inhibitor trichostatin A. We found that HDAC inhibition after stab wound injury suppressed RG proliferation but promoted neuronal differentiation. Moreover, HDAC inhibition suppressed the injury-induced decline in expression of Notch signaling target genes, her4.1 and her6 after OT injury. These results suggest that HDACs regulate regenerative neurogenesis through changes in Notch target gene expression by histone deacetylation. HDACs and histone acetylation are promising molecular targets for neuronal regeneration and further studies about the molecular mechanisms behind the regulation of regeneration by histone acetylation are necessary.

CTHRC1 promotes wound repair by increasing M2 macrophages via regulating the TGF-ß and notch pathways.

The healing of acute wounds is vital to humans and is a well-orchestrated process that involves systemic and local factors. However, there is a lack of effective and safe clinical therapies. The collagen triple helix repeat containing 1 (CTHRC1) protein is a type of exocrine protein that has been recently reported to contribute to tissue repair. Our aim is to validate the promoting effects of CTHRC1 on the healing of acute wounds and to elucidate the underlying molecular mechanism. Therefore, we first established acute wound healing mouse models and confirmed that CTHRC1 accelerates the healing process of acute wounds. Then, we characterized wound macrophages using a polyvinylalcohol (PVA) sponge model and used Western blotting to investigate the molecular mechanism. We found that CTHRC1 increased the M2 macrophage population and the TGF-ß expression level as a result of the activation of the TGF-ß and Notch pathways, which eventually contributed to the promotion of wound healing. Inhibition of the Notch pathway showed attenuated M2 macrophage recruitment, and it decreased the TGF-ß expression level. These results substantiate our hypothesis that CTHRC1 promotes wound healing by recruiting M2 macrophages and regulating the TGF-ß and Notch pathways.

Comparison of the detrimental features of microglia and infiltrated macrophages in traumatic brain injury: A study using a hypnotic bromovalerylurea.

Microglia and blood-borne macrophages in injured or diseased brains are difficult to distinguish because they share many common characteristics. However, the identification of microglia-specific markers and the use of flow cytometry have recently made it easy to discriminate these types of cells. In this study, we analyzed the features of blood-borne macrophages, and activated and resting microglia in a rat traumatic brain injury (TBI) model. Oxidative injury was indicated in macrophages and neurons in TBI lesions by the presence of 8-hydroxy-2'-deoxyguanosine (8-OHdG). Generation of mitochondrial reactive oxygen species (ROS) was markedly observed in granulocytes and macrophages, but not in activated or resting microglia. Dihydroethidium staining supported microglia not being the major source of ROS in TBI lesions. Furthermore, macrophages expressed NADPH oxidase 2, interleukin-1ß (IL-1ß), and CD68 at higher levels than microglia. In contrast, microglia expressed transforming growth factor ß1 (TGFß1), interleukin-6 (IL-6), and tumor necrosis factor α at higher levels than macrophages. A hypnotic, bromovalerylurea (BU), which has anti-inflammatory effects, reduced both glycolysis and mitochondrial oxygen consumption. BU administration inhibited chemokine CCL2 expression, accumulation of monocytes/macrophages, 8-OHdG generation, mitochondrial ROS generation, and proinflammatory cytokine expression, and markedly ameliorated the outcome of the TBI model. Yet, BU did not inhibit microglial activation or expression of TGFß1 and insulin-like growth factor 1 (IGF-1). These results indicate that macrophages are the major aggravating cell type in TBI lesions, in particular during the acute phase. Activated microglia may even play favorable roles. Reduction of cellular energy metabolism in macrophages and suppression of CCL2 expression in injured tissue may lead to amelioration of TBI.

The Synthetic Steroid Tibolone Decreases Reactive Gliosis and Neuronal Death in the Cerebral Cortex of Female Mice After a Stab Wound Injury.

Previous studies have shown that estradiol reduces reactive gliosis after a stab wound injury in the cerebral cortex. Since the therapeutic use of estradiol is limited by its peripheral hormonal effects, it is of interest to determine whether synthetic estrogenic compounds with tissue-specific actions regulate reactive gliosis. Tibolone is a synthetic steroid that is widely used for the treatment of climacteric symptoms and/or the prevention of osteoporosis. In this study, we have assessed the effect of tibolone on reactive gliosis in the cerebral cortex after a stab wound brain injury in ovariectomized adult female mice. By 7 days after brain injury, tibolone reduced the number of glial fibrillary acidic protein (GFAP) immunoreactive astrocytes, the number of ionized calcium binding adaptor molecule 1 (Iba1) immunoreactive microglia, and the number of microglial cells with a reactive phenotype in comparison to vehicle-injected animals. These effects on gliosis were associated with a reduction in neuronal loss in the proximity to the wound, suggesting that tibolone exerts beneficial homeostatic actions in the cerebral cortex after an acute brain injury.

Usefulness of basophil activation test for the diagnosis of IgE mediated hypersensitivity to tetanus toxoid vaccine.

A great number of vaccinated patients develop specific anti-tetanus toxoid IgE, but usually do not undergo any adverse effect. Most of the allergic reactions to tetanus toxoid vaccine usually present with unspecific symptoms of local inflammation. In the presence of severe reactions, and in a special way if the vaccine is provided together with other drugs, it is difficult to establish which is the harmful drug responsible for IgE-mediated adverse reaction. A patient with an anaphylactic reaction after the administration of Toxoid Tetanic (TT) along with several drugs is described. All skin test were negative. The basophils activation test (BAT) in a clear way, identified TT as the allergen that triggered anaphylaxis. The results achieved demonstrates the usefulness of BAT to clarify patients with hypersensibility to tetanus toxoide when the clinic is severe and the vaccine has been administered together with other drugs.

Neuroprotection and Blood-Brain Barrier Restoration by Salubrinal After a Cortical Stab Injury.

Following a central nervous system (CNS) injury, restoration of the blood-brain barrier (BBB) integrity is essential for recovering homeostasis. When this process is delayed or impeded, blood substances and cells enter the CNS parenchyma, initiating an additional inflammatory process that extends the initial injury and causes so-called secondary neuronal loss. Astrocytes and profibrotic mesenchymal cells react to the injury and migrate to the lesion site, creating a new glia limitans that restores the BBB. This process is beneficial for the resolution of the inflammation, neuronal survival, and the initiation of the healing process. Salubrinal is a small molecule with neuroprotective properties in different animal models of stroke and trauma to the CNS. Here, we show that salubrinal increased neuronal survival in the neighbourhood of a cerebral cortex stab injury. Moreover, salubrinal reduced cortical blood leakage into the parenchyma of injured animals compared with injured controls. Adjacent to the site of injury, salubrinal induced immunoreactivity for platelet-derived growth factor subunit B (PDGF-B), a specific mitogenic factor for mesenchymal cells. This effect might be responsible for the increased immunoreactivity for fibronectin and the decreased activation of microglia and macrophages in injured mice treated with salubrinal, compared with injured controls. The immunoreactivity for PDGF-B colocalized with neuronal nuclei (NeuN), suggesting that cortical neurons in the proximity of the injury were the main source of PDGF-B. Our results suggest that after an injury, neurons play an important role in both, the healing process and the restoration of the BBB integrity. J. Cell. Physiol. 232: 1501-1510, 2017. © 2016 Wiley Periodicals, Inc.

Investigating wound healing, tyrosinase inhibitory and antioxidant activities of the ethanol extracts of Salvia cryptantha and Salvia cyanescens using in vivo and in vitro experimental models.

ETHNOPHARMACOLOGICAL RELEVANCE: Salvia L. species are widely used against wounds and skin infections in Turkish folk medicine. AIM OF THE STUDY: The aim of the present study is to evaluate wound healing activity of the ethanol (EtOH) extracts of Salvia cryptantha and Salvia cyanescens. MATERIALS AND METHODS: For the assessment of wound healing activity linear incision and circular excision wound models were employed on rats and mice. The wound healing effect was comparatively evaluated with the standard skin ointment Madecassol(®). Inhibition of tyrosinase, a key enzyme in skin aging, was achieved using ELISA microplate reader. Antioxidant activity was evaluated by 2,2-diphenyl-1-picrylhydrazyl (DPPH) and superoxide radical scavenger effect, ferrous ion-chelating ability, and ferric-reducing antioxidant power (FRAP) tests. RESULTS AND CONCLUSIONS: The EtOH extract of Salvia cryptantha treated groups of animals showed 56.5% contraction, whereas the reference drug Madecassol(®) showed 100% contraction. On the other hand, the same extract on linear incision wound model demonstrated a significant increase (33.2%) in wound tensile strength as compared to other groups. The results of histopathological examination maintained the upshot of linear incision and circular excision wound models as well. These findings specify that Salvia cryptantha for wound healing activity can be appealed further phytochemical estimation for spotting its active components.

Wound healing acceleration effect of endemic Ononis species growing in Turkey.

AIM OF THE STUDY: Ononis L. species have been used for healing of wounds, eczema and rheumatic complaints, against skin cancer and lesions and topically used as antiseptic and antimicrobial agent in folk medicine. In the present study, the aqueous and methanolic extracts of three endemic Ononis species growing in Turkey, including Ononis sessilifolia Bornm., Ononis basiadnata Hub.-Mor. and Ononis macrosperma Hub.-Mor. were assessed for their in vivo wound healing and anti-inflammatory activities. MATERIALS AND METHODS: In vivo wound healing activities of the plants were evaluated by using linear incision and circular excision experimental models subsequently histopathological analysis. The healing potential was comparatively assessed with a reference ointment Madecassol(®), which contains 1% extract of Centella asiatica. In vivo inhibitory effect of the extracts on acetic acid-induced increase in capillary permeability was studied for the assessment of anti-inflammatory activity. RESULTS: The aqueous and ethanolic extracts of the aerial parts of O. macrosperma demonstrated the highest activity in both wound models and significant anti-inflammatory activity in acetic acid-induced increase in capillary permeability test. Furthermore, ethanolic extract of the aerial parts of O. sessilifolia showed anti-inflammatory effect but was devoid of wound healing activity. The rest of the species did not show remarkable wound healing effect. Ethyl acetate fraction of O. macrosperma ethanolic extract demonstrated significant but reduced wound healing activity, which revealed a possible combined effect. The results of histopathological examination supported the outcome of linear incision and circular excision wound models. CONCLUSION: The experimental study revealed that the aerial parts of O. macrosperma display remarkable wound healing and anti-inflammatory activities.

Biochemical, functional, and pharmacological characterization of AT-56, an orally active and selective inhibitor of lipocalin-type prostaglandin D synthase.

We report here that 4-dibenzo[a,d]cyclohepten-5-ylidene-1-[4-(2H-tetrazol-5-yl)-butyl]-piperidine (AT-56) is an orally active and selective inhibitor of lipocalin-type prostaglandin (PG) D synthase (L-PGDS). AT-56 inhibited human and mouse L-PGDSs in a concentration (3-250 microm)-dependent manner but did not affect the activities of hematopoietic PGD synthase (H-PGDS), cyclooxygenase-1 and -2, and microsomal PGE synthase-1. AT-56 inhibited the L-PGDS activity in a competitive manner against the substrate PGH(2) (K(m) = 14 microm) with a K(i) value of 75 microm but did not inhibit the binding of 13-cis-retinoic acid, a nonsubstrate lipophilic ligand, to L-PGDS. NMR titration analysis revealed that AT-56 occupied the catalytic pocket, but not the retinoid-binding pocket, of L-PGDS. AT-56 inhibited the production of PGD(2) by L-PGDS-expressing human TE-671 cells after stimulation with Ca(2+) ionophore (5 microm A23187) with an IC(50) value of about 3 microm without affecting their production of PGE(2) and PGF(2alpha) but had no effect on the PGD(2) production by H-PGDS-expressing human megakaryocytes. Orally administered AT-56 (<30 mg/kg body weight) decreased the PGD(2) production to 40% in the brain of H-PGDS-deficient mice after a stab wound injury in a dose-dependent manner without affecting the production of PGE(2) and PGF(2alpha) and also suppressed the accumulation of eosinophils and monocytes in the bronco-alveolar lavage fluid from the antigen-induced lung inflammation model of human L-PGDS-transgenic mice.

[Penetrating abdominal trauma]. / Trauma abdominal penetrante.

BACKGROUND: The abdomen ranks in third place of body areas injured by trauma. Evaluation and stabilization of these patients form the cornerstone in emergency medicine. Diagnostic approach and treatment outcome are influenced by several factors. Injury mechanism and pattern vary according to geography and there is an association with drugs and alcohol. Physical examination remains the most reliable indicator for surgery. Associated injuries are present in up to 26% of cases. We undertook this study to determine penetrating abdominal trauma incidence and frequency, demographic factors, rate of immediate and delayed laparotomies, and associated complications as well as to define the usefulness of penetrating abdominal trauma index (PATI). METHODS: An observational, prospective, longitudinal descriptive study was carried out at the Hospital Central "Ignacio Morones Prieto," San Luis Potosi, Mexico from January 1, 2005 to December 31, 2005 on patients who underwent exploratory laparotomy for penetrating abdominal trauma. Twenty one variables were studied. Basic statistical analysis, ANOVA, chi(2) and Student's t-test were used. RESULTS: Of the 79 patients who were included, 93.67% were males. The third decade of life was the most affected, with a night presentation being predominant as a result of personal violence. Drug use was observed in 50.6%; stab wounds in 63.3%. The most frequent locations were the left upper and right lower quadrants and epigastrium; solitary wounds were predominant. Associated injuries were most common in the thorax and limbs. Of the laparotomies performed, 92.4% were urgent and 60.53% were therapeutic; 15.19% required reoperations; complications were observed in 39.24%; and mortality rate was 3.9%. CONCLUSIONS: Due to high non-therapeutic and negative laparotomies rates, a more selective approach is needed, including repetitive physical examination and the appropriate use of auxiliary diagnostic studies.

Non-infective subcutaneous emphysema of the hand secondary to a minor webspace injury.

Subcutaneous emphysema in the hand is commonly associated with infection or high-pressure injection injuries, with other non-infectious causes being reported as rarities in the literature. We describe an unusual case of minor injury to the first webspace resulting in significant subcutaneous emphysema.

Evaluation of an in situ forming hydrogel wound dressing based on oxidized alginate and gelatin.

Wound dressings that can be formed in situ offer several advantages over the use of preformed dressings such as conformability without wrinkling or fluting in the wound bed, ease of application and improved patient compliance and comfort. Here we describe such an in situ forming hydrogel wound dressing from gelatin, oxidized alginate and borax. Periodate oxidized alginate rapidly cross-links proteins such as gelatin in the presence of borax to give in situ forming hydrogels that are both non-toxic and biodegradable. The composite matrix has the haemostatic effect of gelatin, the wound healing-promoting feature of alginate and the antiseptic property of borax to make it a potential wound dressing material. The hydrogel was found to have a fluid uptake of 90% of its weight which would prevent the wound bed from accumulation of exudates. The water vapour transmission rate (WVTR) of the hydrogel was found to be 2686+/-124 g/m2/day indicating that the hydrogel can maintain a moist environment over wound bed in moderate to heavily exuding wound which would enhance epithelial cell migration during the healing process. The wound healing efficacy of hydrogel was evaluated in experimental full thickness wounds using a rat model which demonstrated that within 2 weeks, the wound covered with gel was completely filled with new epithelium without any significant adverse reactions. These in situ forming hydrogels fulfil many critical elements desirable in a wound dressing material.

The effect of topical tretinoin on tissue strength and skin components in a murine incisional wound model.

BACKGROUND: Vitamin A derivatives modulate the inflammatory phase in wound healing. Retinoic acid can restore decreased tensile strength and collagen content in steroid- or diabetes-impaired wounds. It is hypothesized that retinoic acid can lead to accelerated healing with improved breaking strength in unimpaired incisional wounds. MATERIALS AND METHODS: Skin incisions were made in 45 CD-1 mice. The sutured wounds were treated once daily with topical all-trans-retinoic acid 0.1% (n = 15), vehicle ointment (n = 15), or left untreated (n = 15). Skin biopsies at 1-, 2-, and 3-week intervals were examined using hematoxylin and eosin (H&E), Masson's trichrome, and immunoperoxidase staining methods. Wound breaking strength was determined by biomechanical analysis. RESULTS: Incisions treated with retinoic acid exhibited a significantly reduced breaking strength at week 1 when compared to the vehicle and control group. Histologic examination showed a prolonged inflammatory reaction with abundant deposition of granulation tissue. Despite an increased fibroplastic proliferation in the tretinoin-treated wounds, the production of collagen was diminished. CONCLUSIONS: Topical retinoic acid does not enhance the healing of unimpaired incisional wounds. The inadequate tensile strength in the early phase of the healing process is possibly the result of an increased dermal inflammatory response and the decreased collagen content. Although these adverse effects disappeared by 3 weeks postwounding, we found no discernible benefit of supplemental retinoic acid in unimpaired wounds.

[The condition of skin tissue and its neural apparatus in rats after infliction of a wound with subsequent application of activated carbon anthracite]. / Stan tkanyn shkiry ta ïï nervovoho aparatu u shchuriv pislia nanesennia rany z nastupnoiu aplikatsiieiu aktyvovanoho vuhletsevoho antratsytu.

The studies made suggest several leads for further study of healing of skin wounds with making use of the activated carbon anthracite (ACA) type carbon sorbent and quercetin-bound ACA type carbon sorbent. The results obtained suggest to us a shorter course and earlier beginning of the connective tissue regeneration after infliction of an incised wound to the skin in test animals under conditions of use of a carbon sorbent, the quercetin-bound one included.

Angiostatic effects of corticosteroid on wound healing of the rabbit ear.

Wound healing is a complex biologic process with initial inflammation, granulation tissue formation, and matrix remodeling. We observed the relation between angiostatic effects and corticosteroid administration time in the rabbit ear chamber. Angiogenesis in the chamber was studied using a microscope-television system. Two experiments were undertaken to represent the systemic and the topical administration of steroids. In experiment 1, 10 mg of triamcinolone acetonide was injected three times intramuscularly (on the day of implantation of the chamber, and the 7th and 14th day after implantation). Vascularization in this group was significantly delayed at the 7th, 14th, and 21st days but no difference from controls was observed in the size and density of vessels after its completion. In experiment 2, 3 mg of triamcinolone acetonide was injected once into the skin adjacent to the chamber on the 10th day after installment of chambers or on the day of installment. In the former group, new vascular growth was delayed until the 21st day after installment. The hemorrhagic zone had narrowed and vascular dilation was observed. In the latter group, endothelial budding was delayed and vascular constriction occurred. New vascular growth was severely delayed and granulation filling of the chamber was not completed. These results suggest not only that the topical administration had the stronger inhibitory effect on neovascularization than the systemic administration but that the effect differed depending on the stage of wound healing. In view of this effect of this steroid, we should pay careful attention to the time when steroids are administered to patients.

Posttreatment with the immunosuppressant cyclosporin A in transient focal ischemia.

Cyclosporin A (CsA) reduces ischemic brain damage when administered in such a way that its penetration across the blood-brain barrier is enhanced. Since only pretreatment has previously been used in focal ischemia, the objective of the present study was to establish whether posttreatment is efficacious and to assess the window of therapeutic opportunity for CsA. To that end, CsA was given 5 min to 6 h after the start of reperfusion following 2 h transient ischemia, and infarct volume was assessed after 48 h by triphenyltetrazolium chloride staining. Attempts were made to circumvent the BBB to CsA by an intracerebral needle lesion, by an increase in the intravenous CsA dose, or by osmotic opening with intracarotid mannitol. The results were compared to those obtained with FK506. Intravenous CsA in a dose of 10 mg/kg failed to reduce infarct volume, unless preceded by a needle lesion. That procedure, and an increase in CsA dose to 50 mg/kg, reduced infarct volume to about 50% of control, but the higher dose had toxic side effects. The coupled intracarotid infusion of mannitol and CsA (10 mg/kg) was more efficacious, without overt side effects. However, mannitol proved dispensable since CsA alone reduced infarct volume to 30% of control, with a therapeutic window of 3-6 h. When given after 5 min of reflow, CsA reduced infarct volume to 10% of control and was clearly more neuroprotective than FK506. Possibly, this is because CsA blocks the mitochondrial permeability transition pore which is opened under adverse conditions.

Administration of prosaposin ameliorates spatial learning disturbance and reduces cavity formation following stab wounds in rat brain.

The effectiveness of prosaposin as a neurotrophic factor was investigated using rats with bilateral stab wounds, injecting 240 ng per day of prosaposin for 3 days. In Morris water maze task, after 3 weeks postoperation, the stab-wounds rats show significant impairment in acquisition compared with the sham-operated rats. In the transfer test the mean number of crossings of the platform place in stab-wounds was significantly lower than that in sham-operated rats (P < 0.01). The stab-wounds rats treated with prosaposin showed significant improvement (P < 0.05). The cavities following stab wounds in the rats treated with prosaposin were significantly smaller than those in the rats treated with (P < 0.05). Our data support that prosaposin is likely to be a new agent for brain injury.