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Biochem Biophys Res Commun ; 577: 32-37, 2021 11 05.
Article En | MEDLINE | ID: mdl-34500233

4,8-Sphingadienines (SD), metabolites of glucosylceramides (GlcCer), are sometimes determined as key mediators of the biological activity of dietary GlcCer, and cis/trans geometries of 4,8-SD have been reported to affect its activity. Since regulating excessive activation of mast cells seems an important way to ameliorate allergic diseases, this study was focused on cis/trans stereoisomeric-dependent inhibitory effects of 4,8-SD on mast cell activation. Degranulation of RBL-2H3 was inhibited by treatment of 4-cis-8-trans- and 4-cis-8-cis-SD, and their intradermal administrations ameliorated ear edema in passive cutaneous anaphylaxis reaction, but 4-trans-8-trans- and 4-trans-8-cis-SD did not. Although the activation of mast cells depends on the bound IgE contents, those stereoisomers did not affect IgE contents on RBL-2H3 cells after the sensitization of anti-TNP IgE. These results indicated that 4-cis-8-trans- and 4-cis-8-cis-SD directly inhibit the activation of mast cells. In conclusion, it was assumed that 4,8-SD stereoisomers with cis double bond at C4-position shows anti-allergic activity by inhibiting downstream pathway after activation by the binding of IgE to mast cells.

Anti-Allergic Agents/pharmacology , Cell Degranulation/drug effects , Ethanolamines/pharmacology , Mast Cells/drug effects , Passive Cutaneous Anaphylaxis/drug effects , Animals , Anti-Allergic Agents/chemistry , Caco-2 Cells , Cell Line, Tumor , Ear/pathology , Edema/prevention & control , Ethanolamines/chemistry , Ethanolamines/metabolism , Female , Glucosylceramides/chemistry , Glucosylceramides/metabolism , Glucosylceramides/pharmacology , Humans , Mast Cells/physiology , Mice, Inbred BALB C , Molecular Structure , Plant Extracts/chemistry , Plant Extracts/pharmacology , Rats , Stereoisomerism
Int J Mol Sci ; 22(14)2021 Jul 09.
Article En | MEDLINE | ID: mdl-34299012

Atopic dermatitis (AD) represents a severe global burden on physical, physiological and mental health. Innate immune cell basophils are essential for provoking allergic inflammation in AD. However, the roles of novel immunoregulatory cytokine IL-37 in basophils remain elusive. We employed in vitro co-culture of human basophils and human keratinocyte HaCaT cells and an in vivo MC903-induced AD murine model to investigate the anti-inflammatory mechanism of IL-37. In the in vitro model, IL-37b significantly decreased Der p1-induced thymic stromal lymphopoietin (TSLP) overexpression in HaCaT cells and decreased the expression of TSLP receptor as well as basophil activation marker CD203c on basophils. IL-37 could also reduce Th2 cytokine IL-4 release from TSLP-primed basophils ex vivo. In the in vivo model, alternative depletion of basophils ameliorated AD symptoms and significantly lowered the Th2 cell and eosinophil populations in the ear and spleen of the mice. Blocking TSLP alleviated the AD-like symptoms and reduced the infiltration of basophils in the spleen. In CRISPR/Cas9 human IL-37b knock-in mice or mice with direct treatment by human IL-37b antibody, AD symptoms including ear swelling and itching were significantly alleviated upon MC903 challenge. Notably, IL-37b presence significantly reduced the basophil infiltration in ear lesions. In summary, IL-37b could regulate the TSLP-mediated activation of basophils and reduce the release of IL-4. The results, therefore, suggest that IL-37 may target TSLP-primed basophils to alleviate AD.

Basophils/immunology , Cytokines/metabolism , Dermatitis, Atopic/metabolism , Interleukin-1/metabolism , Animals , Anti-Inflammatory Agents/therapeutic use , Basophils/drug effects , Cell Line , Coculture Techniques , Cytokines/antagonists & inhibitors , Cytokines/pharmacology , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/genetics , Dermatitis, Atopic/immunology , Down-Regulation , Ear/pathology , Eosinophils/metabolism , Gene Knock-In Techniques , Humans , Interleukin-1/genetics , Interleukin-1/pharmacology , Interleukin-1/therapeutic use , Interleukin-4/metabolism , Keratinocytes/metabolism , Mice , Mice, Inbred C57BL , Mice, Transgenic , Phosphoric Diester Hydrolases/metabolism , Pyrophosphatases/metabolism , Spleen/immunology , Spleen/metabolism , Th2 Cells/immunology , Up-Regulation
Carbohydr Polym ; 268: 118238, 2021 Sep 15.
Article En | MEDLINE | ID: mdl-34127220

Tacrolimus is a natural macrolide that exhibits an anti-proliferative action by T-lymphocytic cells inhibition. Hence, it was tested as a potential topical treatment to improve and control psoriatic plaques. In this study, for the first time the lipophilic tacrolimus in chitosan nanoparticles was used to achieve the desired response and dermal retention of the drug using a modified ionic gelation technique. The hydrophobic drug, tacrolimus, was successfully encapsulated into the synthesized positively-charged particles (140.8 nm ± 50.0) and EE of (65.5% ± 1.3). Local skin deposition of the drug was significantly enhanced with 82.0% ± 0.6 of the drug retained in the skin compared to 34.0% ± 0.9 from tarolimus® ointment. An outstanding response to the prepared formula was the enhanced hair growth rate in the treated animals, which can be considered an excellent sign of the skin recovery from the induced psoriatic plaques after only three days of treatment.

Chitosan/chemistry , Drug Carriers/chemistry , Immunosuppressive Agents/therapeutic use , Nanoparticles/chemistry , Psoriasis/drug therapy , Tacrolimus/therapeutic use , Administration, Cutaneous , Animals , Chitosan/administration & dosage , Drug Carriers/administration & dosage , Drug Liberation , Ear/pathology , Imiquimod , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/chemistry , Mice, Inbred C57BL , Nanoparticles/administration & dosage , Particle Size , Psoriasis/chemically induced , Psoriasis/pathology , Rats, Sprague-Dawley , Skin/drug effects , Skin/pathology , Tacrolimus/administration & dosage , Tacrolimus/chemistry
J Comp Pathol ; 185: 30-44, 2021 May.
Article En | MEDLINE | ID: mdl-34119229

American Cocker Spaniels (ACSs) develop aural ceruminous gland hyperplasia and ectasia more often than dogs of other breeds. Data on the cause and development of these breed characteristic histopathological changes are lacking. We performed video-otoscopic examinations and dermatological work-up on 28 ACSs, obtained aural biopsies from each dog and assessed the statistical associations between the presence of ceruminous gland hyperplasia and ectasia and disease history, clinical or microbiological findings and underlying cause of otitis externa (OE). Histological lesions of ceruminous gland hyperplasia and ectasia were observed in aural biopsies from 6/13 clinically healthy ears and 13/15 ears with OE from 19/28 examined dogs. Nine of 28 dogs had histologically normal ceruminous glands (odds ratio [OR] 6.2, 95% confidence interval [CI] 1.1-36.6). Bacterial growth in microbiological culture of aural exudate (OR 14.1, 95% CI 2.1-95.3) was associated with ceruminous glandular changes, whereas previous history of OE, cutaneous findings or underlying allergies were not. Pedigree analysis and a genome-wide association study (GWAS) were performed on 18 affected and eight unaffected dogs based on histopathological diagnosis. While the GWAS indicated a tentative, but not statistically significant, association of ceruminous gland hyperplasia and ectasia with chromosome 31, a larger cohort is needed to confirm this preliminary result. Based on our results, ceruminous gland hyperplasia and ectasia may also precede clinical signs of OE in ACSs and a genetic aetiological component is likely Further studies with larger cohorts are warranted to verify our preliminary results.

Apocrine Glands/pathology , Dog Diseases , Otitis Externa , Animals , Breeding , Dilatation, Pathologic/veterinary , Dog Diseases/genetics , Dogs , Ear/pathology , Genome-Wide Association Study/veterinary , Hyperplasia/veterinary , Otitis Externa/veterinary , United States
An Bras Dermatol ; 96(4): 429-435, 2021.
Article En | MEDLINE | ID: mdl-34006401

BACKGROUND: Tacrolimus is used to prevent unaesthetic scars due to its action on fibroblast activity and collagen production modulation. OBJECTIVES: To evaluate the action pathways, from the histopathological point of view and in cytokine control, of tacrolimus ointment in the prevention of hypertrophic scars. METHODS: Twenty-two rabbits were submitted to the excision of two 1-cm fragments in each ear, including the perichondrium. The right ear received 0.1% and 0.03% tacrolimus in ointment base twice a day in the upper wound and in the lower wound respectively. The left ear, used as the control, was treated with petrolatum. After 30 days, collagen fibers were evaluated using special staining, and immunohistochemistry analyses for smooth muscle actin, TGF-ß and VEGF were performed. RESULTS: The wounds treated with 0.1% tacrolimus showed weak labeling and a lower percentage of labeling for smooth muscle actin, a higher proportion of mucin absence, weak staining, fine and organized fibers for Gomori's Trichrome, strong staining and organized fibers for Verhoeff when compared to controls. The wounds treated with 0.03% tacrolimus showed weak labeling for smooth muscle actin, a higher proportion of mucin absence, strong staining for Verhoeff when compared to the controls. There was absence of TGF-ß and low VEGF expression. STUDY LIMITATIONS: The analysis was performed by a single pathologist. Second-harmonic imaging microscopy was performed in 2 sample areas of the scar. CONCLUSIONS: Both drug concentrations were effective in suppressing TGF-ß and smooth muscle actin, reducing mucin, improving the quality of collagen fibers, and the density of elastic fibers, but only the higher concentration influenced elastic fiber organization.

Cicatrix, Hypertrophic , Animals , Cicatrix, Hypertrophic/drug therapy , Cicatrix, Hypertrophic/pathology , Cicatrix, Hypertrophic/prevention & control , Ear/pathology , Ointment Bases , Rabbits , Tacrolimus , Wound Healing
Sci Rep ; 11(1): 10643, 2021 05 20.
Article En | MEDLINE | ID: mdl-34017019

Wideband Absorbance Immittance (WAI) has been available for more than a decade, however its clinical use still faces the challenges of limited understanding and poor interpretation of WAI results. This study aimed to develop Machine Learning (ML) tools to identify the WAI absorbance characteristics across different frequency-pressure regions in the normal middle ear and ears with otitis media with effusion (OME) to enable diagnosis of middle ear conditions automatically. Data analysis included pre-processing of the WAI data, statistical analysis and classification model development, and key regions extraction from the 2D frequency-pressure WAI images. The experimental results show that ML tools appear to hold great potential for the automated diagnosis of middle ear diseases from WAI data. The identified key regions in the WAI provide guidance to practitioners to better understand and interpret WAI data and offer the prospect of quick and accurate diagnostic decisions.

Acoustic Impedance Tests , Ear/pathology , Machine Learning , Otitis Media with Effusion/diagnosis , Adolescent , Adult , Aged , Child , Child, Preschool , Databases as Topic , Humans , Image Processing, Computer-Assisted , Infant , Middle Aged , Neural Networks, Computer , Otitis Media with Effusion/diagnostic imaging , Pressure , ROC Curve , Radio Waves , Statistics as Topic , Young Adult
Vet J ; 271: 105655, 2021 May.
Article En | MEDLINE | ID: mdl-33840482

Porcine ear necrosis (PEN) is a condition that mainly occurs in intensive pig production systems and mostly affects piglets after weaning. The syndrome manifests itself with lesions on the pinna, which can heal or become more severe resulting in partial loss of the ear. The pathogenesis of the condition is not fully known. Three different hypotheses for the development of PEN are described in this review: (1) damage of the epidermis due to Staphylococcal exfoliative toxins; (2) occlusion of small blood vessels; and (3) ear biting with subsequent ß-hemolytic streptococcal infection. Risk factors have not been completely elucidated, but viral and bacterial infections, and husbandry factors such as environment, housing conditions and management, have been suggested. It is also possible that some cases are due to a combination of these factors. The role of parasitic infestations has been not investigated. Due to bacterial involvement, severely affected pigs can be treated with antimicrobials. Control and preventive measures should focus on reducing potential risk factors by implementing herd immunization, as well as improvement of sanitary conditions, feed quality (with respect to mycotoxin contamination), management (appropriate stocking density), and environmental conditions (e.g. number of drinkers and feeders and/or optimal ventilation). Further research is needed to better understand the precise etiology and pathogenesis of PEN, so that risk factors can be identified and more targeted control measures can be implemented.

Ear/pathology , Necrosis/veterinary , Sus scrofa , Swine Diseases/pathology , Animals , Anti-Bacterial Agents/therapeutic use , Housing, Animal , Infections/veterinary , Necrosis/microbiology , Necrosis/therapy , Risk Factors , Swine , Swine Diseases/epidemiology , Swine Diseases/etiology , Weaning
J Forensic Leg Med ; 80: 102173, 2021 May.
Article En | MEDLINE | ID: mdl-33895542

Blast injuries seen in various accidents involving pressurized containers like gas cylinders, tires, et cetera, and acts of terrorism. The associated factors can vary from poor handling of equipment to inadequate safety precautions. These injuries include a variety of injuries, such as, injuries due to shock wave, burns, fractures, et cetera, involving multi-organ systems, especially lungs and hollow organs, due to the high-pressurized shock wave. The presented case is of the death of a 24-years-old male as a result of a blast of the compressor present in the AC outdoor unit during the filling of the gas. Here, the body showed injuries due to shock wave, secondary impact, tertiary impact because of fall on the ground, and quaternary injuries due to burns. The cause of death was Blast lung associated with Subarachnoid hemorrhage.

Blast Injuries/pathology , Explosions , Accidents, Occupational , Burns/pathology , Ear/pathology , Hemorrhage/pathology , Humans , Lung/pathology , Male , Subarachnoid Hemorrhage, Traumatic/pathology , Young Adult
J Cutan Pathol ; 48(6): 739-744, 2021 Jun.
Article En | MEDLINE | ID: mdl-33617003

BACKGROUND: The distinction between chondrodermatitis nodularis helicis (CNH) and hyperplastic actinic keratosis (HAK) on the ear can pose a diagnostic challenge. We aimed to identify histopathological characteristics that could distinguish between CNH and HAK on routine sections using penalized least absolute shrinkage and selection operator (LASSO) logistic regression analysis. METHODS: Cases of CNH (n = 80) and HAK (n = 28) were analyzed for selected histopathological characteristics. Fisher's exact test and LASSO regression were performed. RESULTS: In univariate analyses, the following were significantly associated with CNH: ulceration, acanthosis, granular layer in the majority of the lesion, hypergranulosis at the periphery of the lesion, hyperkeratosis at the periphery of the lesion, hyperparakeratosis at the periphery of the lesion, fibrosis, increased blood vessels, vertically oriented blood vessels, and fibrin. A LASSO model excluding atypia found that fibrin, fibrosis, presence of granular layer, ulceration, and vertically oriented blood vessels were most predictive of CNH. Keratinized strap cells were not a significant predictor. CONCLUSION: We have identified features that may aid in differentiating these entities and demonstrated that a LASSO regression model can identify predictors that may improve diagnostic accuracy. Our results indicate that the highest diagnostic accuracy in this dilemma is dependent on obtaining biopsy specimens with visible dermis.

Cartilage Diseases/pathology , Dermatitis/pathology , Hyperplasia/pathology , Keratosis, Actinic/pathology , Biopsy , Diagnosis, Differential , Ear/pathology , Fibrosis/pathology , Humans , Keratosis, Actinic/diagnosis , Logistic Models , Neovascularization, Pathologic/pathology , Prurigo/diagnosis , Prurigo/pathology , Retrospective Studies
Biochem Biophys Res Commun ; 546: 124-129, 2021 03 26.
Article En | MEDLINE | ID: mdl-33582554

Microsomal prostaglandin (PG) E synthase-1 (mPGES-1) and prostacyclin (PGI2) synthase (PGIS) are PG terminal synthases that work downstream of cyclooxygenase and synthesize PGE2 and PGI2, respectively. Although the involvement of PG receptors in acquired cutaneous immune responses was recently shown, the roles of these PG terminal synthases remain unclear. To identify the pathophysiological roles of mPGES-1 and PGIS in cutaneous immune systems, we applied contact hypersensitivity (CHS) to mPGES-1 and PGIS knockout (KO) mice as a model of acquired immune responses. Mice were treated with 1-fluoro-2,4-dinitrobenzene (DNFB) and evaluated for ear thickness and histopathological features. The results showed that the severity of ear swelling in both gene-deficient mice was much lower than that in wild-type (WT) mice. Histological examination of DNFB-treated ears showed that inflammatory cell infiltration and edema in the dermis were also less apparent in both genotypic mice. LC-MS analysis further showed that the increment in PGE2 levels in DNFB-treated ear tissue was reduced in mPGES-1 KO mice, and that 6-keto PGF1α (a stable metabolite of PGI2) was not detected in PGIS KO mice. Furthermore, we made bone marrow (BM) chimera and found that transplantation of WT mouse-derived BM cells restored the impaired CHS response in mPGES-1 KO mice but did not restore the response in PGIS KO mice. These results indicated that mPGES-1 in BM-derived cells and PGIS in non-BM-derived cells might play critical roles in DNFB-induced CHS. mPGES-1-derived PGE2 and PGIS-derived PGI2 might coordinately promote acquired cutaneous immune responses.

Cytochrome P-450 Enzyme System/metabolism , Dermatitis, Contact/enzymology , Intramolecular Oxidoreductases/metabolism , Prostaglandin-E Synthases/metabolism , Adoptive Transfer , Animals , Bone Marrow Cells , Cytochrome P-450 Enzyme System/deficiency , Cytochrome P-450 Enzyme System/genetics , Dermatitis, Contact/etiology , Dermatitis, Contact/genetics , Dinitrofluorobenzene/adverse effects , Ear/pathology , Female , Interferon-gamma/metabolism , Interleukins/metabolism , Intramolecular Oxidoreductases/deficiency , Intramolecular Oxidoreductases/genetics , Mice , Mice, Knockout , Prostaglandin-E Synthases/deficiency , Prostaglandin-E Synthases/genetics , Prostaglandins/metabolism , Tumor Necrosis Factor-alpha/metabolism
Proc Natl Acad Sci U S A ; 118(1)2021 01 05.
Article En | MEDLINE | ID: mdl-33443188

Dysregulation of inflammatory cytokines in keratinocytes promote the pathogenesis of the skin inflammation, such as allergic contact dermatitis (ACD). High-mobility group box 1 protein (HMGB1) has been implicated in the promotion of skin inflammation upon its extracellular release as a damage-associated molecular pattern molecule. However, whether and how HMGB1 in keratinocytes contributes to ACD and other skin disorders remain elusive. In this study, we generated conditional knockout mice in which the Hmgb1 gene is specifically deleted in keratinocytes, and examined its role in ACD models. Interestingly, the mutant mice showed exacerbated skin inflammation, accompanied by increased ear thickening in 2,4-dinitrofluorobenezene-induced ACDs. The mRNA expression of interleukin-24 (IL-24), a cytokine known to critically contribute to ACD pathogenesis, was elevated in skin lesions of the mutant mice. As with constitutively expressed, IL-4-induced Il24 mRNA, expression was also augmented in the Hmgb1-deficient keratinocytes, which would account for the exacerbation of ACD in the mutant mice. Mechanistically, we observed an increased binding of trimethyl histone H3 (lys4) (H3K4me3), a hallmark of transcriptionally active genes, to the promoter region of the Il24 gene in the hmgb1-deficient cells. Thus, the nuclear HMGB1 is a critical "gate keeper" in that the dermal homeostasis is contingent to its function in chromatin remodeling. Our study revealed a facet of nuclear HMGB1, namely its antiinflammatory function in keratinocytes for the skin homeostasis.

Chromatin Assembly and Disassembly , Dermatitis, Allergic Contact/metabolism , HMGB1 Protein/metabolism , Histones/metabolism , Interleukins/metabolism , Keratinocytes/metabolism , Animals , Dermatitis, Allergic Contact/genetics , Dermatitis, Allergic Contact/prevention & control , Dinitrofluorobenzene/toxicity , Disease Models, Animal , Ear/pathology , Gene Deletion , Gene Expression Regulation/genetics , HMGB1 Protein/deficiency , HMGB1 Protein/genetics , Inflammation/genetics , Inflammation/metabolism , Interleukin-4/pharmacology , Interleukins/genetics , Mice , Mice, Knockout , Promoter Regions, Genetic , Skin/immunology , Skin/metabolism , Skin/pathology , Transplantation Chimera
Otolaryngol Head Neck Surg ; 164(2): 300-301, 2021 02.
Article En | MEDLINE | ID: mdl-32779961

In the setting of COVID-19 (coronavirus disease 2019)-associated moderate and severe acute respiratory distress, persistently hypoxemic patients often require prone positioning for >16 hours. We report facial pressure wounds and ear necrosis as a consequence of prone positioning in patients undergoing ventilation in the intensive care unit in a tertiary medical center in New York City.

COVID-19/therapy , Facial Injuries/etiology , Patient Positioning/adverse effects , Pressure Ulcer/etiology , Prone Position , Respiration, Artificial/adverse effects , COVID-19/complications , Critical Care , Ear/pathology , Facial Injuries/pathology , Humans , Necrosis , Pressure Ulcer/pathology
Bioorg Chem ; 106: 104471, 2021 01.
Article En | MEDLINE | ID: mdl-33257003

Karanja (Pongamia pinnata) is a medicinal tree used in the Indian traditional ayurvedic system for treating several ailments. The seeds contain a unique furano-flavonoid karanjin, which has shown to possess many medicinal properties. Its usage at the clinical level is affected due to poor solubility and absorption. In the present investigation, molecular modifications of karanjin were attempted and evaluated their effect on anti-inflammatory activity. Firstly, Karanja ketone was obtained from karanjin by hydrolysis, and it was converted into karanja ketone oxime. The oxime undergoes Beckmann rearrangement and cyclized to yield furano benzoxazole (karanja oxazole). The new derivatives were purified with >95% purity (HPLC) and spectrally characterized (HR-MS, FTIR, and NMR). Among the test compounds, karanja ketone oxime exhibited higher antioxidant activity with an IC50 value of 360 µg/ml (DPPH). Soy lipoxygenase-1 (LOX-1) inhibitory activity of oxime was higher (IC50 = 65.4 µM) than other compounds. Fluorescence studies showed that oxime had higher quenching capacity with a Qmax of 76.3% and a binding constant of 0.9 × 105 M-1 for soy LOX-1. In-silico interaction studies showed that karanja ketone oxime had the least binding energy of -5.76 kcal/mol with LOX-1 by forming two hydrogen bonds with hydrophobic amino acids Leu 390 and Gly 392. The compounds were evaluated for their acute anti-inflammatory activity by the paw and ear edema in the rat model. Karanjin inhibits paw edema and ear edema by 34.13% and 51.13%, respectively, whereas the derivatives inhibited by 45-57 % and 70-76.8%. This study reports a rational approach to synthesize karanjin derivatives with considerable anti-inflammatory properties, both in-vitro and in-vivo.

Anti-Inflammatory Agents/therapeutic use , Benzopyrans/therapeutic use , Inflammation/drug therapy , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/isolation & purification , Anti-Inflammatory Agents/metabolism , Benzopyrans/chemical synthesis , Benzopyrans/isolation & purification , Benzopyrans/metabolism , Catalytic Domain , Dose-Response Relationship, Drug , Ear/pathology , Edema/drug therapy , Edema/pathology , Free Radical Scavengers/chemical synthesis , Free Radical Scavengers/isolation & purification , Free Radical Scavengers/metabolism , Free Radical Scavengers/therapeutic use , Inflammation/pathology , Lipoxygenase/chemistry , Lipoxygenase/metabolism , Lipoxygenase Inhibitors/chemical synthesis , Lipoxygenase Inhibitors/isolation & purification , Lipoxygenase Inhibitors/metabolism , Lipoxygenase Inhibitors/therapeutic use , Male , Millettia/chemistry , Molecular Docking Simulation , Protein Binding , Rats, Wistar , Seeds/chemistry
Int J Dev Biol ; 64(7-8-9): 423-432, 2020.
Article En | MEDLINE | ID: mdl-33063836

Transforming growth factor beta (TGFß) signalling is involved in several aspects of regeneration in many organs and tissues of primitive vertebrates. It has been difficult to recognize the role of this signal in mammal regeneration due to the low ability of this animal class to reconstitute tissues. Nevertheless, ear-holes in middle-age female mice represent a model to study the limited epimorphic-like regeneration in mammals. Using this model, in this study we explored the possible participation of TGFß signalling in mammal regeneration. Positive pSmad3 cells, as well as TGFß1 and TGFß3 isoforms, were detected during the redifferentiation phase in the blastema-like structure. Daily administration of the inhibitor of the TGFß intracellular pathway, SB431542, during 7 days from the re-differentiation phase, resulted in a decreased level of pSmad3 accompanied by a transitory higher growth of the new tissue, larger cartilage nodules, and new muscle formation. These phenotypes were associated with a decrease in the number of α-SMA-positive cells and loose packing of collagen I. These results indicate that the modulation of the fibrosis mediated by TGFß signalling contributes to enhancing the differentiation of cartilage and muscle during limited ear-hole regeneration.

Cell Differentiation/physiology , Ear/physiopathology , Regeneration/physiology , Signal Transduction/physiology , Transforming Growth Factor beta/metabolism , Animals , Benzamides/pharmacology , Cell Differentiation/drug effects , Dioxoles/pharmacology , Ear/pathology , Extracellular Matrix Proteins/metabolism , Female , Fibrosis , Mice, Inbred BALB C , Microscopy, Fluorescence/methods , Regeneration/drug effects , Signal Transduction/drug effects , Smad3 Protein/metabolism , Transforming Growth Factor beta3/metabolism
Molecules ; 25(18)2020 Sep 05.
Article En | MEDLINE | ID: mdl-32899525

Many studies have reported the biological activities of retrofractamide C (RAC). However, few studies have investigated the anti-inflammatory effect of RAC. In the present study, we investigated the anti-inflammatory effect of RAC using lipopolysaccharide (LPS)-induced J774A.1 cells and a xylene-induced mouse ear edema model. Treatment with RAC decreased LPS-induced nitric oxide (NO) and prostaglandin E2 (PGE2) secretion and inducible NO synthase (iNOS) and cyclooxygenase 2 (COX2) protein expression. It also downregulated the LPS-induced production of interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) but not tumor necrosis factor α (TNF-α). In the LPS-induced signaling pathway, RAC inhibited the phosphorylation of extracellular signal-regulated kinase (ERK) and nuclear factor kappa light chain enhancer of activated B cells (NF-κB) but not c-Jun N-terminal kinase (JNK) or p38. In a xylene-induced mouse ear edema model, RAC treatment alleviated edema formation and inflammatory cell infiltration. In conclusion, the present study indicates that RAC has the potential to have anti-inflammatory effects and could be a prospective functional food.

Amides/pharmacology , Ear/pathology , Edema/pathology , Extracellular Signal-Regulated MAP Kinases/metabolism , Lipopolysaccharides/pharmacology , NF-kappa B/metabolism , Piper/chemistry , Amides/chemistry , Animals , Cell Line , Cyclooxygenase 2/metabolism , Dinoprostone/biosynthesis , Gene Expression Regulation/drug effects , Inflammation Mediators/metabolism , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Interleukin-6/genetics , Interleukin-6/metabolism , JNK Mitogen-Activated Protein Kinases/metabolism , Male , Mice, Inbred ICR , Nitric Oxide/metabolism , Nitric Oxide Synthase Type II/metabolism , Phosphorylation/drug effects , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism , Xylenes , p38 Mitogen-Activated Protein Kinases/metabolism
J Plast Surg Hand Surg ; 54(6): 382-387, 2020 Dec.
Article En | MEDLINE | ID: mdl-32915110

INTRODUCTION: In our study, we aimed to search and compare the effects of valsartan and enalapril on the pathological scar formation on the basis of histomorphological parameters. MATERIALS AND METHODS: Nine New Zealand albino male rabbits, which were divided into three groups, were included in the study. A previously described rabbit ear wound model was used. Enalapril was administered 0.75 mg/kg/day on the first group and valsartan was administered 10 mg/kg/day on the second group for 40 days. The third group was the control group. Results were evaluated on the 40th day with scar elevation index calculation and histological studies. Histological studies were done by using Hematoxylin-eosin, Masson trichrome and Sirius Red stains. RESULTS: Enalapril and valsartan groups were both significantly effective on the prevention of pathological scar formation when compared to the control group in terms of fibroblast count, capillary count, type 1/3 collagen ratio, collagen organization, and epithelial thickness. There was no significant difference between the enalapril and control group on the scar elevation index. Valsartan group was more efficient than the enalapril group on the reduction of fibroblast count and epithelial thickness. CONCLUSION: Both Valsartan and Enalapril are found to be effective for the prevention of pathological scar formation.

Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Cicatrix, Hypertrophic/prevention & control , Enalapril/pharmacology , Valsartan/pharmacology , Wound Healing/drug effects , Animals , Cicatrix, Hypertrophic/pathology , Collagen/analysis , Collagen/chemistry , Ear/pathology , Fibroblasts , Male , Models, Animal , Rabbits
Molecules ; 25(17)2020 Sep 03.
Article En | MEDLINE | ID: mdl-32899132

In the context of the cancer-inflammation relationship and the use of natural products as potential antitumor and anti-inflammatory agents, the alkaloid-enriched fraction of Boehmeriacaudata (BcAEF) aerial parts was evaluated. In vitro antiproliferative studies with human tumor cell lines showed high activity at low concentrations. Further investigation on NCI-H460 cells showed an irreversible effect on cell proliferation, with cell cycle arrest at G2/M phase and programmed cell death induction. Molecular docking studies of four alkaloids identified in BcAEF with colchicine's binding site on ß-tubulin were performed, suggesting (-)-C (15R)-hydroxycryptopleurine as the main inductor of the observed mitotic death. In vivo studies showed that BcAEF was able to reduce Ehrlich tumor volume progression by 30 to 40%. Checking myeloperoxidase activity, BcAEF reduced neutrophils migration towards the tumor. The in vivo anti-inflammatory activity was evaluated by chemically induced edema models. In croton oil-induced ear edema and carrageenan (CG)-induced paw edema models, BcAEF reduced edema around 70 to 80% together with inhibition of activation and/or migration of neutrophils to the inflammatory area. All together the results presented herein show BcAEF as a potent antitumor agent combining antiproliferative and anti-inflammatory properties, which could be further explored in (pre)clinical studies.

Alkaloids/chemistry , Anti-Inflammatory Agents/pharmacology , Antineoplastic Agents/pharmacology , Boehmeria/chemistry , Computer Simulation , Plant Extracts/pharmacology , Animals , Apoptosis/drug effects , Caspases/metabolism , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Clone Cells , Disease Models, Animal , Ear/pathology , Edema/pathology , Enzyme Activation/drug effects , Exocytosis , Humans , Molecular Docking Simulation , Paclitaxel/pharmacology , Peroxidase/metabolism , Phosphatidylserines/metabolism , Reference Standards , Toxicity Tests, Acute
Medicine (Baltimore) ; 99(30): e21313, 2020 Jul 24.
Article En | MEDLINE | ID: mdl-32791720

BACKGROUND: Congenital auricular deformities (CAD) are prevalent worldwide. The objective of this study is to investigate the effectiveness and safety of ear molding for children with CAD at their early days. METHODS: One hundred and nighty children (under 3 days) with CAD will be included in the study. Participants will be randomly allocated to treatment or waiting list group (n = 95). The treatment group will receive ear molding within 3 days after birth for 2 weeks. The control group will receive usual care and receive the same ear molding at 6th week if spontaneously recover is not occur. Physician and parent assessment of improvement, parent's anxiety, depression, and quality of life and adverse events will be measured at baseline, 3rd and 6th week of initial treatment. The primary outcome recovery rate will be compared between groups using Chi square test. Secondary continuous outcomes will be compared using analysis of variance. DISCUSSION: This study is the first randomized controlled trial to examine the effectiveness, safety and cost-effectiveness of ear molding for CAD comparing with waiting list, to inform clinical decision of CAD treatments and relevant guideline development.

Congenital Microtia/epidemiology , Cost-Benefit Analysis/methods , Ear/abnormalities , Hearing Aids/adverse effects , Case-Control Studies , Clinical Decision-Making , Ear/pathology , Hearing Aids/statistics & numerical data , Humans , Infant, Newborn , Parents/psychology , Quality of Life , Safety , Treatment Outcome , Visual Analog Scale , Waiting Lists