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Acne is a chronic inflammatory skin disease with wide-ranging effects, involving factors such as Propionibacterium acnes (P. acnes) infection and sebum hypersecretion. Current acne treatments are challenged by drug resistance. 5-aminolaevulinic acid (ALA) -based photodynamic therapy (PDT) has been widely used in the clinical treatment of acne, however, the mechanism of its action remains to be elucidated. In this study, by constructing a mice ears model of P. acnes infection, we found that ALA-PDT inhibited the proliferation of P. acnes in vivo and in vitro, significantly ameliorated ear swelling, and blocked the chronic inflammatory process. In vitro, ALA-PDT inhibited lipid secretion and regulated the expression of lipid synthesis and metabolism-related genes in SZ95 cells. Further, we found that ALA-PDT led to DNA damage and apoptosis in SZ95 cells by inducing mitochondrial stress and oxidative stress. Altogether, our study demonstrated the great advantages of ALA-PDT for the treatment of acne and revealed that the mechanism may be related to the blockade of chronic inflammation and the suppression of lipid secretion by ALA-PDT., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Tail docking is widely used to control tail biting in pigs, but it is a painful and stressful procedure. The impact of non-docking trials on tail damage (TD) and ear lesions (EL) from weaning to slaughter was assessed on four commercial farms., Methods: A total of 898 docked pigs (396 DP) or undocked pigs (502 UP) were assessed for tail damage and ear lesions at the beginning and end of the weaner stage, during fattening and at the abattoir during slaughter., Results: The percentage of UP with shortened tails increased significantly from weaning to fattening, but the percentage of non-inflamed tails and tails without fresh lesions increased. In terms of severity of lesion, a lower percentage of pigs scored as 'no visible lesion' at the end of weaning compared to fattening, both for UP and DP (p < 0.05). DP always had a lower percentage of TD, whereas UP had a lower percentage of EL at the end of weaning., Limitation: It was not possible to statistically compare different preventive strategies trialed on farms as alternatives to docking., Conclusion: This study highlights that combining tail length and lesion score at slaughter could be a reliable on-farm welfare indicator., (© 2024 The Author(s). Veterinary Record published by John Wiley & Sons Ltd on behalf of British Veterinary Association.)

Fucoidan from Saccharina japonica (SJF) was isolated and characterized, and its anti-inflammatory effects on fine dust/ambient particulate matter (PM)-stimulated HaCaT keratinocytes were investigated. SJF increased cell viability by reducing intracellular ROS production in PM-stimulated HaCaT keratinocytes. Moreover, SJF downregulated the expression/production of inflammatory cytokines (IL-6, IL-8, IL-13, IL-25, IL-33, TNF-α, IFN-γ, and TSLP) and chemokines (MDC and TARC) through modulating NF-κB/MAPK signaling in PM-stimulated HaCaT keratinocytes. Extended studies investigated the impact of SJF-treated HaCaT keratinocyte culture media on HDFs. Interestingly, media from SJF-treated HaCaT keratinocytes on HDFs demonstrated a notable downregulation of the production of inflammatory mediators such as TSLP, IL-6, IL-8, IL-13, and TNF-α, as well as TARC and MDC. Furthermore, the study examined the impact of SJF on 12-O-tetradecanoylphorbol 13-acetate (TPA) induced ear edema in BALB/c mice and results indicated the reduced ear thickness and decreased iNOS and COX-2 expression. Our study confirmed the effectiveness of SJF in ameliorating PM-induced skin inflammation in in vitro experiments, along with the TPA-induced in vivo inflammatory model., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: Handheld otoscopy is the standard tool used to teach ear examination in undergraduate and postgraduate medical education. Previous studies have shown that the undergraduate teaching of ear examination with handheld otoscopes is inadequate, resulting in low self-reported levels of student confidence in their diagnostic skills. With the increase in popularity of endoscopic ear surgery, an increasing number of otolaryngologists are using endoscopes for office examinations of the ear due to themethod's superior visualization and excellent image qualities. However, medical students usually do not receive exposure to endoscopic ear examination during their undergraduate curriculum. The aim of this study is to assess our preliminary experience with teaching endoscopic ear examination to undergraduate medical students. Methods: A two-hour-long pilot practical course on basic ear examination was administered to undergraduate medical students with little to no previous experience with ear examination. The course was designed to minimize the duration of campus attendance and patient contact during the COVID-19 pandemic. The course included theoretical didactics, exemplary digital endoscopic images and peer physical practice of ear examination with both a handheld otoscope and a 0-degree endoscope. At the end of the course, the students completed a survey questionnaire consisting of eight questions mainly relating to their subjective confidence level with ear examination using either handheld otoscopes or endoscopes and their overall preference for either examination tool. Results: Most students expressed a preference for ear examination with endoscopes over that with handheld otoscopes and reported an improved confidence level in their diagnostic ability with the former technique. The vast majority of students supported the teaching of endoscopic ear examination to future medical students. Conclusion: The findings of this pilot project report and survey study support the early exposure of novice medical learners to endoscopic ear examination, whichmay help improve the confidence and diagnostic skill of medical students with regard to ear examination. The findings may have implications for the undergraduate teaching of ear examination in the post-COVID-19 era. [ABSTRACT FROM AUTHOR]

Objective: To survey hearing and balance problems of a sampling group of Thai elders in the central region of Thailand. Methods: A population study was people aged 60 and over who agreed to join the survey at the 14 elderly social associations. The questionnaires were used as a self-report for hearing and balance problems. After ears examination by ENT specialists, the participants underwent air-conduction audiometry for hearing screening. Results:828 participants (259 (31.3%) males and 569 (68.7%) females, age ranged from 60 to 97 (median=68, mean ± SD = 69.65 ± 6.89 years), had completed screening program for hearing and balance problems using both questionnaires and examinations. There was a statistically significant correlation between self-report hearing loss and severe or profound hearing loss in both ears (P 70 years old especially in those with underlying diseases. Hearing and balance screening will provide early detection and primary intervention to minimize the negative impact in the elderly’s daily life.

Background: Current strategies for hypertrophic scar prevention and treatment are limited., Objective: To facilitate these efforts, a minimally invasive hypertrophic scar model was created in a rabbit ear for the first time based on previous methods used to induce ischemia., Methods: Six New Zealand white rabbits (12 ears total) were studied. First, ischemia was achieved by ligating the cranial artery, cranial vein and central artery, while preserving the caudal artery, caudal vein and central vein, respectively. The relative level of ischemia induced at time of surgery, both baseline and maximum perfusion, was assessed with a fluorescent light-assisted angiography and demonstrated lower rates of perfusion in the ischemic ears. Following vascular injury, a 2-cm full thickness linear wound was created on the ventral ear and closed with 4 - 0 Nylon sutures under high tension. For each rabbit, one ear received a combination of ischemia and wounding with suture tension (n = 6), while the other ear was non-ischemic with wounding and suture tension alone (n = 6)., Results: Four weeks post-operatively, ischemic ears developed scar hypertrophy (histological scar thickness: 1.1 ± 0.2 mm versus 0.5 ± 0.1 mm, p < 0.05)., Conclusion: Herein, we describe a novel, prototypical minimally invasive rabbit ear model of hypertrophic scar formation that can allow investigation of new drugs for scar prevention., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Hypertrophic scars (HS) still remain an urgent challenge in the medical community. Traditional Chinese medicine (TCM) has unique advantages in the treatment of HS. However, due to the natural barrier of the skin, it is difficult for the natural active components of TCM to more effectively penetrate the skin and exert therapeutic effects. Therefore, the development of an efficient drug delivery system to facilitate enhanced transdermal absorption of TCM becomes imperative for its clinical application. In this study, we designed a compound Salvia miltiorrhiza - Blumea balsamifera nanoemulsion gel (CSB-NEG) and investigated its therapeutic effects on rabbit HS models. The prescription of CSB-NEG was optimized by single-factor, pseudoternary phase diagram, and central composite design experiments. The results showed that the average particle size and PDI of the optimized CSB-NE were 46.0 ± 0.2 nm and 0.222 ± 0.004, respectively, and the encapsulation efficiency of total phenolic acid was 93.37 ± 2.56%. CSB-NEG demonstrated excellent stability and skin permeation in vitro and displayed a significantly enhanced ability to inhibit scar formation compared to the CSB physical mixture in vivo . After 3 weeks of CSB-NEG treatment, the scar appeared to be flat, pink, and flexible. Furthermore, this treatment also resulted in a decrease in the levels of the collagen I/III ratio and TGF-β 1 and Smad2 proteins while simultaneously promoting the growth and remodeling of microvessels. These findings suggest that CSB-NEG has the potential to effectively address the barrier properties of the skin and provide therapeutic benefits for HS, offering a new perspective for the prevention and treatment of HS.

Objectives/hypothesis: To assess the confidence and abilities of medical students to diagnose specific types of otologic pathology, and to determine how different training experiences in medical school impact these outcomes.Study Design: Survey analysis.Methods: Sixty third- and fourth-year medical students completed a computerized online survey. Participants answered questions about their otoscopic training experience and confidence, and provided diagnoses for 72 digital images taken with a high-definition video otoscope that showed common otologic pathologies of the tympanic membrane and middle ear space.Results: Most participants (65%) had received less exposure to otoscopic training in medical school than they expected. Confidence in diagnostic ability was low. For diagnostic ability, the mean percent correct across pathologies was 54% ± 7.7%. Medical school year (P = .006), intended specialty (P = .022), and total number of otolaryngology rotations (P = .048) were predictive of diagnostic accuracy on univariable logistic regression analyses, but medical school year (P = .039) was the only significant independent predictor in multivariable analysis. Intended specialty (P = .047) and total number of otolaryngology rotations (P = .035) were predictive of prequiz diagnostic confidence on univariable logistic regression analyses.Conclusions: Medical students were not satisfied with their exposure to otoscopic training. Intended specialty, total number of otolaryngology rotations, and year in medical school predicted diagnostic accuracy. Intended specialty and total number of otolaryngology rotations predicted diagnostic confidence. Additional studies are needed to investigate how training experiences can be improved to optimize otoscopy training during medical school.Level Of Evidence: NA Laryngoscope, 129:1891-1897, 2019. [ABSTRACT FROM AUTHOR]

The skin epidermis is constantly renewed throughout life 1,2 . Disruption of the balance between renewal and differentiation can lead to uncontrolled growth and tumour initiation 3 . However, the ways in which oncogenic mutations affect the balance between renewal and differentiation and lead to clonal expansion, cell competition, tissue colonization and tumour development are unknown. Here, through multidisciplinary approaches that combine in vivo clonal analysis using intravital microscopy, single-cell analysis and functional analysis, we show how SmoM2-a constitutively active oncogenic mutant version of Smoothened (SMO) that induces the development of basal cell carcinoma-affects clonal competition and tumour initiation in real time. We found that expressing SmoM2 in the ear epidermis of mice induced clonal expansion together with tumour initiation and invasion. By contrast, expressing SmoM2 in the back-skin epidermis led to a clonal expansion that induced lateral cell competition without dermal invasion and tumour formation. Single-cell analysis showed that oncogene expression was associated with a cellular reprogramming of adult interfollicular cells into an embryonic hair follicle progenitor (EHFP) state in the ear but not in the back skin. Comparisons between the ear and the back skin revealed that the dermis has a very different composition in these two skin types, with increased stiffness and a denser collagen I network in the back skin. Decreasing the expression of collagen I in the back skin through treatment with collagenase, chronic UV exposure or natural ageing overcame the natural resistance of back-skin basal cells to undergoing EHFP reprogramming and tumour initiation after SmoM2 expression. Altogether, our study shows that the composition of the extracellular matrix regulates how susceptible different regions of the body are to tumour initiation and invasion., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: Ultrashort wave diathermy (USWD) is commonly used in diseases associated with osteoarticular and soft tissue injuries. However, while accelerating wound healing and preventing joint stiffness, there have been few reports on whether it leads to excessive hypertrophic scarring. The aim was to investigate the effects of different doses of USWD on hypertrophic scars., Materials and Methods: A rabbit model of hypertrophic scars was used to determine which dose of USWD reduced scar hyperplasia. The scar thickness was calculated using Sirius red staining. All protein expression levels were determined by western blotting, including fibrosis, collagen deposition, and neoangiogenesis related proteins. Subsequently, flow cytometry and ELISAs were used to determine the proportions of macrophage and inflammatory levels., Results: The wounds with USWD in histopathology showed the dermis was more markedly thickened in the 120 mA group, whereas the wounds with the 60 mA were less raised, comparing with the 0 mA; all detected protein levels were increased significantly, the 120 mA group comparing with the others, including heat shock, fibrosis, and neoangiogenesis, whereas the collagen deposition relative protein levels were decreased, the 60 mA group comparing with Sham group; Finally, in the proportion of macrophages and inflammatory levels the 120 mA group were the highest, and the group Sham was lower than group 60 mA., Conclusions: In hypertrophic scars, the 60 mA USWD could relieve scar formation and inflammatory reactions; however, higher doses could result in opposite consequences.

In adult mammals, skin wounds typically heal by scarring rather than through regeneration. In contrast, "super-healer" Murphy Roths Large (MRL) mice have the unusual ability to regenerate ear punch wounds; however, the molecular basis for this regeneration remains elusive. Here, in hybrid crosses between MRL and non-regenerating mice, we used allele-specific gene expression to identify cis-regulatory variation associated with ear regeneration. Analyzing three major cell populations (immune, fibroblast, and endothelial), we found that genes with cis-regulatory differences specifically in fibroblasts were associated with wound-healing pathways and also co-localized with quantitative trait loci for ear wound-healing. Ectopic treatment with one of these proteins, complement factor H (CFH), accelerated wound repair and induced regeneration in typically fibrotic wounds. Through single-cell RNA sequencing (RNA-seq), we observed that CFH treatment dramatically reduced immune cell recruitment to wounds, suggesting a potential mechanism for CFH's effect. Overall, our results provide insights into the molecular drivers of regeneration with potential clinical implications., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Auriculocondylar syndrome (ARCND) is a genetic and rare craniofacial condition caused by abnormal development of the first and second pharyngeal arches during the embryonic stage and is characterized by peculiar auricular malformations (question mark ears), mandibular condyle hypoplasia, micrognathia and other less-frequent features. GNAI3, PLCB4 and EDN1 have been identified as pathogenic genes in this syndrome so far, all of which are implicated in the EDN1-EDNRA signal pathway. Therefore, ARCND is genetically classified as ARCND1, ARCND2 and ARCND3 based on the mutations in GNAI3, PLCB4 and EDN1, respectively. ARCND is inherited in an autosomal dominant or recessive mode with significant intra- and interfamilial phenotypic variation and incomplete penetrance, rendering its diagnosis difficult and therapies individualized. To raise clinicians' awareness of the rare syndrome, we focused on the currently known pathogenesis, pathogenic genes, clinical manifestations and surgical therapies in this review., Competing Interests: Declaration of competing interest All authors reported no conflicts of interest in this work., (Copyright © 2023 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Skin is the human body's first line of defense and one of the most exposed organs to environmental chemicals. Allergic contact dermatitis (ACD) is a common skin disease that manifests as a local rash, redness, and skin lesions. The occurrence and development of ACD are influenced by both genetic and environmental factors. Although many scholars have constructed a series of models of ACD in recent years, the experimental protocols of these models are all different, which makes it difficult for readers to establish them well. Therefore, a stable and efficient animal model is of great significance to further study the pathogenesis of atopic dermatitis. In this study, we detail a modeling method using 1-fluoro-2,4-dinitrobenzene (DNFB) to induce ACD-like symptoms in the ears of mice and describe several methods for assessing the severity of dermatitis during modeling. This experimental protocol has been successfully applied in some experiments and has a certain promotional role in the field of ACD research.

Background: Cartilage-cutting and cartilage-sparing techniques are the two types of otoplasty procedures. Because of the significant risk of haematoma, skin necrosis, and ear deformity, cartilage-cutting techniques have been questioned. As a result; suture-based cartilage-sparing procedures such as Mustarde and Furnas suture procedures have grown in popularity. However, these techniques have a tendency for deformity recurrence due to cartilage memory and suture fatigue, as well as the possibility of suture extrusion and pinpricking sensation of the sutures., Methods: In this study, we used a medially based adipo-dermal flap including perichondrium which is elevated from the back of the auricle to cover and support a cartilage-sparing otoplasty, thirty-four patients (14 female and 20 male) were operated using this technique. The medially based perichondrio-adipo-dermal flap is advanced anteriorly and fixed to the helical rim under cover of the distal skin flap. This procedure sought to cover the suture line preventing suture extrusion and support in the repair of the deformity preventing its recurrence., Results: The average operative time was 80min, ranging from 65 to 110min. The patients passed the early postoperative period uneventfully except for 2 patients; one patient (2.9%) developed haematoma, and the other patient developed a small area of necrosis on the new antihelical fold. In late the postoperative period recurrence of the deformity developed in one patient. No patients developed suture extrusion or granuloma., Conclusion: The treatment to repair prominent ears is easy and safe, with benefits such as a natural-looking antihelical fold and minimal tissue stress. The medially or proximally based adipo-dermal flap may help to lower recurrence rates and suture extrusion., (Copyright © 2021 Sociedad Española de Otorrinolaringología y Cirugía de Cabeza y Cuello. Published by Elsevier España, S.L.U. All rights reserved.)

Objective: To investigate the effect and influencing factors of individualized operation for congenital preauricular fistula in children. Methods: The clinical data of 98 cases （109 ears） of congenital preauricular fistula treated in Department of Otolaryngology，Fuzhou Children's Hospital of Fujian Medical University from July 2016 to December 2020 were retrospectively analyzed. According to the characteristics and infection of preauricular fistula，they were divided into common type and variant type，static period of inflammation and period of infection.Individual surgical methods such as classical fistula resection, double fusiform incision and fistula location resection were used respectively.The efficacy，complication and influencing factors of different surgical methods were analyzed. Results: The operation time of classical fistula resection was shorter, and the difference was statistically significant（ t = －2.905 and－3.005 respectively, all P <0.05）. According to the stages and types of fistulas, the selection of individualized surgical methods had achieved good results. There was no significant difference in incision complications and fistula recurrence among different surgical methods （all P >0.05）. Conclusion: Once infection occurs in congenital preauricular fistula, surgical resection should be performed as soon as possible after infection control, or as early as possible after infection maximum control if infection cannot completely subside. Surgical incision design should be individualized, complete resection of fistulas and lesions, minimally invasive and aesthetic., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.)

Background: Auriculocondylar syndrome (ARCND) is a rare genetic disease that affects structures derived from the first and second pharyngeal arches, mainly resulting in micrognathia and auricular malformations. To date, pathogenic variants have been identified in three genes involved in the EDN1-DLX5/6 pathway ( PLCB4 , GNAI3 and EDN1 ) and some cases remain unsolved. Here we studied a large unsolved four-generation family., Methods: We performed linkage analysis, resequencing and Capture-C to investigate the causative variant of this family. To test the pathogenicity of the CNV found, we modelled the disease in patient craniofacial progenitor cells, including induced pluripotent cell (iPSC)-derived neural crest and mesenchymal cells., Results: This study highlights a fourth locus causative of ARCND, represented by a tandem duplication of 430 kb in a candidate region on chromosome 7 defined by linkage analysis. This duplication segregates with the disease in the family (LOD score=2.88) and includes HDAC9 , which is located over 200 kb telomeric to the top candidate gene TWIST1 . Notably, Capture-C analysis revealed multiple cis interactions between the TWIST1 promoter and possible regulatory elements within the duplicated region. Modelling of the disease revealed an increased expression of HDAC9 and its neighbouring gene, TWIST1 , in neural crest cells. We also identified decreased migration of iPSC-derived neural crest cells together with dysregulation of osteogenic differentiation in iPSC-affected mesenchymal stem cells., Conclusion: Our findings support the hypothesis that the 430 kb duplication is causative of the ARCND phenotype in this family and that deregulation of TWIST1 expression during craniofacial development can contribute to the phenotype., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Summary: Objective: Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disorder caused by a mutation in the gene encoding the enzyme α-L-iduronidase. This enzyme is responsible for degradation of dermatan and heparan sulfates. Enzyme deficiency results in their accumulation in lysosomes of virtually all organs, resulting in severe somatic and neurological changes. Clinical findings of otitis media with mixed hearing loss are common. Cellular and molecular mechanisms of ear pathology and hearing loss are not understood. The purpose of this study is to describe the age-related audiologic and histopathologic changes of the ear in the mouse model of MPS I. Methods: Auditory brainstem responses (ABR) were obtained to clicks and tone bursts at 1–32kHz, and pathological changes to middle and inner ears were studied with light and electron microscopy in 53 mice that included: (1) wild type (+/+)—five at 2 months, five at 4–6 months, and five at 13–19 months; (2) heterozygotes (+/−)—four at 2 months, five at 4–6 months, and eight at 13–19 months; and (3) homozygotes (−/−)—five at 2 months, six at 4–6 months, and five at 13–19 months. Histopathology was also done on five newborn −/− mice. Results: In newborns, no lysosomal storage was observed and the ear appeared age appropriately normal. In all other −/− mice, cells with lysosomal storage vacuoles were observed in spiral ligament, spiral prominence, spiral limbus, basilar membrane, epithelial and mesothelial cells of Reissner''s membrane, endothelial cells of vessels, and some ganglion cells; their number increased with aging. Hair cell loss was not observed at 2 or 6 months, but there was total loss of the organ of Corti in year-old mice. Hearing of −/− mice was significantly decreased at all ages compared to +/+ and +/−. Hearing loss progressed from mild to moderate loss at 2 months to profound at 6 months and total deafness by 1 year of age. Conclusions: Progressive age-related changes suggest early therapeutic intervention to prevent sensory cell damage and hearing loss. [Copyright &y& Elsevier]

We report 2 patients who underwent Mohs micrographic surgery (MMS) and operative closure on the ear. Both cases were complicated by necrosis resulting in the formation of auricular defects. These cases highlight the importance of the auricular vasculature and the associated watershed regions during operative planning for MMS as well as the complications that can arise with vascular compromise. This case report also provides a review of the auricular vasculature with special attention to these vulnerable watershed regions.

Purpose: To present a large series ears with tympanic membrane perforations (TMP), to describe their characteristics, and to propose a new classification system based on the pathogenesis of TMP., Methods: This cross-sectional study was conducted at a tertiary university hospital with 1003 ears (792 consecutive patients with TMP in at least 1 ear). Otoendoscopy and audiometry were performed. Perforation measurements and their locations were digitally assessed. TMP with no suggestive signs of previous retraction were classified as Group 1, and those with possible previous retraction were classified as Group 2. Signs of retraction previous to the TMP, symptom length, perforation size and location, status of the contralateral ear, and hearing status were compared., Results: Group 1 comprised 63.5% of the included ears. Compared to Group 2, Group 1 presented a higher rate of central perforations (99% vs. 53%), a shorter duration of symptoms, smaller perforations (mean area: 18.5% vs. 41.4%), a higher rate of perforations in the anterior quadrants, better hearing levels (mean tritonal gap: 23.9 dB vs. 29.2 dB), and a lower rate of abnormal contralateral ears (28% vs. 66%)., Conclusion: The classification of TMP into two groups based on signs of previous retractions is feasible and indicates two different levels of disease severity. While the group without previous signs of retraction comprises ears with more limited disease, membranes with previous retraction seem to show more severe disease and, consequently, a less functional middle ear., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Karl Wittmaack (1876-1972) was professor for Oto-Rhino-Laryngology at the universities of Jena (1908-1925) and Hamburg (1926-1946). He contributed a lot of pioneer work to experimental pathology of the ear. He left a unique collection of serial sections of temporal bones from animals (55,000 slides) and man (102,000 slides). This paper gives some data on Wittmaack's life, his temporal bone collection and the unpublished list of his publications. [ABSTRACT FROM AUTHOR]

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., Competing Interests: Declaration of competing interest The authors have declared no conflicts of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Spiny mice (Acomys cahirinus) are terrestrial mammals that evolved unique scar-free regenerative wound-healing properties. Myofibroblasts (MFs) are the major scar-forming cell type in skin. We found that following traumatic injury to ear pinnae, MFs appeared rapidly in both Acomys and mouse yet persisted only in mouse. The timing of MF loss in Acomys correlated with wound closure, blastema differentiation, and nuclear localization of the Hippo pathway target protein Yap. Experiments in vitro revealed an accelerated PP2A-dependent dephosphorylation activity that maintained nuclear Yap in Acomys dermal fibroblasts (DFs) and was not detected in mouse or human DFs. Treatment of Acomys in vivo with the nuclear Yap-TEAD inhibitor verteporfin prolonged MF persistence and converted tissue regeneration to fibrosis. Forced Yap activity prevented and rescued TGF-β1-induced human MF formation in vitro. These results suggest that Acomys evolved modifications of Yap activity and MF fate important for scar-free regenerative wound healing in vivo., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Auriculocondylar syndrome (ARCND) is an autosomal monogenic disorder characterised by external ear abnormalities and micrognathia due to hypoplasia of the mandibular rami, condyle and coronoid process. Genetically, three subtypes of ARCND (ARCND1, ARCND2 and ARCND3) have been reported. To date, five pathogenic variants of GNAI3 have been reported in ARCND1 patients. Here, we report a novel variant of GNAI3 (NM&#95;006496:c.807C>A:p.(Asn269Lys)) in a Japanese girl with micrognathia using trio-based whole exome sequencing analysis. The GNAI3 gene encodes a heterotrimeric guanine nucleotide-binding protein. The novel variant locates the guanine nucleotide-binding site, and the substitution was predicted to interfere with guanine nucleotide-binding by in silico structural analysis. Three-dimensional computer tomography scan, or cephalogram, displayed severely hypoplastic mandibular rami and fusion to the medial and lateral pterygoid plates, which have been recognised in other ARCND1 patients, but have not been described in ARCND2 and ARCND3, suggesting that these may be distinguishable features in ARCND1., (© 2021. The Author(s).)

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., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Correct positioning of T cells within infected tissues is critical for T cell activation and pathogen control. Upon tissue entry, effector T cells must efficiently locate antigen-presenting cells (APC) for peripheral activation. We reveal that tissue entry and initial peripheral activation of Th1 effector T cells are tightly linked to perivascular positioning of chemokine-expressing APCs. Dermal inflammation induces tissue-wide de novo generation of discrete perivascular CXCL10 + cell clusters, enriched for CD11c + MHC-II + monocyte-derived dendritic cells. These chemokine clusters are "hotspots" for both Th1 extravasation and activation in the inflamed skin. CXCR3-dependent Th1 localization to the cluster micro-environment prolongs T-APC interactions and boosts function. Both the frequency and range of these clusters are enhanced via a T helper 1 (Th1)-intrinsic, interferon-gamma (IFNγ)-dependent positive-feedback loop. Thus, the perivascular CXCL10 + clusters act as initial peripheral activation niches, optimizing controlled activation broadly throughout the tissue by coupling Th1 tissue entry with enhanced opportunities for Th1-APC encounter., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021. Published by Elsevier Inc.)

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.

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-β 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-β 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-β 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., (Copyright © 2021 Sociedade Brasileira de Dermatologia. Published by Elsevier España, S.L.U. All rights reserved.)

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., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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.

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 β-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., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2021 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.)

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., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Microsomal prostaglandin (PG) E synthase-1 (mPGES-1) and prostacyclin (PGI 2 ) synthase (PGIS) are PG terminal synthases that work downstream of cyclooxygenase and synthesize PGE 2 and PGI 2 , 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 PGE 2 levels in DNFB-treated ear tissue was reduced in mPGES-1 KO mice, and that 6-keto PGF 1α (a stable metabolite of PGI 2 ) 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 PGE 2 and PGIS-derived PGI 2 might coordinately promote acquired cutaneous immune responses., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest associated with this manuscript., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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.

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., Competing Interests: The authors declare no competing interest.

Background: Treacher Collins syndrome (TCS) is a rare autosomal dominant or recessive disorder, that involves unique bilateral craniofacial malformations. The phenotypes of TCS are extremely diverse. Interventional surgery can improve hearing loss and facial deformity in TCS patients., Method: We recruited seven TCS families. Variant screening in probands was performed by targeted next-generation sequencing (NGS). The variants identified were confirmed by Sanger sequencing. The pathogenicity of all the mutations was evaluated using the guidelines of the American College of Medical Genetics and Genomics (ACMG) and InterVar software., Results: Three frameshift variants, two nonsense variants, one missense variant, and one splicing variant of TCOF1 were identified in the seven TCS probands. Five variants including c.1393C > T, c.4111 + 5G>C, c.1142delC, c.2285&#95;2286delCT, and c.1719delG had not been previously reported. Furthermore, we report the c.149A > G variant for the first time in a Chinese TCS patient. We provided prenatal diagnosis for family 4. Proband 7 chose interventional surgery., Conclusion: We identified five novel variants in TCOF1 in Chinese patients with TCS, which expands the mutation spectrum of TCOF1 in TCS. Bone conduction hearing rehabilitation can improve hearing for TCS patients and prenatal diagnosis can provide fertility guidance for TCS families., (© 2020 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

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 IC 50 value of 360 µg/ml (DPPH). Soy lipoxygenase-1 (LOX-1) inhibitory activity of oxime was higher (IC 50  = 65.4 µM) than other compounds. Fluorescence studies showed that oxime had higher quenching capacity with a Q max of 76.3% and a binding constant of 0.9 × 10 5 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., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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.

Sphingosine-1-phosphate (S1P) and its receptors have been implicated in functions of Langerhans cells and atopic dermatitis. In this study, we investigated the roles of S1P receptor type 2 (S1P 2 ) in a mouse model of atopic dermatitis, which was induced by topical application of 2,4-dinitrochlorobenzene (DNCB) on ventral skin on D0, followed by repeated DNCB challenge on both ears from D7 to D49. Wild-type mice with atopic dermatitis displayed severe inflammation and mast cell accumulation in ear tissues and elevated IgE levels in serum. Furthermore, the mice showed significantly increased sizes of draining lymph nodes, high levels of inflammatory cytokines (IL-4, IL-13, IL-17, and IFN-γ) in the ears and lymph nodes and high levels of chemokines CCL17 and CCL22 in ears. Administration of JTE-013, a selective antagonist of S1P 2 (3 mg/kg, i.p, from D19 to D49) before DNCB challenge significantly suppressed DNCB-induced atopic responses in ears and lymph nodes. JTE-013 administration also significantly decreased the lymph nodes sizes, the levels of inflammatory cytokines (IL-4, IL-13, IL-17, and IFN-γ) in the ears and lymph nodes, and the levels of chemokines CCL17 and CCL22 in ears. Furthermore, the inflammatory responses of atopic dermatitis were greatly ameliorated in S1pr2 gene-deficient mice. As CCL17 and CCL22 are CCR4 ligands, acting as Th2-attracting chemokines, we investigated CCL17 and CCL22 expression in bone marrow-derived dendritic cells (BMDCs) from wild-type and S1pr2 gene-deficient mice. Addition of IL-4 (10 ng/mL) markedly increased the levels of CCL17 and CCL22, but IL-4-induced CCL17 and CCL22 expression was significantly blunted in BMDCs from S1pr2 gene-deficient mice. Furthermore, pretreatment with JTE-013 (1-30 μM) dose-dependently suppressed this induction in BMDCs from wild-type mice. Our results demonstrate that blockage of S1P 2 ameliorates not only DNCB-induced atopic dermatitis symptoms but also Th2 cell-attracting capacity of dendritic cells, suggesting S1P 2 as a potential therapeutic target for atopic dermatitis.

High dose intake of docosahexaenoic acid showed beneficial effects on atopic dermatitis in patients and was found to increase regulatory T cells in mice, but its molecular target has not been identified. Free fatty acid receptor 4 (FFA4, also known as GPR120) is a receptor sensing polyunsaturated long-chain fatty acids including docosahexaenoic acid. In the present study, we examined whether FFA4 acted as a therapeutic target of docosahexaenoic acid for treating atopic dermatitis. Experimental atopic dermatitis was induced in mice by 2,4-dinitrochlorobenzene (DNCB) sensitization on day 0, followed by repeated DNCB challenges from D7 to D48. The mice were treated with a selective agonist compound A (30 mg· kg -1 · d -1 , ip) from D19 to D48, and sacrificed on D49. We found that DNCB-induced atopic dermatitis-like skin lesions, i.e. hypertrophy and mast cell infiltration in skin tissues, as well as markedly elevated serum IgE levels. Administration of compound A significantly suppressed the atopic responses in ears and lymph nodes, such as hypertrophy and mast cell infiltration in the ears, enlarged sizes of lymph nodes, and elevated serum IgE and levels of cytokines IL-4, IL-13, IL-17, and IFN-γ in ear tissue. The therapeutic effects of compound A were abolished by FFA4 knockout. Similarly, increased CD4 + Foxp3 + regulatory T-cell population in lymph nodes was observed in wide-type mice treated with compound A, but not seen in FFA4-deficient mice. In conclusion, we demonstrate that activation of FFA4 ameliorates atopic dermatitis by increasing CD4 + Foxp3 + regulatory T cells, suggesting FFA4 as a therapeutic target for atopic dermatitis.

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-1β (IL-1β) 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.

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 Boehmeria caudata (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 β-tubulin were performed, suggesting (-)-C (15 R )-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.