Bone Marrow Mesenchymal Stem Cell-Derived Dermcidin-Containing Migrasomes enhance LC3-Associated Phagocytosis of Pulmonary Macrophages and Protect against Post-Stroke Pneumonia.

Pneumonia is one of the leading causes of death in patients with acute ischemic stroke (AIS). Antibiotics fail to improve prognosis of patients with post-stroke pneumonia, albeit suppressing infection, due to adverse impacts on the immune system. The current study reports that bone marrow mesenchymal stem cells (BM-MSC) downregulate bacterial load in the lungs of stroke mice models. RNA-sequencing of the lung from BM-MSC-treated stroke models indicates that BM-MSC modulates pulmonary macrophage activities after cerebral ischemia. Mechanistically, BM-MSC promotes the bacterial phagocytosis of pulmonary macrophages through releasing migrasomes, which are migration-dependent extracellular vesicles. With liquid chromatography-tandem mass spectrometry (LC-MS/MS), the result shows that BM-MSC are found to load the antibacterial peptide dermcidin (DCD) in migrasomes upon bacterial stimulation. Besides the antibiotic effect, DCD enhances LC3-associated phagocytosis (LAP) of macrophages, facilitating their bacterial clearance. The data demonstrate that BM-MSC is a promising therapeutic candidate against post-stroke pneumonia, with dual functions of anti-infection and immunol modulation, which is more than a match for antibiotics treatment.

Application of Topical Sandalore® Increases Epidermal Dermcidin Synthesis in Organ-Cultured Human Skin ex vivo.

INTRODUCTION: Several olfactory receptors (ORs) are expressed in human skin, where they regulate skin pigmentation, barrier function, wound healing, and hair growth. Previously, we found that the selective activation of OR family 2 subfamily AT member 4 (OR2AT4) by the synthetic, sandalwood-like odorant Sandalore® differentially stimulates the expression of antimicrobial peptides (AMPs) in human scalp hair follicle epithelium ex vivo. As OR2AT4 is also expressed by epidermal keratinocytes, we hypothesized that it may modulate intraepidermal AMP synthesis, thereby contributing to skin microbiome management. METHODS: We investigated this hypothesis in organ-cultured human skin in the presence of Sandalore® and antibiotics and evaluated epidermal production of two AMPs, LL37 (cathelicidin) and dermcidin (DCD), as well as OR2AT4, by quantitative immunohistomorphometry. Moreover, we quantified DCD secretion into the culture medium by ELISA and studied the effect of culture medium on selected bacterial and fungal strains. RESULTS: Topical application of Sandalore®to organ-cultured human skin increased OR2AT4 protein expression, the number of DCD-positive intraepidermal cells, and DCD secretion into culture media, without significantly affecting epidermal LL37 expression. In line with the significantly increased secretion of DCD into the culture medium, we demonstrated, in a spectrophotometric assay, that application of conditioned media from Sandalore®-treated skin promotes Staphylococcus epidermidis, Malassezia restricta, and, minimally, Cutibacterium acnes and inhibits Staphylococcus aureus growth. CONCLUSION: In addition to demonstrating for the first time that DCD can be expressed by epidermal keratinocytes, our pilot study suggests that topical treatment of human skin with a cosmetic odorant (Sandalore®) has the potential to alter the composition of the human skin microbiome through the selective upregulation of DCD. If confirmed, Sandalore® could become an attractive adjuvant, nondrug treatment for dermatoses characterized by dysbiosis due to overgrowth of S. aureus and Malassezia, such as atopic dermatitis and seborrheic dermatitis.

Enhancement of hypericin nanoparticle-mediated sonoinduced disruption of biofilm and persister cells of Streptococcus mutans by dermcidin-derived peptide DCD-1L.

BACKGROUND: Streptococcus mutans is considered a major significant contributor to dental caries and its effective removal is difficult due to the formation of biofilm. Therefore, the development of adjuvant therapeutic strategies with anti-biofilm properties is a promising approach. In the present study, we examined the effect of dermcidin-derived peptide DCD-1 L on the antibacterial activity of hypericin nanoparticle (HypNP)-mediated antimicrobial sonodynamic therapy (aSDT) against persister cells growing- and biofilm cultures of S. mutans. MATERIALS AND METHODS: Following synthesis and confirmation of HypNP, the fractional inhibitory concentration (FIC) index of HypNP and DCD-1 L was determined by checkerboard assay. Cellular uptake of HypNP-DCD-1 L and generation of endogenous reactive oxygen species (ROS) were assessed and followed by the determination of antimicrobial sonoactivity of HypNP-DCD-1 L against persister cells growing- and biofilm cultures of S. mutans. The water-insoluble extracellular polysaccharide (EPS) and expression of the gtfD, comDE, and smuT genes were then evaluated in persister cells growing- and biofilm cultures of S. mutans. RESULTS: There was a synergistic activity in the combination of HypNP and DCD-1 L against S. mutans with an FIC index value of 0.37. The HypNP-DCD-1L-mediated aSDT also displayed the highest cellular uptake and endogenous ROS generation by bacterial cells. When biofilm and persister cells of S. mutans were treated with HypNP-DCD-1 L and subsequently exposed to ultrasound waves, 5.1 log and 3.8 log reductions, respectively, in bacterial numbers were observed (P<0.05). According to the data, EPS in both persister cells growing- and biofilm cultures of S. mutans were significantly decreased after exposure to the HypNP-DCD-1L-mediated aSDT (P<0.05). In addition, the quantitative real-time PCR data illustrated the high level of similarities in very low-expression profiles of the gtfD before and after all treated groups for persister cells. While, following HypNP-DCD-1L-mediated aSDT treatment, the expression levels of gtfD, comDE, and smuT were significantly lower in treated persister cells growing- and biofilm cultures of S. mutans in comparison with control groups (P<0.05). CONCLUSIONS: Combined, the results of this study indicate that ultrasound waves-activated HypNP-DCD-1 L can sonoinactivate S. mutans biofilms and persister cells, as well as reduce effectively pathogenicity potency of S. mutans. Hence, HypNP-DCD-1L-mediated aSDT may be proposed as a promising adjunctive therapeutic approach for dental caries.

A rare loss-of-function genetic mutation suggest a role of dermcidin deficiency in hidradenitis suppurativa pathogenesis.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with a multifactorial aetiology that involves a strict interplay between genetic factors, immune dysregulation and lifestyle. Familial forms represent around 40% of total HS cases and show an autosomal dominant mode of inheritance of the disease. In this study, we conducted a whole-exome sequence analysis on an Italian family of 4 members encompassing a vertical transmission of HS. Focusing on rare damaging variants, we identified a rare insertion of one nucleotide (c.225dupA:p.A76Sfs*21) in the DCD gene encoding for the antimicrobial peptide dermcidin (DCD) that was shared by the proband, his affected father and his 11-years old daughter. Since several transcriptome studies have shown a significantly decreased expression of DCD in HS skin, we hypothesised that the identified frameshift insertion was a loss-of-function mutation that might be associated with HS susceptibility in this family. We thus confirmed by mass spectrometry that DCD levels were diminished in the affected members and showed that the antimicrobial activity of a synthetic DCD peptide resulting from the frameshift mutation was impaired. In order to define the consequences related to a decrease in DCD activity, skin microbiome analyses of different body sites were performed by comparing DCD mutant and wild type samples, and results highlighted significant differences between the groins of mutated and wild type groups. Starting from genetic analysis conducted on an HS family, our findings showed, confirming previous transcriptome results, the potential role of the antimicrobial DCD peptide as an actor playing a crucial part in the etio-pathogenesis of HS and in the maintenance of the skin's physiological microbiome composition; so, we can hypothesise that DCD could be used as a novel target for personalised therapeutic approach.

Dermcidin-derived polypeptides: DCD(86-103) induced inflammatory reaction in the skin by activation of mast cells via ST2.

BACKGROUND: Psoriasis is a chronic inflammatory disease. Mast cells are significantly increased and activated in the lesions of patients with psoriasis, contributing to psoriatic inflammation. Dermcidin (DCD) is a natural antibacterial peptide secreted by sweat glands and is usually transported to the epidermal surface by sweat. Whether DCD is involved in mast cell activation remains unclear and the mechanisms by which DCD is involved in skin inflammatory reactions require further investigation. METHODS: We investigated whether dermcidin-derived polypeptides DCD(86-103) activate mast cells and induce skin inflammatory reactions that contribute to psoriasis. Wild-type mice were treated with DCD(86-103) to observe the inflammatory reactions in the skin and cytokine release in vivo. The release of inflammatory mediators by mouse primary mast cells and LAD2 cells was measured in vitro. Molecular docking analysis, molecular dynamics simulation, and siRNA transfection were used to identify DCD(86-103). RESULTS: DCD(86-103) caused a skin inflammatory reaction in wild-type mice via cytokine release. Moreover, DCD(86-103) directly activated mast cells and induced cytokine release in vitro. ST2 may be a key receptor that mediates the activation effect of DCD(86-103) on mast cells leading to cytokine release. CONCLUSION: DCD(86-103) may have induced an inflammatory reaction and participated in the occurrence and development of psoriasis.

Aptamer decorated emodin nanoparticles-assisted delivery of dermcidin-derived peptide DCD-1L: Photoactive bio-theragnostic agent for Enterococcus faecalis biofilm destruction.

BACKGROUND: Despite the high success rate of root canal treatment, failures are observed in a broad range of cases. Therefore, the need for novel approaches with the development of new generations of antimicrobial agents and intracellular drug delivery systems as adjunctive therapy is undeniable. In this study, we investigated the antimicrobial effects of antimicrobial photodynamic therapy (aPDT) using dermcidin­derived peptide DCD­1L loaded onto aptamer-functionalized emodin nanoparticles (Apt@EmoNp-DCD-1L) against Enterococcus faecalis as one of the most common bacteria involved in recurrent root canal treatment failures. MATERIALS AND METHODS: Following preparation of EmoNp-DCD-1L, the binding of selected labeled Apt to EmoNp-DCD-1L was performed, followed by the specificity of Apt@EmoNp-DCD-1L to E. faecalis was determined. The antimicrobial potential of aPDT was then assessed after the determination of the minimum inhibitory concentration (MIC) of Apt@EmoNp-DCD-1L. The molecular docking analysis was conducted to evaluate the potential binding modes of EmoNp to the proteins involved in E. faecalis pathogenesis. Eventually, the anti-virulence capacity of Apt@EmoNp-DCD-1L-mediated aPDT was investigated via quantitative real-time PCR (qRT-PCR) assay following measurement of intracellular reactive oxygen species (ROS) generation. RESULTS: The binding specificity of Apt@EmoNp-DCD-1L to E. faecalis was confirmed by flow cytometry. The results showed that the cell viability of E. faecalis exposed to aPDT groups employing the sub-MIC doses of Apt@EmoNp-DCD-1L (7.8 and 15.6 µM) was significantly reduced compared to the control group (P < 0.05). Also, Apt@EmoNp-DCD-1L in combination with a blue laser light was capable of enhancing the anti-biofilm activity of aPDT against E. faecalis biofilm. Data obtained from the qRT-PCR analysis showed significant downregulation in the expression level of genes involved in bacterial biofilm formation after exposure to aPDT (P < 0.05). CONCLUSIONS: This in vitro study highlights that aPDT with the minimum concentration of Apt@EmoNp-DCD-1L can be considered as a targeted bio-theragnostic agent for the detection and elimination of E. faecalis in the dispersed and biofilm states.

The relation of dermcidin with insulin resistance and inflammation in women with polycystic ovary syndrome.

OBJECTIVE: Polycystic ovary syndrome is the most common endocrinopathy among women of reproductive age. Polycystic ovary syndrome is a metabolic disorder associated with insulin resistance and subclinical inflammation. Dermcidin, an antimicrobial peptide, involves in insulin resistance and inflammatory processes. Dermcidin suppresses the secretion of insulin production from the liver/pancreas and also increases insulin resistance. We aimed to discover whether dermcidin levels were altered in polycystic ovary syndrome women compared to controls and determine the link of dermcidin with hormonal-metabolic parameters in polycystic ovary syndrome women. METHODS: The current research was designed as a case-control study and Rotterdam 2003 criteria were used for diagnosing polycystic ovary syndrome. A total of 75 subjects with polycystic ovary syndrome and 75 age- and body mass index-matched subjects as controls were enrolled in the study. The insulin resistance state was determined using a homeostatic model assessment of insulin resistance and quantitative insulin sensitivity check index. High-sensitivity C-reactive protein levels were assessed to define inflammation. RESULTS: Circulating dermcidin levels were measured by enzyme-linked immunosorbent assay. Dermcidin levels were significantly increased in polycystic ovary syndrome subjects compared to controls (172.53±42.41 ng/mL vs. 108.44±31.69 ng/mL, p<0.001). Homeostatic model assessment of insulin resistance and high-sensitivity C-reactive protein levels were markedly increased, whereas quantitative insulin sensitivity check index levels were notably decreased in women with polycystic ovary syndrome compared to controls. Linear regression analysis revealed that dermcidin exhibited an independent link with homeostatic model assessment of insulin resistance and high-sensitivity C-reactive protein, whereas dermcidin displayed an inversely independent link with quantitative insulin sensitivity check index. CONCLUSION: Increased dermcidin levels were associated with insulin resistance and inflammation in polycystic ovary syndrome women, suggesting that dermcidin may play a role in the pathophysiology of polycystic ovary syndrome.

Preclinical Development of Seriniquinones as Selective Dermcidin Modulators for the Treatment of Melanoma.

The bioactive natural product seriniquinone was discovered as a potential melanoma drug, which was produced by the as-yet-undescribed marine bacterium of the rare genus Serinicoccus. As part of a long-term research program aimed at the discovery of new agents for the treatment of cancer, seriniquinone revealed remarkable in vitro activity against a diversity of cancer cell lines in the US National Cancer Institute 60-cell line screening. Target deconvolution studies defined the seriniquinones as a new class of melanoma-selective agents that act in part by targeting dermcidin (DCD). The targeted DCD peptide has been recently examined and defined as a "pro-survival peptide" in cancer cells. While DCD was first isolated from human skin and thought to be only an antimicrobial peptide, currently DCD has been also identified as a peptide associated with the survival of cancer cells, through what is believed to be a disulfide-based conjugation with proteins that would normally induce apoptosis. However, the significantly enhanced potency of seriniquinone was of particular interest against the melanoma cell lines assessed in the NCI 60-cell line panel. This observed selectivity provided a driving force that resulted in a multidimensional program for the discovery of a usable drug with a new anticancer target and, therefore, a novel mode of action. Here, we provided an overview of the discovery and development efforts to date.

Human Dermcidin Protects Mice Against Hepatic Ischemia-Reperfusion-Induced Local and Remote Inflammatory Injury.

Background: Hepatic ischemia and reperfusion (I/R) injury is commonly associated with surgical liver resection or transplantation, and represents a major cause of liver damage and graft failure. Currently, there are no effective therapies to prevent hepatic I/R injury other than ischemic preconditioning and some preventative strategies. Previously, we have revealed the anti-inflammatory activity of a sweat gland-derived peptide, dermcidin (DCD), in macrophage/monocyte cultures. Here, we sought to explore its therapeutic potential and protective mechanisms in a murine model of hepatic I/R. Methods: Male C57BL/6 mice were subjected to hepatic ischemia by clamping the hepatic artery and portal vein for 60 min, which was then removed to initiate reperfusion. At the beginning of reperfusion, 0.2 ml saline control or solution of DCD (0.5 mg/kg BW) or DCD-C34S analog (0.25 or 0.5 mg/kg BW) containing a Cys (C)→Ser (S) substitution at residue 34 was injected via the internal jugular vein. For survival experiments, mice were subjected to additional resection to remove non-ischemic liver lobes, and animal survival was monitored for 10 days. For mechanistic studies, blood and tissue samples were collected at 24 h after the onset of reperfusion, and subjected to measurements of various markers of inflammation and tissue injury by real-time RT-PCR, immunoassays, and histological analysis. Results: Recombinant DCD or DCD-C34S analog conferred a significant protection against lethal hepatic I/R when given intravenously at the beginning of reperfusion. This protection was associated with a significant reduction in hepatic injury, neutrophilic CXC chemokine (Mip-2) expression, neutrophil infiltration, and associated inflammation. Furthermore, the administration of DCD also resulted in a significant attenuation of remote lung inflammatory injury. Mechanistically, DCD interacted with epidermal growth factor receptor (EGFR), a key regulator of liver inflammation, and significantly inhibited hepatic I/R-induced phosphorylation of EGFR as well as a downstream signaling molecule, protein kinase B (AKT). The suppression of EGFR expression by transducing Egfr-specific shRNA plasmid into macrophages abrogated the DCD-mediated inhibition of nitric oxide (NO) production induced by a damage-associated molecular pattern (DAMP), cold-inducible RNA-binding protein, CIRP. Conclusions: The present study suggests that human DCD and its analog may be developed as novel therapeutics to attenuate hepatic I/R-induced inflammatory injury possibly by impairing EGFR signaling.

Chemerin and Dermcidin in Human Milk and Their Alteration in Gestational Diabetes.

BACKGROUND: Chemerin and dermcidin, which have antimicrobial properties, are molecules that are also related to insulin resistance and inflammation. RESEARCH AIMS: The aims were to determine the amounts of chemerin and dermcidin in the milk and blood of mothers with gestational diabetes, and to compare the amounts of chemerin and dermcidin in the milk and blood of mothers with and without diabetes. METHODS: This was a two-group nonrandomized longitudinal study with a convenience sampling of mothers without gestational diabetes (n = 27) and mothers with gestational diabetes (n = 26). Human milk and blood samples were obtained from these mothers during colostrum, transitional, and mature milk periods. The amount of chemerin and dermcidin in these samples was measured by enzyme-linked immunosorbent assay. RESULTS: The presence of chemerin and dermcidin was first detected in human milk. The amounts of chemerin and dermcidin in the blood of all the mothers were greater in the colostrum period and lowest in the mature period. The amount of chemerin and dermcidin in the milk of all the mothers was greater than that in the blood. The amounts of chemerin and dermcidin were significantly increased in both blood and human milk within the gestational age samples. CONCLUSIONS: Chemerin and dermcidin may contribute to the protection of infants from infections during infancy. Increased amounts of these molecules found within the gestational diabetes group may also prevent adverse maternal and fetal outcomes.

[A novel protein peptide associated with ischemic heart disease: dermcidin].

OBJECTIVE: Dermcidin (DCD) was found in isolated human skin sweat glands with antimicrobial effect, and was defined as a kind of new small molecule antimicrobial peptide. It was a part of human sweat glands in the skin as the immune system's innate defense. With the studies of DCD, its extensive biological functions are gradually discovered. Since 2010, a number of studies have shown that DCD may be a new risk factor for atherosclerosis. And the role of DCD in ischemic heart disease has drawn increasing attention in particular its relationship with insulin secretion and glycemic control, nitric oxide (NO) synthesis and hypertension, platelet aggregation and acute myocardial infarction (AMI). In those experiments, it was also confirmed that aspirin had antagonistic and reverse effects on various biological functions of DCD. Further research on the role of DCD in cardiovascular and cerebrovascular diseases may lead to the prevention, early warning, prognosis evaluation and treatment breakthrough of cardiovascular and cerebrovascular events.

The in Vitro Immune-Modulating Properties of a Sweat Gland-Derived Antimicrobial Peptide Dermcidin.

The epidermal barriers of the skin serve as the first layer of defense by limiting the access of many pathogens to the blood circulation. In addition, human skin also contains sweat glands that can secrete a wide array of antimicrobial peptides to restrain the growth of various microbes. In the case of microbial infection, macrophages and monocytes constitute the first line of defense by producing a wide array of proinflammatory cytokines and chemokines. This process is triggered either by pathogen-associated molecular pattern molecules (such as bacterial endotoxin) or damage-associated molecular pattern molecules (such as HMGB1). In light of our findings that a sweat gland-derived antimicrobial peptide, dermcidin, affected both pathogen-associated molecular pattern and damage-associated molecular pattern-induced cytokines/chemokines by macrophages/monocytes, we propose that dermcidin may play an important role in the regulation of the innate immune responses to infection and injury. Future investigations are warranted to further test this understudied hypothesis in both preclinical and clinical settings.

Dermcidin: a skeletal muscle myokine modulating cardiomyocyte survival and infarct size after coronary artery ligation.

AIMS: Coronary artery disease is the leading cause of death in western countries, and its association with lower extremity peripheral artery disease (LE-PAD) represents an independent predictor of worse outcome. However, the molecular mechanisms underlying these effects are currently unknown. METHODS AND RESULTS: To investigate these processes, we used in vitro approaches and several mouse models: (i) unilateral limb ischaemia by left common femoral artery ligation [peripheral ischaemia (PI), n = 38]; (ii) myocardial infarction by permanent ligation of the left descending coronary artery (MI, n = 40); (iii) MI after 5 weeks of limb ischaemia (PI + MI, n = 44); (iv) sham operation (SHAM, n = 20). Compared with MI, PI + MI hearts were characterized by a significant increase in cardiomyocyte apoptosis, larger infarct areas, and decreased cardiac function. By using a proteomic approach, we identified a ≅ 8 kDa circulating peptide, Dermcidin (DCD), secreted by ischaemic skeletal muscles, enhancing cardiomyocytes apoptosis under hypoxic conditions and infarct size after permanent coronary artery ligation. siRNA interference experiments to reduce DCD circulating levels significantly reduced infarct size and ameliorated cardiac function after MI. CONCLUSION: Our data demonstrate that chronic limb ischaemia activates detrimental pathways in the ischaemic heart through humoral mechanisms of remote organ crosstalk. Thus, DCD may represent a novel important myokine modulating cardiomyocyte survival and function.

Dermcidin exerts its oncogenic effects in breast cancer via modulation of ERBB signaling.

BACKGROUND: We previously identified dermicidin (DCD), which encodes a growth and survival factor, as a gene amplified and overexpressed in a subset of breast tumors. Patients with DCD-positive breast cancer have worse prognostic features. We therefore searched for specific molecular signatures in DCD-positive breast carcinomas from patients and representative cell lines. METHODS: DCD expression was evaluated by qRT-PCR, immunohistochemical and immunoblot assays in normal and neoplastic tissues and cell lines. To investigate the role of DCD in breast tumorigenesis, we analyzed the consequences of its downregulation in human breast cancer cell lines using three specific shRNA lentiviral vectors. Genes up- and down-regulated by DCD were identified using Affymetrix microarray and analyzed by MetaCore Platform. RESULTS: We identified DCD splice variant (DCD-SV) that is co-expressed with DCD in primary invasive breast carcinomas and in other tissue types and cell lines. DCD expression in breast tumors from patients with clinical follow up data correlated with high histological grade, HER2 amplification and luminal subtype. We found that loss of DCD expression led to reduced cell proliferation, resistance to apoptosis, and suppressed tumorigenesis in immunodeficient mice. Network analysis of gene expression data revealed perturbed ERBB signaling following DCD shRNA expression including changes in the expression of ERBB receptors and their ligands. CONCLUSIONS: These findings imply that DCD promotes breast tumorigenesis via modulation of ERBB signaling pathways. As ERBB signaling is also important for neural survival, HER2+ breast tumors may highjack DCD's neural survival-promoting functions to promote tumorigenesis.

Seriniquinone, a selective anticancer agent, induces cell death by autophagocytosis, targeting the cancer-protective protein dermcidin.

Natural products continue to provide vital treatment options for cancer. Although their translation into chemotherapeutics is complex, collaborative programs continue to deliver productive pipelines for cancer chemotherapy. A new natural product, seriniquinone, isolated from a marine bacterium of the genus Serinicoccus, demonstrated potent activity over a select set of tumor cell lines with particular selectivity toward melanoma cell lines. Upon entering the cell, its journey began by localization into the endoplasmic reticulum. Within 3 h, cells treated with seriniquinone underwent cell death marked by activation of autophagocytosis and gradually terminated through a caspase-9 apoptotic pathway. Using an immunoaffinity approach followed by multipoint validation, we identified the target of seriniquinone as the small protein, dermcidin. Combined, these findings revealed a small molecule motif in parallel with its therapeutic target, whose potential in cancer therapy may be significant. This discovery defines a new pharmacophore that displayed selective activity toward a distinct set of cell lines, predominantly melanoma, within the NCI 60 panel. This selectivity, along with the ease in medicinal chemical modification, provides a key opportunity to design and evaluate new treatments for those cancers that rely on dermcidin activity. Further, the use of dermcidin as a patient preselection biomarker may accelerate the development of more effective personalized treatments.

The diagnosis of high altitude illness by the determination of plasma dermcidin isoform 2 levels by enzyme linked immunosorbent assay.

BACKGROUND: High altitude illness (HAI) is a cluster of syndromes which develops due to the injury of the central nervous system produced by the reduction of the partial pressure of O2 in the atmosphere which disappears on decent. The HAI also results in a prothrombotic condition leading to acute coronary syndrome (ACS), which cannot be controlled on descent to the ground level. There is no diagnosis in HAI to forewarn of the impending ACS. A protein identified to be dermcidin isoform 2 (dermcidin), produced in the system due to environmental stresses, has been reported to be a potent diabetogenic agent. Investigation was carried out to determine the systemic stimulation of dermcidin synthesis at different levels of altitudes in normal adult male volunteers to assess the feasibility of developing a diagnosis for ACS in HAI due to dermcidin synthesis. METHODS: Normal, nondiabetic, normotensive male volunteers (25 - 35 years old, n = 16) participated in the study. The plasma dermcidin level was determined by enzyme linked immunosorbent assay (ELISA) and by in vitro translation of dermcidin mRNA. The plasma insulin level was determined by ELISA and blood glucose level was determined in a glucometer (Behringer). RESULTS: The plasma dermcidin level in the volunteers at ground level was 10 +/- 2.10 nM and increased to 80 +/- 4.62 nM at 15000 feet altitude. For each 1000 feet increase of altitude, the dermcidin level increased by 5.83 +/- 0.21 nM with a Coefficient of Correlation "r" = +0.9405. The increase of plasma dermcidin level was found to be inversely related to the decrease of plasma insulin level from 23 microunit/mL to 5 microunit/mL from sea level to 15000 feet height ("r" = -0.9951) with concomitant increase of blood sugar level from 80 +/- 3.6 mg/dL to 135 +/- 2.01 mg/dL. CONCLUSIONS: These results suggest the feasibility of a diagnosis of a prediabetic condition by determining the plasma dermcidin level in HAI by simple ELISA which may also be useful to forewarn of the possibility of developing an impending prothrombotic condition in HAI.

Investigations in associated protozoa-bacterial infections of cyprinids from a fish farm situated on the Jijia river in N-E of Romania / Investigações sobre infecções protozoárias-bacterianas associadas a ciprinídeos da exploração piscícola no rio Jijia, situado no NE da Romênia

In autumn 2011 in cyprinid farms located in Iasi on the Jijia river, several infections with bacterial strains and macroscopical external cysts on the skin were diagnosedwhich developed as a result of the stress induced by biotic and abiotic factors. On the examination of the cyst contents the presence of numerous spores was observed, mostly of the Dermocystidium sp genusThe samples were taken from the common carp (Cyprinus carpio) and crucian carp (Carassius auratus gibelio) species from the fish farm as well as from the Jijia River. 35 fish were examined, all of them showing cysts, fragmentation of their dorsal fin and congestion of the gills. Histological examination of the skin showed a field of multiple dermal cysts with round light eosinophilic formations (14-16µm) containing a central refractable body similar to that reported for Dermocystidium sp. Gills samples were taken from the affected areas for the SEM examination with the purpose of evaluating not only aspects of normal morphology, but also aspects of some modifications of the affected areas as well as the presence of the etiologically incriminated bacteria Pseudomonas fluorescens. The isolates were identified through phenotypic methods. All the strains that showed mobility and oxidase-positivity were tested using API 20 NE strip. Consequently, they were taxonomically grouped into the species Pseudomonas fluorescens. The scanning electron microscope (SEM) was used for the first time in the characterization of the bacterial lesions produced by Pseudomonas strains on Cyprinus carpio and Carassius auratus gibelio gills. The diagnosis of septicemia with conditional pathogen species of Pseudomonas fluorescens was correlated with the results of the physico-chemical investigations of water and the data concerning the breeding conditions of the investigated livestock...

No outono de 2011, em fazendas de ciprinídeos localizadas em Iasi, no rio Jijia, diversas infecções bacterianas e cistos externos macroscópicos na pele se desenvolveram como resultado do estresse induzido por fatores bióticos e abióticos. No exame do conteúdo dos cistos, a presença de diversos esporos foi observada, a maioria do gênero Dermocystidium sp. As amostras foram colhidas das seguintes espécies: carpa comum (Cyprinus carpio) e carpa cruciana (Carassius auratus gibelio) de fazenda piscícola, além do rio Jijia. Assim sendo, 35 peixes foram examinados, todos demonstrando cistos, fragmentação da barbatana dorsal e congestão das guelras. O exame histológico da pele mostrou um campo de múltiplos cistos dérmicos com formações circulares claras eosinofílicas (14-16µm) contendo corpo central refratado similar ao relatado para Dermocystidium sp. Amostras de guelras foram retiradas das áreas afetadas para exame MEV, com o propósito de se avaliar não apenas os aspectos da morfologia normal, mas também os aspectos de algumas modificações das áreas afetadas, além da presença da bactéria etiologicamente incriminada: Pseudomonas fluorescens. Os isolados foram identificados por meio de métodos fenotípicos. Todas as amostras que mostraram mobilidade e positividade-oxidase foram testadas usando-se fita API 20 NE. Consequentemente, estas foram taxonomicamente agrupadas na espécie Pseudomonas fluorescens. O microscópio eletrônico de varredura (MEV) foi usado pela primeira vez na caracterização de lesões bacterianas produzidas por Pseudomonas nas guelras de Cyprinus carpio e Carassius auratus gibelio. O diagnóstico de septicemia com espécies condicionais de patogênico de Pseudomonas fluorescens foi correlacionado com os resultados das investigações físico-químicas da água e de dados sobre as condições de reprodução dos animais investigados...

Dermcidin expression is associated with disease progression and survival among breast cancer patients.

Improved diagnostic screening has led to earlier detection of many tumors, but screening may still miss many aggressive tumor types. Proteomic and genomic profiling studies of breast cancer samples have identified tumor markers that may help improve screening for more aggressive, rapidly growing breast cancers. To identify potential blood-based biomarkers for the early detection of breast cancer, we assayed serum samples via matrix-assisted laser desorption ionization-time of flight mass spectrometry from a rat model of mammary carcinogenesis. We found elevated levels of a fragment of the protein dermcidin (DCD) to be associated with early progression of N-methylnitrosourea-induced breast cancer, demonstrating significance at weeks 4 (p = 0.045) and 5 (p = 0.004), a time period during which mammary pathologies rapidly progress from ductal hyperplasia to adenocarcinoma. The highest serum concentrations were observed in rats bearing palpable mammary carcinomas. Increased DCD was also detected with immunoblotting methods in 102 serum samples taken from women just prior to breast cancer diagnosis. To validate these findings in a larger population, we applied a 32-gene in vitro DCD response signature to a dataset of 295 breast tumors and assessed correlation with intrinsic breast cancer subtypes and overall survival. The DCD-derived gene signature was significantly associated with subtype (p < 0.001) and poorer overall survival [HR (95 % CI) = 1.60 (1.01-2.51), p = 0.044]. In conclusion, these results present novel evidence that DCD levels may increase in early carcinogenesis, particularly among more aggressive forms of breast cancer.

HSP70 natively and specifically associates with an N-terminal dermcidin-derived peptide that contains an HLA-A*03 antigenic epitope.

Tumor cells very often have elevated expression of HSP70, the anti-apoptotic properties of which contribute to overall tumor survival. Independent of its anti-apoptotic properties, HSP70 was also suggested to be involved in the antigen presentation process by chaperoning cytosolic peptides, thus protecting them from rapid degradation and securing the peptide pool for further processing. In this study, we identified a 33-amino acid N-terminal dermcidin (DCD)-derived peptide from the repertoire of in vivo HSP70-associated peptides isolated from a leukemic cell line, K562. The DCD peptide has been previously shown to be involved in tumorigenesis, to increase tumor survival rate, to improve tumor stress resistance, and to aid growth. We show that HSP70 is a specific binding partner for the DCD prosurvival peptide and define an ATP-dependent DCD-binding site (GNPCH). We also identify an HLA-A*03 antigenic epitope within the DCD peptide, which follows and partially overlaps the HSP70-binding site (CHEASAAQK). This study describes the interaction between HSP70 and the DCD-derived prosurvival peptide, an interaction that may direct the peptide toward antigen presentation and independently contribute to the prosurvival mechanism mediated by DCD.