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12(S)-hydroxyheptadecatrienoic acid (12-HHT) is a bioactive fatty acid synthesized from arachidonic acid via the cyclooxygenase pathway and serves as an endogenous ligand for the low-affinity leukotriene B4 receptor 2 (BLT2). Although the 12-HHT/BLT2 axis contributes to the maintenance of epithelial homeostasis, 12-HHT metabolism under physiological conditions is unclear. In this study, 12-keto-heptadecatrienoic acid (12-KHT) and 10,11-dihydro-12-KHT (10,11dh-12-KHT) were detected as 12-HHT metabolites in the human megakaryocytic cell line MEG01s. We found that 12-KHT and 10,11dh-12-KHT are produced from 12-HHT by 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and prostaglandin reductase 1 (PTGR1), key enzymes in the degradation of prostaglandins, respectively. The 15-PGDH inhibitor SW033291 completely suppressed the production of 12-KHT and 10,11dh-12-KHT in MEG01s cells, resulting in a 9-fold accumulation of 12-HHT. 12-KHT and 10,11dh-12-KHT were produced in mouse skin wounds, and the levels were significantly suppressed by SW033291. Surprisingly, the agonistic activities of 12-KHT and 10,11dh-12-KHT on BLT2 were comparable to that of 12-HHT. Taken together, 12-HHT is metabolized into 12-KHT by 15-PGDH, and then 10,11dh-12-KHT by PTGR1 without losing the agonistic activity.

The efficacy of n-3 polyunsaturated fatty acids (PUFAs) in improving outcomes in a renal ischemia-reperfusion injury (IRI) model has previously been reported. However, the underlying mechanisms remain poorly understood and few reports demonstrate how dietary n-3 PUFAs influence the composition of membrane phospholipids in the kidney. Additionally, it has not been elucidated whether perilla oil (PO), which is mainly composed of the n-3 alpha-linolenic acid, mitigates renal IRI. In this study, we investigated the effect of dietary n-3 PUFAs (PO), compared with an n-6 PUFA-rich soybean oil (SO) diet, on IRI-induced renal insufficiency in a rat model. Levels of membrane phospholipids containing n-3 PUFAs were higher in the kidney of PO-rich diet-fed rats than the SO-rich diet-fed rats. Levels of blood urea nitrogen and serum creatinine were significantly higher in the ischemia-reperfusion group than the sham group under both dietary conditions. However, no significant differences were observed in blood urea nitrogen, serum creatinine, or histological damage between PO-rich diet-fed rats and SO-rich diet-fed rats. In the kidney of PO-rich diet-fed rats, levels of arachidonic acid and arachidonic acid-derived pro-inflammatory lipid mediators were lower than SO-rich diet-fed rats. Eicosapentaenoic acid and eicosapentaenoic acid-derived lipid mediators were significantly higher in the kidney of PO-rich than SO-rich diet-fed rats. These results suggest that dietary n-3 PUFAs alter the fatty acid composition of membrane phospholipids and lipid mediators in the kidney; however, this does not attenuate renal insufficiency or histological damage in a renal IRI model.

In a recent publication, Wisenden et al. (2020) examined responses of territorial male Red-winged Blackbirds (Agelaius phoeniceus) to models constructed with ultraviolet (UV)-reflective red epaulets for the purpose of determining if the addition of UV reflectance to epaulets (“UV+”) changed the effectiveness of signals to receivers relative to “control” epaulets under field conditions. The authors hypothesized that “UV+epaulet coloration represents a visual signal with increased efficacy in territorial interactions.” They presented behavioral data but no visual modeling data. Our aims in this commentary are to suggest alternative terms to those used by the authors, to express concern about the use of sunscreen to manipulate the UV condition of surfaces, and to make a plea for additional data collection in future studies of avian visual ecology. The terms UV+ and UV– should be reserved for studies that create environments free from UV radiation for comparison with environments that include UV radiation. We believe that commercial sunscreens are not an appropriate choice for altering the UV conditions of surfaces presented during behavioral trials because they potentially introduce confounding influences from other sensory inputs or irritation of peripheral nerves. Wisenden et al. altered the UV absorbance of their sunscreen-treated models but did not present absorbance spectra and may not have collected those data. We acknowledge that the lack of absorbance spectra is not unusual. We implore any such future studies to collect absorbance spectra of treated and control surfaces so that those data may be used to improve visual models for UV-sensitive animals.

Primary hepatic tumors mainly include hepatocellular carcinoma (HCC), which is one of the most frequent causes of cancer‐related deaths worldwide. Thus far, HCC prognosis has remained extremely poor given the lack of effective treatments. Numerous studies have described the roles played by microRNAs (miRNAs) in cancer progression and the potential of these small noncoding RNAs for diagnostic or therapeutic applications. The current consensus supports the idea that direct repression of a wide range of oncogenes by a single key miRNA could critically affect the malignant properties of cancer cells in a synergistic manner. In this study, we aimed to investigate the oncogenes controlled by miR‐493‐5p, a major tumor suppressor miRNA that inactivates miR‐483‐3p oncomir in hepatic cancer cells. Using global gene expression analysis, we highlighted a set of candidate genes potentially regulated by miR‐493‐5p. In particular, the canonical MYCN protooncogene (MYCN) appeared to be an attractive target of miR‐493‐5p given its significant inhibition through 3′‐UTR targeting in miR‐493‐5p‐rescued HCC cells. We showed that MYCN was overexpressed in liver cancer cell lines and clinical samples from HCC patients. Notably, MYCN expression levels were inversely correlated with miR‐493‐5p in tumor tissues. We confirmed that MYCN knockdown mimicked the anticancer effect of miR‐493‐5p by inhibiting HCC cell growth and invasion, whereas MYCN rescue hindered miR‐493‐5p activity. In summary, miR‐493‐5p is a pivotal miRNA that modulates various oncogenes after its reexpression in liver cancer cells, suggesting that tumor suppressor miRNAs with a large spectrum of action could provide valuable tools for miRNA replacement therapies., Our study highlighted the MYCN protooncogene as a critical target of microRNA (miR)‐493‐5p tumor suppressor. We found that MYCN was overexpressed in hepatic cancer cells and that miR‐493‐5p negatively repressed MYCN at the posttranscriptional level. We confirmed that MYCN silencing mimicked the anticancer activity of miR‐493‐5p by inhibiting hepatic tumor cell growth and invasion.

Wound healing is an important process in the human body to protect against external threats. A dysregulation at any stage of the wound healing process may result in the development of various intractable ulcers or excessive scar formation. Numerous factors such as growth factors, cytokines, and chemokines are involved in this process and play vital roles in tissue repair. Moreover, recent studies have demonstrated that lipid mediators derived from membrane fatty acids are also involved in the process of wound healing. Among these lipid mediators, we focus on eicosanoids such as prostaglandins, thromboxane, leukotrienes, and specialized pro-resolving mediators, which are produced during wound healing processes and play versatile roles in the process. This review article highlights the roles of eicosanoids on skin wound healing, especially focusing on the biosynthetic pathways and biological functions, i.e., inflammation, proliferation, migration, angiogenesis, remodeling, and scarring.

We have proposed that analysis of ribosome-loaded mRNAs (i.e., the translatome) is useful for elucidation of pharmacological effects of phytocompounds in immune cells, regarding the involvement of post-transcriptional regulation mechanisms. In the present study, we compared the effects of pachymic acid from Poria cocos fungus and moronic acid from propolis with those of hydrocortisone on the translatomes of THP-1 macrophages exposed to bacterial lipopolysaccharide (LPS) to find clues to their biological effects. Polysome-associated RNAs collected from cells treated for 3 h with LPS plus each of the compounds were analyzed by DNA microarray followed by analyses of pathways/gene ontologies (GO). Upregulated mRNAs in enriched pathways that were found to contain AUUUA (AU)-rich motifs were checked by real-time PCR, and expression of candidate RNA-binding proteins stabilizing/destabilizing such AU-rich mRNAs was checked by Western blotting. The numbers of upregulated and downregulated genes (fold-changes ± 2.0 versus vehicle-control) were, respectively, 209 and 125 for moronic acid, 23 and 2 for pachymic acid, and 214 and 59 for hydrocortisone treatment. Overlapping with hydrocortisone treatment for upregulation were 158 genes in moronic acid and 17 in pachymic acid treatment; of these, 16 overlapped within all treatments (C-X-C motif chemokine ligands, interferon-induced protein with tetratricopeptide repeats, etc.). Pathway analyses showed GO enrichments such as 'immune response', 'receptor binding', 'extracellular space' etc. The pachymic acid-upregulated mRNAs (highly overlapped with the other 2 treatments) showed the presence of signal peptides and AU-rich motifs, suggesting regulation by AU-rich element (ARE)-binding proteins. The expression of ARE-binding protein HuR/ELAV-1 was increased by the 3 compounds, and AUF1/hnRNP D was decreased by pachymic acid. These results suggested that pachymic acid and moronic acid effects may involve as yet unknown post-transcriptional modulation via ARE-binding proteins resembling that of glucocorticoids.

Primary liver tumors are mainly represented by hepatocellular carcinoma (HCC), one of the most aggressive and resistant forms of cancer. Liver tumorigenesis is characterized by an accumulation of epigenetic abnormalities, leading to gene extinction and loss of hepatocyte differentiation. The aim of this work was to investigate the feasibility of converting liver cancer cells toward a less aggressive and differentiated phenotype using a process called epigenetic reconditioning. Here, we showed that an epigenetic regimen with non-cytotoxic doses of the demethylating compound 5-azacytidine (5-AZA) promoted an anti-cancer response by inhibiting HCC cell tumorigenicity. Furthermore, epigenetic reconditioning improved sorafenib response. Remarkably, epigenetic treatment was associated with a significant restoration of differentiation, as attested by the increased expression of characteristic hepatocyte markers in reconditioned cells. In particular, we showed that reexpression of these epigenetically silenced liver genes following 5-AZA treatment or after knockdown of DNA methyltransferase 1 (DNMT1) was the result of regional CpG demethylation. Lastly, we confirmed the efficacy of HCC differentiation therapy by epigenetic reconditioning using an in vivo tumor growth model. In summary, this work demonstrates that epigenetic reconditioning using the demethylating compound 5-AZA shows therapeutic significance for liver cancer and is potentially attractive for the treatment of solid tumors., Graphical Abstract, Curative management of primary liver cancer is limited given its resistance to chemotherapies. In this issue of Molecular Therapy, Gailhouste and colleagues show that demethylating agent-based treatments have anti-cancer effects on hepatic tumor cells, which supports the development of alternative epigenetic differentiation therapies to attenuate the aggressiveness and drug resistance of solid tumors.

Red-winged Blackbirds (Agelaius phoeniceus) experience high rates of nest predation and are therefore expected to exhibit adaptations to reduce the risk of eavesdropping by predators. We used a simulated predator and observations of adult and nestling behavior to test predictions of the predator eavesdropping hypothesis. Females (n = 42) delayed their feeding visits significantly longer and took significantly longer to complete their round trips when a plastic American crow (Corvus brachyrhynchos) was 20 m from their nests than when a black wood block was at the same location, but time spent off territory foraging did not differ significantly. Nestlings (n = 35 broods) begged appropriately (in response to a female at the nest) significantly less and at significantly lower intensity when the plastic crow was 20 m from their nests than when the wood block was at the same location, but the crow had no significant effect on the amount or intensity of inappropriate (no female present) begging. These a...

I observed male Red-winged Blackbirds (Agelaius phoeniceus) defend and provision nests, and I documented survival of pair-fed and female-fed broods to determine whether male parental behavior affects nestling survival and nest success. Broods provisioned by both males and females (n = 208) had significantly higher daily survival and were significantly more likely to produce fledglings than those fed only by females (n = 268). Examination of male responses to a crow model during incubation (n = 114) showed that males were more aggressive towards the simulated predator at nests they would later provision than at nests fed only by females. These results show that male provisioning is associated with more aggressive nest defense and increased nestling and nest survival, and suggest that parental behavior of male Red-winged Blackbirds is both plastic and adaptive.

Nest predation is the most frequent cause of nest failure in birds such as the Red-winged Blackbird (Agelaius phoeniceus) that nest on or near the substrate. Nestlings should therefore exhibit adaptations to reduce the risk of nest predation. We tested the nestling antipredator hypothesis by examining the begging responses of Red-winged Blackbird nestlings to vocalizations of (1) an important nest predator (American Crow, Corvus brachyrhynchos), (2) a predator that rarely preys on nestlings (Cooper’s Hawk, Accipiter cooperii), and (3) a nonpredator (Northern Flicker, Colaptes auratus). We performed playbacks with (1) both parents present at the nest, (2) male at the nest, and (3) neither parent present. Following playback, we measured duration of nestling begging after the parent departed (begging persistence), bouts of otherwise normal begging when no parent was present (parent-absent begging), and calling without postural components of begging (nonpostural begging). When the male or both parents were present during playback, adults responded with alarm calls and nestlings significantly reduced parent-absent begging following American Crow and Cooper’s Hawk playbacks. Nonpostural begging was significantly reduced following Cooper’s Hawk playback, but there were no significant differences in the other begging variables. When neither parent was present, we found no significant differences in nonpostural begging in response to the 3 playback types, but parent-absent begging was significantly reduced following American Crow and Cooper’s Hawk playbacks when compared to Northern Flicker playbacks. These results show that nestlings suppress their vocal begging in response to calls of predators including Cooper’s Hawks even though they are not common nest predators.

The recognition of and differential responses to salient stimuli are among the main drivers of behavioral plasticity, yet, how animals evolve and modulate functional responses to novel classes of antagonistic stimuli remain poorly understood. We studied free-living male red-winged blackbirds (Agelaius phoeniceus) to test whether gene expression responses in blood are distinct or shared between patterns of aggressive behavioral responses directed at simulated conspecific versus heterospecific intruders. In this species, males defend territories against conspecific males and respond aggressively to female brown-headed cowbirds (Molothrus ater), a brood parasite that commonly lays eggs in blackbird nests. Both conspecific songs and parasitic calls elicited aggressive responses from focal subjects and caused a downregulation in genes associated with immune system response, relative to control calls of a second, harmless heterospecific species. In turn, only the conspecific song treatment elicited an increase in singing behavior and an upregulation of genes associated with metabolic processes relative to the two heterospecific calls. Our results suggest that aspects of antagonistic behaviors to both conspecifics and brood parasites can be mediated by similar physiological responses, suggestive of shared molecular and behavioral pathways involved in the recognition and reaction to both evolutionarily old and new enemies.

Numerous studies have described the critical role played by microRNAs (miRNAs) in cancer progression and the potential of these small non-coding RNAs for diagnostic or therapeutic applications. However, the mechanisms responsible for the altered expression of miRNAs in malignant cells remain poorly understood. Herein, via epigenetic unmasking, we identified a group of miRNAs located in the imprinted delta like non-canonical Notch ligand 1 (DLK1)-maternally expressed 3 (MEG3) locus that were repressed in hepatic tumor cells. Notably, miR-493-5p epigenetic silencing was correlated with hypermethylation of the MEG3 differentially regulated region (DMR) in liver cancer cell lines and tumor tissues from patients. Experimental rescue of miR-493-5p promoted an anti-cancer response by hindering hepatocellular carcinoma (HCC) cell growth in vitro and tumor progression in vivo. We found that miR-493-5p mediated part of its tumor-suppressor activity by abrogating overexpression of insulin-like growth factor 2 (IGF2) and the IGF2-derived intronic oncomir miR-483-3p in HCC cells characterized by IGF2 loss of imprinting (LOI). In summary, this study describes an unknown miRNA-dependent regulatory mechanism between two distinct imprinted loci and a possible therapeutic window for liver cancer patients exhibiting IGF2-miR-483 LOI and amplification.

Although some signals seem adapted to maximize transmission of cues to intended receivers, others appear to have been selected to deny specific types of cues to unwanted receivers. We review three categories of avian vocal signals that have been suggested to show adaptation for cue denial: aerial predator alarm calls, begging calls, and soft songs and calls. Evidence supports the conclusion that aerial alarm calls are adapted to deny localization cues and that begging calls and soft songs are adapted to deny detection. Selection for denial of cues in acoustic signals has also been documented in a variety of other animals. In summary, eavesdropping by unwanted receivers is often as important in shaping the structure of acoustic signals as is selection for transmission to intended receivers.

I used 20 years of nest records and predation at silent control and begging-call playback nests to determine whether begging calls of Red-winged Blackbirds (Agelaius phoeniceus) attract predators. Survival analysis provided no evidence that vocal begging affected nest predation. Survival schedules during egg and nestling periods were not significantly different, and vocal begging activity was not significantly correlated with daily nest survival. I found that predation at 35 no-longer-active nests at which begging calls were played at natural volume, at a typical rate, and following a normal schedule was slightly but not significantly higher than at 35 silent control nests. Selection may have favored adaptations of nestling Red-winged Blackbirds' begging calls that reduce the risk of predation.

The Red-winged Blackbird (Agelaius phoeniceus; redwing) is a commonly used accepter host species that incubates eggs and cares for nestlings and fledglings of the obligate brood parasitic Brown-headed Cowbird (Molothrus ater; cowbird). This host species, however, may reduce the risk of parasitism with a frontloaded antiparasite strategy in which it attacks parasites that approach active host nests. To test this frontloaded parasite-defense hypothesis (FPDH), we presented taxidermic models of a female Northern Cardinal (Cardinalis cardinalis), which represents no threat to redwings, a male cowbird, which cannot lay a parasitic egg, and a female cowbird, together with species- and sex-specific vocalization playbacks for 5 min. We conducted these presentations at 25 active redwing nests at Newark Road Prairie in south-central Rock County, Wisconsin, USA, where 18% of redwing nests were parasitized by cowbirds in 2015. As predicted by the FPDH, the female cowbird mount elicited the most aggressive re...

We tested the nestling discrimination hypothesis by observing responses of female Red-winged Blackbirds (Agelaius phoeniceus) to playback of begging calls by conspecifics or Brown-headed Cowbirds (Molothrus ater). Female redwings departed the nest to forage and returned with food significantly faster in response to redwing playback than to cowbird playback. We also observed feeding rates at redwing nests before and after we removed either a redwing or cowbird nestling. Female redwing feeding rates changed significantly with these manipulations, but there was no difference in response to redwing versus cowbird nestling removal. Although the removal experiment shows that parasitized and unparasitized broods receive equal care from their hosts, the playback results are consistent with the hypothesis that female Red-winged Blackbirds detect a difference between begging calls of conspecifics and parasites.

We aimed to investigate the bioactive components of Alpinia japonica as anti-inflammatory compounds using searches of the Alpinia genus, and subsequently demonstrated that alpinone 3-acetate markedly inhibits 12-O-tetradecanoyiphorbol 13-acetate-induced inflammation in a mouse model of ear edema. To assess other bioactivities of alpinone 3-acetate, we performed translatome analyses and compared them with those of hydrocortisone. Polysome-associated mRNAs were prepared from alpinone 3-acetate- or hydrocortisone-treated and control cells from 12-O-tetradecanoyiphorbol 13-acetate-induced THP-1-derived macrophages cultured in the presence of Escherichia coli O-111 lipopolysaccharide. Subsequent microarray analysis revealed that alpinone 3-acetate and hydrocortisone upregulated and downregulated the same 155 and 41 genes, respectively. Moreover, direct comparisons of translationally regulated genes indicated 5 and 10 gene probes that were upregulated and downregulated by alpinone 3-acetate and hydrocortisone, respectively. In conclusion, assays of 12-O-tetradecanoyiphorbol 13-acetate-induced inflammation ear edema in mice and polysome profiling of alpinone 3-acetate bioactivities indicated similar medicinal possibilities to those of hydrocortisone.

Cancer prevention by supplements offers the most cost-effective long-term health strategy. Methanol extracts from the aerial parts of Epimedium koreanum were previously found to inhibit 12- O -tetradecanoylphorbol-13-acetate (TPA)-induced inflammatory ear oedema and tumour promotion by TPA in the two-stage mouse skin carcinogenesis model. Four prenyl flavonol glycosides ( 1 ‒ 4 ) were isolated from the active fraction of this extract, and were identified. The isolated compounds showed inhibitory activity against TPA-induced ear inflammatory ear oedema. The 50% inhibitory dose (ID 50 ) of icariin ( 1 ), epimedin A ( 2 ), epimedin B ( 3 ) and epimedin C ( 4 ) for TPA-induced inflammation ranged from 114 to 255 nmol/ear, suggesting greater potency than indomethacin (ID 50 : 908 nmol/ear), an anti-inflammatory drug. Thus, the epimedium herb may be useful in cancer prevention.