Suppression of neointimal hyperplasia induced by arteriovenous anastomosis and balloon injury in rats by multimeric tumor necrosis factor-related apoptosis-inducing ligand.

Excessive blood vessel wall thickening, known as intimal hyperplasia, can result from injury or inflammation and increase the risk of vascular diseases. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) plays key roles in tumor surveillance, autoimmune diseases, and apoptosis; however, its role in vascular stenosis remains controversial. Treatment with recombinant isoleucine zipper hexamerization domain soluble TRAIL (ILz(6):TRAIL) significantly inhibited the progression of neointimal hyperplasia (NH) induced by anastomosis of the carotid artery and jugular vein dose dependently, and adenovirus expressing secretable ILz(6):TRAIL also inhibited NH induced by balloon injury in the femoral artery of rats. This study demonstrated the preventive and partial regressive effects of ILz(6):TRAIL on anastomosis of the carotid artery and jugular vein- or balloon-induced NH.

Development of a digital star-shot analysis system for comparing radiation and imaging isocenters of proton treatment machine.

PURPOSE: To directly compare the radiation and imaging isocenters of a proton treatment machine, we developed and evaluated a real-time radiation isocenter verification system. METHODS: The system consists of a plastic scintillator (PI-200, Mitsubishi Chemical Corporation, Tokyo, Japan), an acrylic phantom, a steel ball on the detachable plate, Raspberry Pi 4 (Raspberry Pi Foundation, London, UK) with camera module, and analysis software implemented through a Python-based graphical user interface (GUI). After kV imaging alignment of the steel ball, the imaging isocenter defined as the position of the steel ball was extracted from the optical image. The proton star-shot was obtained by optical camera because the scintillator converted proton beam into visible light. Then the software computed both the minimum circle radius and the radiation isocenter position from the star-shot. And the deviation between the imaging isocenter and radiation isocenter was calculated. We compared our results with measurements obtained by Gafchromic EBT3 film (Ashland, NJ, USA). RESULTS: The minimum circle radii were averaged 0.29 and 0.41 mm while the position deviations from the radiation isocenter to the laser marker were averaged 0.99 and 1.07 mm, for our system and EBT3 film, respectively. Furthermore, the average position difference between the radiation isocenter and imaging isocenter was 0.27 mm for our system. Our system reduced analysis time by 10 min. CONCLUSIONS: Our system provided automated star-shot analysis with sufficient accuracy, and it is cost-effective alternative to conventional film-based method for radiation isocenter verification.

Effects of Fermented Polygonum cuspidatum on the Skeletal Muscle Functions.

Plant extract fermentation is widely employed to enhance the nutritional and pharmaceutical value of functional foods. Polygonum cuspidatum (Pc) contains flavonoids, anthraquinones, and stilbenes, imparting protective effects against inflammatory diseases, cancer, diabetes, and cardiovascular diseases. However, the effects of fermented Pc on skeletal muscle strength remain unexplored. In this study, we generated fermented Pc using a complex of microorganisms containing Lactobacillus spp. (McPc) and assessed its effects on muscle strength and motor function in mice. Compared to unfermented Pc water extract, elevated levels of emodin and resveratrol were noted in McPc. This was identified and quantified using UPLC-QTOF/MS and HPLC techniques. Gene expression profiling through RNA-seq and quantitative RT-PCR revealed that McPc administration upregulated the expression of genes associated with antioxidants, glycolysis, oxidative phosphorylation, fatty acid oxidation, and mitochondrial biogenesis in cultured C2C12 myotubes and the gastrocnemius muscle in mice. McPc significantly improved skeletal muscle strength, motor coordination, and traction force in mice subjected to sciatic neurectomy and high-fat diet (HFD). McPc administration exhibited more pronounced improvement of obesity, hyperglycemia, fatty liver, and hyperlipidemia in HFD mice compared to control group. These findings support the notion that emodin and resveratrol-enriched McPc may offer health benefits for addressing skeletal muscle weakness.

Flavobacterium humidisoli sp. nov., isolated from riverside soil.

A novel Gram-stain-negative, yellow-pigmented, non-motile and rod-shaped bacterial strain designated MMS21-Er5T was isolated and subjected to polyphasic taxonomic characterization. MMS21- Er5T could grow at 4-34 °C (optimum, 30 °C), at pH 6-8 (optimum, pH 7) and in the presence of 0-2% NaCl (optimum, 1 %). The results of phylogenetic analysis based on 16S rRNA gene sequences indicated that MMS21- Er5T showed low levels of sequence similarities with other species, as the highest similarity of 97.83 % was observed with Flavobacterium tyrosinilyticum THG DN8.8T, then 97.68 % with 'Flavobacterium ginsengiterrae' DCY 55 and 97.63 % with Flavobacterium banpakuense 15F3T, which were well below the suggested cutoff for species distinction. The whole genome sequence of MMS21-Er5T consisted of a single contig of 5.63 Mbp, and the DNA G+C content was 34.06 mol%. The in-silico DNA-DNA hybridization and orthologous average nucleotide identity values were highest with Flavobacterium tyrosinilyticum KCTC 42726T (45.7 and 91.92% respectively). The predominant respiratory quinone for the strain was menaquinone-6 (MK-6), the major cellular fatty acid was iso-C15 : 0, and the diagnostic polar lipids were phosphatidylethanolamine and phosphatidyldiethanolamine. The combination of physiological and biochemical tests clearly distinguished the strain from related species of the genus Flavobacterium. On the basis of these results, strain MMS21-Er5T evidently represents a novel species of the genus Flavobacterium, for which the name Flavobacterium humidisoli sp. nov. is proposed (type strain=MMS21-Er5T=KCTC 92256T =LMG 32524T).

Solitalea lacus sp. nov., isolated from pond sediment.

A Gram-stain-negative, strictly aerobic, oxidase-positive, catalase-negative, motile by gliding, creamy white-pigmented bacterium, designated strain S2-8T, isolated from a sediment sample from a Wiyang pond in the Republic of Korea, was subjected to polyphasic taxonomic analysis. Growth was observed at 10-40 °C (optimum: 30 °C), pH 7-8 and 0-0.5% NaCl. Phylogenetic analyses based on 16S rRNA gene sequences revealed that strain S2-8T belonged to the family Sphingobacteriaceae in the phylum Bacteroidota and was closely related to Solitalea longa HR-AVT, Solitalea canadensis DSM 3403T and Solitalea koreensis R2A36-4T with 97.2, 96.7 and 93.7 % 16S rRNA gene sequence similarities, respectively. Average nucleotide identity and digital DNA-DNA hybridization values for these type strains were 72.0-75.2% and 21.2-21.9 %, respectively. The major respiratory quinone is menaquinone-7. The major fatty acids were iso-C15 : 0, iso-C17 : 0 3-OH and summed feature 3 (comprising C16 : 1 ω7c and/or C16 : 1 ω6c). The major polar lipids were phosphatidylethanolamine, two unidentified amino acids and four unidentified lipids. The G+C content of genomic DNA was 37.9 mol%. Based on polyphasic taxonomic analysis, it was observed that strain S2-8T is a novel species belonging to the genus Solitalea, for which the name Solitalea lacus sp. nov. is proposed. The type strain is S2-8T (= KACC 22266T= JCM 34533T).

Rapid production method with increased yield of high-purity extracellular vesicles obtained using extended mitochondrial targeting domain peptide.

Extracellular vesicles (EVs) are nano-sized membranous structures involved in intercellular communication and various physiological and pathological processes. Here, we present a novel method for rapid (within 15 min), large-scale production of high-purity EVs using eMTDΔ4, a peptide derived from Noxa. The treatment of mesenchymal stem cells derived from human Wharton's jelly after trypsinization and subsequent eMTDΔ4 stimulation in a chemically defined sucrose buffer with orbital shaking led to a substantial increase (approximately 30-fold) in EV production with markedly high purity (approximately 45-fold). These EVs (TS-eEVs) showed higher regenerative and immunomodulatory potential than natural EVs obtained from the culture media after 48 h. The calcium chelator BAPTA-AM and calpain inhibitor ALLM, but not the natural EV biogenesis inhibitor GW4869, blocked the TS-eEV production induced by eMTDΔ4, indicating that the eMTDΔ4-mediated regulation of intracellular calcium levels and calpain activity are closely associated with the rapid, mass production of TS-eEVs. The present study may lead to considerable advances in EV-based drug development and production of stem cell-derived EVs for cell therapy.

Isothiocyanate groups of 4,4'-diisothiocyanatostilbene-2,2'-disulfonate (DIDS) inhibit cell penetration of octa-arginine (R8)-fused peptides.

Delivering biomolecules, such as antibodies, proteins, and peptides, to the cytosol is an important and challenging aspect of drug development and chemical biology. Polyarginine-a well-known cell-penetrating peptide (CPP)-is capable of exploiting its positive charge and guanidium groups to carry a fused cargo into the cytosol. However, the precise mechanism by which this occurs remains ambiguous. In the present study, we established a new method of quantitatively assessing cell penetration. The method involves inducing cell death by using a polyarginine (R8) to deliver a peptide-ie, mitochondrial targeting domain (MTD)-to the cytosol. We found that 4,4'-diisothiocyanatostilbene-2,2'-di-sulfonate (DIDS)-an anion channel blocker-inhibited the ability of octa-arginine (R8)-fused MTD to penetrate cells. Other anion channel blockers did not inhibit the penetration of peptides fused with R8. Comparison of DIDS with other structurally similar chemicals revealed that the isothiocyanate group of DIDS may be primarily responsible for the inhibitory effect than its stilbene di-sulfonate backbone. These results imply that the inhibitory effect of DIDS may not be derived from the interaction between stilbene di-sulfonate and the anion channels, but from the interaction between the isothiocyanate groups and the cell membrane. Our new MTD method enables the quantitative assessment of cell penetration. Moreover, further studies on the inhibition of CPPs by DIDS may help clarify the mechanism by which penetration occurs and facilitate the design of new penetrative biomolecules.

A peptide containing Noxa mitochondrial-targeting domain induces cell death via mitochondrial and endoplasmic reticulum disruption.

Noxa is a weak apoptosis activator consisting of a BH3 domain and a mitochondrial-targeting domain (MTD). BH3 binds Mcl-1 and Bcl2A1 and inactivates their anti-apoptotic activities, while MTD delivers BH3 to mitochondria. Previously we revealed that MTD may also function as an inducer of necrosis via conjugation with octa-arginine, which induces cytosolic Ca2+ influx from mitochondria. However, the mechanism(s) underlying this process has not been elucidated yet. Here, we show that calcium influx induced by an MTD peptide fused with octa-arginine residue (R8:MTD) originates not only from mitochondria but also from the extracellular space. However, calcium spikes were not sufficient for necrosis. R8:MTD induced mitochondrial permeability transition pore opening, fragmentation, and swelling. These mitochondrial events induced by MTD appeared to be necessary for necrosis induction, since DIDS, a VDAC inhibitor, inhibited the mitochondrial swelling and cell death induced by MTD. We show that R8:MTD disrupted endoplasmic reticulum (ER) structures but not peroxisomes or Golgi, indicating that R8:MTD causes necrosis by inducing ER events as well.

Noxa mitochondrial targeting domain induces necrosis via VDAC2 and mitochondrial catastrophe.

Noxa, a Bcl-2 homology 3 (BH3)-only protein of the Bcl-2 family, is responsive to cell stresses and triggers apoptosis by binding the prosurvival Bcl-2-like proteins Mcl1, BclXL, and Bcl2A1. Although the Noxa BH3 domain is necessary to induce apoptosis, the mitochondrial targeting domain (MTD) of Noxa functions as a pronecrotic domain, an inducer of mitochondrial fragmentation, and delivery to mitochondria. In this study, we demonstrate that the extended MTD (eMTD) peptide induces necrotic cell death by interaction with the VDAC2 protein. The eMTD peptide penetrates the cell membrane, causing cell membrane blebbing, cytosolic calcium influx, and mitochondrial swelling, fragmentation, and ROS generation. The MTD domain binds VDACs and opens the mitochondrial permeability transition pore (mPTP) in a CypD-independent manner. The opening of mPTP induced by eMTD is inhibited either by down-regulation of VDAC2 or by the VDACs inhibitor DIDS. These results indicate that the MTD domain of Noxa causes mitochondrial damage by opening mPTP through VDACs, especially VDAC2, during necrotic cell death.

Brain Plasticity Can Predict the Cochlear Implant Outcome in Adult-Onset Deafness.

Sensory plasticity, which is associated with deafness, has not been as thoroughly investigated in the adult brain as it has in the developing brain. In this study, we examined the brain reorganization induced by auditory deprivation in people with adult-onset deafness and its clinical relevance by measuring glucose metabolism before cochlear implant (CI) surgery. F-18 fluorodeoxyglucose positron emission tomography (18F-FDG-PET) scans were performed in 37 postlingually deafened patients during the preoperative workup period, and in 39 normal-hearing (NH) controls. Behavioral CI outcomes were measured at 1 year after implantation using a phoneme identification test with auditory cueing only. In the deaf individuals, areas involved in the auditory pathway such as the inferior colliculus and bilateral superior temporal gyri were hypometabolic compared to the NH controls. The hypometabolism observed in the deaf auditory cortices gradually returned to levels similar to the controls as the duration of deafness increased. However, contrary to our previous findings in congenitally deaf children, this metabolic recovery failed to have a significant prognostic value for the recovery of the speech perception ability in adult CI patients. In a broad occipital area centered on the primary visual cortices, glucose metabolism was higher in the deaf patients than the controls, suggesting that the area had become visually hyperactive for sensory compensation immediately after the onset of deafness. In addition, a negative correlation between the metabolic activity and behavioral speech perception outcomes was observed in the visual association areas. In the medial frontal cortices, cortical metabolism in most patients decreased, but patients who had preserved metabolic activities showed better speech performance. These results suggest that the auditory cortex in people with adult-onset deafness is relatively resistant to cross-modal plasticity, and instead, individual traits in late-stage visual processing and cognitive control seem to be more reliable prognostic markers for adult-onset deafness.

Mucibacter soli gen. nov., sp. nov., a new member of the family Chitinophagaceae producing mucin.

A Gram-stain-negative, mucus-forming, motile by gliding, non-spore-forming and short rod-shaped bacterial strain designated R1-15T was isolated from soil and its taxonomic position was evaluated using a polyphasic approach. Strain R1-15T grew at 15-37°C (optimum, 30°C), at pH 6-7 (optimum, pH 6) and in the presence of 0-1% (w/v) NaCl (optimum, 0%) on 0.1X TSA. On the basis of 16S rRNA gene sequence similarity, the novel strain was assigned to the family Chitinophagaceae of the phylum Bacteroidetes, and its closest related taxa were species of the genera Taibaiella (88.76-90.02% sequence similarity), Lacibacter (89.24-90.00%), Chitinophaga (88.61-89.76%), and Terrimonas (89.04%). Flexirubin- type pigments were produced. The only isoprenoid quinone was MK-7, and the major polar lipid was phosphatidylethanolamine. Based on whole genome comparisons between the strain R1-15T and the type strains of relatives, the orthologous average nucleotide identity values were 66.9-67.0%. The DNA G + C content of strain R1-15T was 43.8 mol%. The combination of phylogenetic, chemotaxonomic and phenotypic data clearly supported separation of strain R1-15T from related taxa, and thus the name Mucibacter soli gen. nov., sp. nov. is proposed. The type strain is R1-15T (= KCTC 62274T = JCM 31190T).

A novel peripheral cannabinoid 1 receptor antagonist, AJ5012, improves metabolic outcomes and suppresses adipose tissue inflammation in obese mice.

The overactivity of cannabinoid 1 receptor (CB1R) is associated with obesity and type 2 diabetes. First-generation CB1R antagonists, such as rimonabant, offered therapeutic advantages for the control of obesity and related metabolic abnormalities, but their therapeutic potential was limited by undesirable neuropsychiatric side effects. Here, we evaluated AJ5012 as a novel potent peripheral CB1R antagonist and, using this antagonist, investigated the role of peripheral CB1R on adipose tissue inflammation in obese mouse models. AJ5012 had a high degree of CB1R and cannabinoid 2 receptor selectivity but a low brain:plasma concentration ratio without eliciting centrally mediated neurobehavioral effects. In diet-induced obese (DIO) mice, AJ5012 did not reduce food intake but did induce a significant weight loss, likely owing to an increased energy expenditure. It was as effective as rimonabant for the improvement of hormonal or metabolic abnormalities, glycemic control, and insulin sensitivity. The treatment of DIO and leptin receptor-deficient mice with AJ5012 also exhibited effects comparable to rimonabant for the prevention of macrophage infiltration, activation of the nucleotide-binding domain and leucine-rich repeat protein 3 inflammasome, and production of proinflammatory cytokines, which resulted in the suppression of adipose tissue inflammation. In addition to macrophage, activation of CB1R in 3T3-L1 adipocytes induced the expression of proinflammatory genes, which was fully inhibited by AJ5012. Our findings identified AJ5012 as a novel peripheral CB1R antagonist and suggest that peripheral CB1R blockade might break the links between insulin resistance and adipose tissue inflammation.-Han, J. H., Shin, H., Park, J.-Y., Rho, J. G., Son, D. H., Kim, K. W., Seong, J. K., Yoon, S.-H., Kim, W. A novel peripheral cannabinoid 1 receptor antagonist, AJ5012, improves metabolic outcomes and suppresses adipose tissue inflammation in obese mice.

Glucose Controls the Expression of Polypyrimidine Tract-Binding Protein 1 via the Insulin Receptor Signaling Pathway in Pancreatic ß Cells.

In pancreatic ß cells, glucose stimulates the biosynthesis of insulin at transcriptional and post-transcriptional levels. The RNA-binding protein, polypyrimidine tract-binding protein 1 (PTBP1), also named hnRNP I, acts as a critical mediator of insulin biosynthesis through binding to the pyrimidine-rich region in the 3'-untranslated region (UTR) of insulin mRNA. However, the underlying mechanism that regulates its expression in ß cells is unclear. Here, we report that glucose induces the expression of PTBP1 via the insulin receptor (IR) signaling pathway in ß cells. PTBP1 is present in ß cells of both mouse and monkey, where its levels are increased by glucose and insulin, but not by insulin-like growth factor 1. PTBP1 levels in immortalized ß cells established from wild-type (ßIRWT) mice are higher than levels in ß cells established from IR-null (ßIRKO) mice, and ectopic re-expression of IR-WT in ßIRKO cells restored PTBP1 levels. However, PTBP1 levels were not altered in ßIRKO cells transfected with IR-3YA, in which the Tyr1158/1162/1163 residues are substituted with Ala. Consistently, treatment with glucose or insulin elevated PTBP1 levels in ßIRWT cells, but not in ßIRKO cells. In addition, silencing Akt significantly lowered PTBP1 levels. Thus, our results identify insulin as a pivotal mediator of glucose-induced PTBP1 expression in pancreatic ß cells.

Mitochondrial targeting domain of NOXA causes necrosis in apoptosis-resistant tumor cells.

The resistance of tumor cells to apoptosis-inducing anticancer agents is regarded as a major impediment for the treatment of cancer patients. This study aimed to examine the possibility whether a necrosis-inducing peptide containing the mitochondria-targeting domain (MTD) of NOXA kills tumor cells that are resistant to apoptosis-inducing anticancer agents. To examine this possibility, we established doxorubicin-resistant (Dox-Res) cells by treating CT26 cells with increasing amounts of doxorubicin. The apoptosis resistance of the Dox-Res CT26 cells was confirmed by measuring the cell viability and activation of caspases. We showed that the MTD-containing peptide fused to eight arginine residues (R8:MTD), a necrosis-inducing peptide, induced necrosis in the Dox-Res CT26 cells, together with a cytosolic calcium spike, reactive oxygen species production, and the release of high mobility group box 1 into the media. Moreover, we demonstrated the killing effect of R8:MTD in tumor tissues generated using the Dox-Res CT26 cells in a mouse model. Therefore, our results suggest that MTD-containing peptides may provide an alternative tool for the elimination of relapsed tumor cells that are not responsive to apoptosis-inducing anticancer agents.

Frontal Sinus Osteoplastic Flap Surgery Using a Surgical Navigation System.

OBJECTIVE: To report the case of a 38-year-old woman who underwent osteoplastic flap surgery for recurrent frontal sinus mucocele. During surgery, the exact shape of the frontal sinus was duplicated using a surgical navigation system. METHODS: In this case report, the authors suggest intraoperative surgical navigation systems are useful for accurately determining the dimensions of the frontal sinus for osteoplastic flap surgery. RESULTS: The patient underwent successful and safe osteoplastic flap surgery using a surgical navigation system. CONCLUSION: Surgical navigation is useful and safe for frontal sinus osteoplastic flap surgery.

Height Changes of Tutoplast-Processed Fascia Lata Over Time After Dorsal Augmentation During Rhinoplasty.

PURPOSE: Tutoplast (Tutogen Medical, Neunkirchen am Brand, Germany)-processed fascia lata (TPFL) has been used for dorsal augmentation in rhinoplasty in the Republic of Korea for approximately 10 years, but few studies have described changes in TPFL in terms of dorsal height over time. We investigated changes in dorsal height after TPFL use as a dorsal implant material during rhinoplasty. MATERIALS AND METHODS: The records of 18 rhinoplasty patients who had undergone dorsal augmentation with TPFL were examined retrospectively. The patients had undergone rhinoplasty from March 2008 to June 2012. Two different ear, nose, and throat doctors analyzed the first follow-up photographs (2 lateral views and 2 oblique views) taken at approximately 1 month postoperatively and the last follow-up photographs taken from 18 to 75 months after surgery. The last follow-up photographs were classified as showing no nasal dorsal height change, slight change, and marked change compared with the first follow-up photographs. RESULTS: Of the 18 patients enrolled, 50% (n = 9) showed no change in the nasal dorsum whereas 33% (n = 6) showed mild depression and 17% (n = 3) showed marked depression of the nasal dorsum at last follow-up. CONCLUSIONS: About half of the patients who had undergone dorsal augmentation using TPFL during rhinoplasty showed mild or marked dorsal depression over time. It is recommended that TPFL be used with another implant during augmentation rhinoplasty or TPFL be used only for a slightly depressed nose. In addition, patients should be informed that TPFL could be resorbed over time.

Self-assembled hyaluronic acid nanoparticles: Implications as a nanomedicine for treatment of type 2 diabetes.

Self-assembled hyaluronic acid nanoparticles (HA-NPs) have been extensively investigated for biomedical and pharmaceutical applications owing to their biocompatibility and receptor-binding properties. Here, we report that an empty HA-NP itself not bearing any drug has therapeutic effects on adipose tissue inflammation and insulin resistance. HA-NPs inhibited not only the receptor-mediated internalization of low-molecular-weight (LMW) free HA but also LMW free HA-induced pro-inflammatory gene expression in mouse primary bone marrow-derived macrophages (BMDMs) isolated from wild-type mice, but not in CD44-null (CD44-/-) BMDMs. An in vivo biodistribution study showed the distribution of HA-NPs and their co-localization with CD44 in adipose tissues including epididymal white adipose tissues (eWATs), but these were rarely observed in the eWATs of CD44-/- mice. In addition, CD44 expression and HA-NP accumulation in the eWATs were increased in mice with diet-induced obesity (DIO) compared to lean mice. Interestingly, treatment with HA-NPs in DIO mice suppressed adipose tissue inflammation as indicated by reduced macrophage content, the production of proinflammatory cytokines and NLRP3 inflammasome activity in eWATs, leading to improved insulin sensitivity and normalized blood glucose levels. Collectively, these results suggest that an empty HA-NP itself can be a therapeutic agent for the treatment of type 2 diabetes.

Blockade of cannabinoid 1 receptor improves glucose responsiveness in pancreatic beta cells.

Cannabinoid 1 receptors (CB1Rs) are expressed in peripheral tissues, including islets of Langerhans, where their function(s) is under scrutiny. Using mouse ß-cell lines, human islets and CB1R-null (CB1R-/- ) mice, we have now investigated the role of CB1Rs in modulating ß-cell function and glucose responsiveness. Synthetic CB1R agonists diminished GLP-1-mediated cAMP accumulation and insulin secretion as well as glucose-stimulated insulin secretion in mouse ß-cell lines and human islets. In addition, silencing CB1R in mouse ß cells resulted in an increased expression of pro-insulin, glucokinase (GCK) and glucose transporter 2 (GLUT2), but this increase was lost in ß cells lacking insulin receptor. Furthermore, CB1R-/- mice had increased pro-insulin, GCK and GLUT2 expression in ß cells. Our results suggest that CB1R signalling in pancreatic islets may be harnessed to improve ß-cell glucose responsiveness and preserve their function. Thus, our findings further support that blocking peripheral CB1Rs would be beneficial to ß-cell function in type 2 diabetes.

Anti-inflammatory effect of astaxanthin in phthalic anhydride-induced atopic dermatitis animal model.

In this study, we investigated anti-dermatitic effects of astaxanthin (AST) in phthalic anhydride (PA)-induced atopic dermatitis (AD) animal model as well as in vitro model. AD-like lesion was induced by the topical application of 5% PA to the dorsal skin or ear of Hos:HR-1 mouse. After AD induction, 100 µL of 1 mg/mL and 2 mg/mL of AST (10 µg or 20 µg/cm2 ) was spread on the dorsum of ear or back skin three times a week for four weeks. We evaluated dermatitis severity, histopathological changes and changes in protein expression by Western blotting for inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and nuclear factor-κB (NF-κB) activity. We also measured tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and immunoglobulin E (IgE) concentration in the blood of AD mice by enzyme-linked immunosorbent assay (ELISA). AST treatment attenuated the development of PA-induced AD. Histological analysis showed that AST inhibited hyperkeratosis, mast cells and infiltration of inflammatory cells. AST treatment inhibited expression of iNOS and COX-2, and NF-κB activity as well as release of TNF-α, IL-1ß, IL-6 and IgE. In addition, AST (5, 10 and 20 µM) potently inhibited lipopolysaccharide (LPS) (1 µg/mL)-induced nitric oxide (NO) production, expression of iNOS and COX-2 and NF-κB DNA binding activities in RAW 264.7 macrophage cells. Our data demonstrated that AST could be a promising agent for AD by inhibition of NF-κB signalling.

Designing a cancer therapeutic peptide by combining the mitochondrial targeting domain of Noxa and ErbB2-targeting moieties.

Many anticancer drugs target epidermal growth factor receptors to inhibit receptor tyrosine kinases and tumor growth. Here, we show that an ErbB2-targeting pronecrotic peptide (KWSY:MTD) selectively kills tumor cells expressing ErbB2 in vitro. An antibody against ErbB2 inhibits KWSY:MTD-induced cell death. KWSY:MTD causes membrane permeability which allows propidium iodide entry into the cytosol and the release of HMGB1 into the media, indicative of necrosis. Mitochondrial swelling occurs in response to KWSY:MTD. Moreover, in vivo analysis using a mouse model shows that KWSY:MTD partially suppressed growth in tumor tissue bearing ErbB2-expressing cells, but did not have obvious toxicity in mouse liver or kidney tissue. Taken together, KWSY:MTD has potential as an ErbB2-targeting anticancer drug.