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Abstract Background Transcriptional coactivator with PDZ-biding motif (TAZ) is widely expressed in most tissues and interacts with several transcription factors to regulate cell proliferation, differentiation, and death, thereby influencing organ development and size control. However, very little is known about the function of TAZ in the immune system and its association with inflammatory skin diseases, so we investigated the role of TAZ in the pathogenesis of psoriasis. Results Interestingly, TAZ was expressed in mast cells associated, particularly in lysosomes, and co-localized with histamine-releasing factor (HRF). TAZ deficiency promoted mast cell maturation and increased HRF expression and secretion by mast cells. The upregulation of HRF in TAZ deficiency was not due to increased transcription but to protein stabilization, and TAZ restoration into TAZ-deficient cells reduced HRF protein. Interestingly, imiquimod (IMQ)-induced psoriasis, in which HRF serves as a major pro-inflammatory factor, was more severe in TAZ KO mice than in WT control. HRF expression and secretion were increased by IMQ treatment and were more pronounced in TAZ KO mice treated with IMQ. Conclusions Thus, as HRF expression was stabilized in TAZ KO mice, psoriatic pathogenesis progressed more rapidly, indicating that TAZ plays an important role in preventing psoriasis by regulating HRF protein stability. Graphical Abstract

Numerous cases of lung injury caused by viral infection were reported during the coronavirus disease-19 pandemic. While there have been significant efforts to develop drugs that block viral infection and spread, the development of drugs to reduce or reverse lung injury has been a lower priority. This study aimed to identify compounds from a library of compounds that prevent viral infection that could reduce and prevent lung epithelial cell damage. We investigated the cytotoxicity of the compounds, their activity in inhibiting viral spike protein binding to cells, and their activity in reducing IL-8 production in lung epithelial cells damaged by amodiaquine (AQ). We identified N-(4-(4-methoxyphenoxy)-3-methylphenyl)-N-methylacetamide (MPoMA) as a non-cytotoxic inhibitor against viral infection and AQ-induced cell damage. MPoMA inhibited the expression of IL-8, IL-6, IL-1β, and fibronectin induced by AQ and protected against AQ-induced morphological changes. However, MPoMA did not affect basal IL-8 expression in lung epithelial cells in the absence of AQ. Further mechanistic analysis confirmed that MPoMA selectively promoted the proteasomal degradation of inflammatory mediator p65, thereby reducing intracellular p65 expression and p65-mediated inflammatory responses. MPoMA exerted potent anti-inflammatory and protective functions in epithelial cells against LPS-induced acute lung injury in vivo. These findings suggest that MPoMA may have beneficial effects in suppressing viral infection and preventing lung epithelial cell damage through the degradation of p65 and inhibition of the production of inflammatory cytokines.

Abstract Background Exercise stimulates the activation of muscle satellite cells, which facilitate the maintenance of stem cells and their myogenic conversion during muscle regeneration. However, the underlying mechanism is not yet fully understood. This study shows that the transcriptional co‐activator with PDZ‐binding motif (TAZ) stimulates muscle regeneration via satellite cell activation. Methods Tazf/f mice were crossed with the paired box gene 7 (Pax7)creERT2 mice to generate muscle satellite cell‐specific TAZ knockout (sKO) mice. Mice were trained in an endurance exercise programme for 4 weeks. Regenerated muscles were harvested and analysed by haematoxylin and eosin staining. Muscle tissues were also analysed by immunofluorescence staining, immunoblot analysis and quantitative reverse transcription PCR (qRT‐PCR). For the in vitro study, muscle satellite cells from wild‐type and sKO mice were isolated and analysed. Mitochondrial DNA was quantified by qRT‐PCR using primers that amplify the cyclooxygenase‐2 region of mitochondrial DNA. Quiescent and activated satellite cells were stained with MitoTracker Red CMXRos to analyse mitochondria. To study the p38 mitogen‐activated protein kinase (MAPK)–TAZ signalling axis, p38 MAPK was activated by introducing the MAPK kinase 6 plasmid into satellite cells and also inhibited by treatment with the p38 MAPK inhibitor, SB203580. Results TAZ interacts with Pax7 to induce Myf5 expression and stimulates mammalian target of rapamycin signalling for satellite cell activation. In sKO mice, TAZ depletion reduces muscle satellite cell number by 38% (0.29 ± 0.073 vs. 0.18 ± 0.034, P = 0.0082) and muscle regeneration. After muscle injury, TAZ levels (2.59‐fold, P

Background: Pulmonary fibrosis (PF) is a progressive lung disease characterized by fibroblast accumulation and collagen deposition, resulting in lung scarring and impaired gas exchange. Current treatments for idiopathic pulmonary fibrosis (IPF) have limited efficacy and significant side effects. Heat shock protein 27 (HSP27) has emerged as a potential therapeutic target for PF due to its involvement in fibrotic processes. However, effective HSP27 inhibitors for PF treatment are still lacking.Methods: To assess the anti-fibrotic effects of NA49, we utilized murine PF models induced by radiation (IR) or bleomycin (BLM). We administered NA49 to the PF mice and evaluated its impact on lung fibrosis progression. We also investigated the molecular mechanisms underlying NA49's effects, focusing on its inhibition of EMT-related signaling pathways.Results: In our study, we evaluated the potential of a novel HSP27 inhibitor, NA49, in preclinical models of PF. NA49 effectively suppressed PF development in radiation and bleomycin-induced PF models. It reduced fibrosis, inhibited NFkB signaling, and downregulated EMT-related molecules. Importantly, we evaluated the safety profile of NA49 by assessing its impact on DNA strand breakage. Compared to previous HSP27 inhibitors, NA49 showed lower levels of DNA damage in human lung epithelial cells, and suggests that NA49 may have reduced toxicity compared to other HSP27 inhibitors. Overall, our results demonstrate that NA49 effectively inhibits PF development in preclinical models. It reduces lung fibrosis, inhibits EMT-related signaling pathways, and exhibits improved safety profiles. These findings highlight the potential of NA49 as a promising candidate for the treatment of PF.Conclusion: NA49 exhibited significant anti-fibrotic effects, inhibiting fibrosis development and EMT-related signaling pathways. Moreover, NA49 showed improved safety profiles compared to previous HSP27 inhibitors.

Mitochondrial biogenesis is stimulated to meet energy requirements in response to extracellular signals including exercise. TAZ is revealed as a novel stimulator for mitochondrial biogenesis and facilitates exercise-induced muscle adaptation.

Psoriasis is a chronic skin inflammation caused by a dysfunctional immune system, which causes systemic inflammation in various organs and tissues. Due to the risk of systemic inflammation and recurrence of psoriasis, it is important to identify the critical targets in the pathogenesis of psoriasis and develop targeted therapeutics. Dimerized translationally controlled tumor protein (dTCTP) promotes immune cell activation as a pro-inflammatory cytokine and plays a role in developing allergic diseases such as asthma and rhinitis. Here, we sought to explore whether dTCTP and its inhibition contributed to the development and control of imiquimod (IMQ)-induced psoriasis. Topical application of IMQ inflamed the skin of the back and ear, increased inflammatory cytokines, and decreased regulatory T cell markers. Interestingly, TCTP was significantly increased in inflamed skin and immune cells such as T cells, B cells, and macrophages after IMQ treatment and was secreted into the serum to undergo dimerization. Extracellular dTCTP treatment selectively suppressed regulatory T (Treg) cells, not other effector T helper (Th) cells, and increased M1 macrophages. Moreover, dTCTP-binding peptide 2 (dTBP2), a dTCTP inhibitor peptide, effectively attenuated the systemic inflammatory responses, including Th17 cell response, and alleviated psoriatic skin inflammation. dTBP2 blocked dTCTP-mediated Treg suppression and stimulated the expression of Treg cell markers in the spleen and inflammatory skin lesions. These results suggest that dTCTP dysregulated immune balance through Treg suppression in psoriatic inflammation and that functional inhibition of dTCTP by dTBP2 maintained immune homeostasis and attenuated inflammatory skin diseases by expanding Treg cells.

Dimeric translationally controlled tumor protein (dTCTP), also known as histamine-releasing factor, amplifies allergic responses and its production has been shown to increase in inflammatory diseases such as allergic asthma. Despite the critical role of dTCTP in allergic inflammation, little is known about its production pathways, associated cellular networks, and underlying molecular mechanisms. In this study, we explored the dTCTP-mediated inflammatory networks and molecular mechanisms of dTCTP associated with lipopolysaccharides (LPS)-induced severe asthma. LPS stimulation increased dTCTP production by mast cells and dTCTP secretion during degranulation, and extracellular dTCTP subsequently increased the production of pro-inflammatory molecules, including IL-8, by airway epithelial cells without affecting mast cell activation. Furthermore, dimeric TCTP-binding peptide 2 (dTBP2), a dTCTP inhibitor peptide, selectively blocked the dTCTP-mediated signaling network from mast cells to epithelial cells and decreased IL-8 production through IkB induction and nuclear p65 export in airway epithelial cells. More importantly, dTBP2 efficiently attenuated LPS-induced severe airway inflammation in vivo, resulting in decreased immune cell infiltration and IL-17 production and attenuated dTCTP secretion. These results suggest that dTCTP produced by mast cells exacerbates airway inflammation through activation of airway epithelial cells in a paracrine signaling manner, and that dTBP2 is beneficial in the treatment of severe airway inflammation by blocking the dTCTP-mediated inflammatory cellular network.

Heat shock protein beta-1 (HSPB1) is a multifaceted protein that controls cellular stress, modulates cell differentiation and development, and inhibits apoptosis of cancer cells. Increased HSPB1 expression is highly associated with poor outcomes in lung cancer by enhancing cell migration and invasion; therefore, targeting HSPB1 may be a promising therapeutic for lung cancer and fibrosis. Although the HSPB1 inhibitor J2 has been reported to exhibit potent antifibrotic effects, it remains unclear whether and how J2 directly modulates inflammatory immune responses in pulmonary fibrosis. In this study, we found that J2 potently attenuated irradiation or bleomycin-induced pulmonary fibrosis by significantly inhibiting the infiltration and activation of T cells and macrophages. J2 inhibited T-cell proliferation and subsequently suppressed T helper cell development. Although there was no significant effect of J2 on cell proliferation of M1 and M2 macrophages, J2 specifically increased the expression of Ym1 in M2 macrophages without affecting the expression of other M2 markers. Interestingly, J2 increased lysosomal degradation of HSPB1 and inhibited HSPB1-induced repression of signal transducer and activator of transcription 6 (STAT6), which simultaneously increased STAT6 and Ym1 expression. Ym1 production and secretion by J2-treated M2 macrophages substantially decreased IL-8 production by airway epithelial cells in vitro and in vivo, resulting in attenuation of airway inflammation. Taken together, we suggest that J2 has potential as a therapeutic agent for pulmonary fibrosis with increased HSPB1 expression through direct immune suppression by Ym1 production by M2 macrophages as well as T-cell suppression.

Dimerized translationally controlled tumor protein (dTCTP) amplifies allergic responses through activation of several types of immune cells and release of inflammatory mediators. In particular, dTCTP plays an important role in histamine release by triggering mast cells and has been proposed as a target in the treatment of allergic diseases. dTCTP-binding peptide 2 (dTBP2) is known to attenuate severe allergic rhinitis and asthma through inhibition of dTCTP activity on airway epithelial cells and T cells; however, it is unclear whether dTBP2 affects mast cell function and mast cell disease. In this study, we explored the effects of dTBP2 on mast cell degranulation and allergen-induced anaphylactic reactions. We found that bacterial product lipopolysaccharide increased the expression of dTCTP in mast cells and rapidly released dTCTP by the mast cell stimulator compound 48/80. Interestingly, the released dTCTP further promoted mast cell degranulation in an autocrine activation manner and increased calcium mobilization in mast cells, which is essential for degranulation. Furthermore, dTBP2 directly and dose-dependently inhibited in vitro mast cell degranulation enhanced by compound 48/80, suggesting a direct and potent anti-anaphylactic activity of dTBP2. dTBP2 also significantly suppressed the dTCTP-induced degranulation and histamine release through inhibition of the p38 MAPK signaling pathway and suppression of lysosomal expansion and calcium mobilization in mast cells. More importantly, in vivo administration of dTBP2 decreased mortality and significantly attenuated histamine release and inflammatory cytokine production in compound 48/80-induced systemic anaphylactic reactions. These results suggest that dTBP2 is beneficial for the control of anaphylaxis with increased dTCTP.

Insulin resistance is associated with development of type 2 diabetes. Here the authors show that TAZ interacts with c-Jun and Tead4, inducing expression of the insulin receptor substrate 1 (IRS1) leading to increased glucose uptake in muscle, and that its activity is counteracted by statin administration.

Testosterone is a hormone essential for male reproductive function. It is produced primarily by Leydig cells in the testicle through activation of steroidogenic acute regulatory protein and a series of steroidogenic enzymes, including a cytochrome P450 side-chain cleavage enzyme (cytochome P450 family 11 subfamily A member 1), 17α-hydroxylase (cytochrome P450 family 17 subfamily A member 1), and 3β-hydroxysteroid dehydrogenase. These steroidogenic enzymes are mainly regulated at the transcriptional level, and their expression is increased by the nuclear receptor 4A1. However, the effect on Leydig cell function of a small molecule-activating ligand, amodiaquine (AQ), is unknown. We found that AQ effectively and significantly increased testosterone production in TM3 and primary Leydig cells through enhanced expression of steroidogenic acute regulatory protein, cytochome P450 family 11 subfamily A member 1, cytochrome P450 family 17 subfamily A member 1, and 3β-hydroxysteroid dehydrogenase. Concurrently, AQ dose-dependently increased the expression of 3-hydroxy-3-methylglutaryl-CoA reductase, a key enzyme in the cholesterol synthesis pathway, through induction of the transcriptional and DNA-binding activities of nuclear receptor 4A1, contributing to increased cholesterol synthesis in Leydig cells. Furthermore, AQ increased the expression of fatty acid synthase and diacylglycerol acyltransferase and potentiated de novo synthesis of fatty acids and triglycerides (TGs). Lipidomics profiling further confirmed a significant elevation of intracellular lipid and TG levels by AQ in Leydig cells. These results demonstrated that AQ effectively promotes testosterone production and de novo synthesis of cholesterol and TG in Leydig cells, indicating that AQ may be beneficial for treating patients with Leydig cell dysfunction and subsequent testosterone deficiency.

Abstract Osteoblast differentiation is regulated through the successive activation of signaling molecules by a complex interplay of extracellular signals such as bone morphogenetic protein (BMP) and Wnt ligands. Numerous studies have identified natural as well as synthetic compounds with osteogenic activity through the regulation of either BMP/SMADs or the Wnt/β-catenin pathway. Here, we attempted to isolate small molecules that concurrently activated both SMADs and β-catenin, which led to the discovery of a novel potent osteogenic compound, DMP-PYT. Upon BMP2 stimulation, DMP-PYT substantially increased osteoblast differentiation featured by enhanced expression of osteoblast-specific genes and accelerated calcification through activation of BMPs expression. DMP-PYT promoted BMP2-induced SMAD1/5/8 phosphorylation and β-catenin expression, the latter in a BMP2-independent manner. DMP-PYT alone enhanced nuclear localization of β-catenin to promote the DNA-binding and transcriptional activity of T-cell factor, thereby resulting in increased osteoblast differentiation in the absence of BMP2. Most importantly, DMP-PYT advanced skeletal development and bone calcification in zebrafish larvae. Conclusively, DMP-PYT strongly stimulated osteoblast differentiation and bone formation in vitro and in vivo by potentiating BMP2-induced activation of SMADs and β-catenin. These results suggest that DMP-PYT may have beneficial effects for preventing and for treating osteoporosis.

Abstract The topographical environment, which mimics the stem cell niche, provides mechanical cues to regulate the differentiation of mesenchymal stem cells (MSC). Diverse topographical variations have been engineered to investigate cellular responses; however, the types of mechanical parameters that affect cells, and their underlying mechanisms remain largely unknown. In this study, we screened nanotopological pillars with size gradient to activate transcriptional coactivator with PDZ binding motif (TAZ), which stimulates osteogenesis of MSC. We observed that a nanotopological plate, 70 nm in diameter, significantly induces osteogenic differentiation with the activation of TAZ. TAZ activation via the nanotopological plate was mediated by actin polymerization and Rho signaling, as evidenced by the cytosolic localization of TAZ under F-actin or Rho kinase inhibitor. The FAK and MAPK pathways also play a role in TAZ activation by the nanotopological plate because the inhibitor of ERK and JNK blocked nanopattern plate induced osteogenic differentiation. Taken together, these results indicate that nanotopology regulates cell differentiation through TAZ activation.

Steroidomics, an analytical technique for steroid biomarker mining, has received much attention in recent years. This systematic review and functional analysis, following the PRISMA statement, aims to provide a comprehensive review and an appraisal of the developments and fundamental issues in steroid high-throughput analysis, with a focus on cancer research. We also discuss potential pitfalls and proposed recommendations for steroidomics-based clinical research. Forty-five studies met our inclusion criteria, with a focus on 12 types of cancer. Most studies focused on cancer risk prediction, followed by diagnosis, prognosis, and therapy monitoring. Prostate cancer was the most frequently studied cancer. Estradiol, dehydroepiandrosterone, and cortisol were mostly reported and altered in at least four types of cancer. Estrogen and estrogen metabolites were highly reported to associate with women-related cancers. Pathway enrichment analysis revealed that steroidogenesis; androgen and estrogen metabolism; and androstenedione metabolism were significantly altered in cancers. Our findings indicated that estradiol, dehydroepiandrosterone, cortisol, and estrogen metabolites, among others, could be considered oncosteroids. Despite noble achievements, significant shortcomings among the investigated studies were small sample sizes, cross-sectional designs, potential confounding factors, and problematic statistical approaches. More efforts are required to establish standardized procedures regarding study design, analytical procedures, and statistical inference.

Mesenchymal stem cell (MSC) differentiation is regulated by the extracellular matrix (ECM) through activation of intracellular signaling mediators. The stiffness of the ECM was shown to be an important regulatory factor for MSC differentiation, and transcriptional coactivator with PDZ-binding motif (TAZ) was identified as an effector protein for MSC differentiation. However, the detailed underlying mechanism regarding the role of ECM stiffness and TAZ in MSC differentiation is not yet fully understood. In this report, we showed that ECM stiffness regulates MSC fate through ERK or JNK activation. Specifically, a stiff hydrogel matrix stimulates osteogenic differentiation concomitant with increased nuclear localization of TAZ, but inhibits adipogenic differentiation. ERK and JNK activity was significantly increased in cells cultured on a stiff hydrogel. TAZ activation was induced by ERK or JNK activation on a stiff hydrogel because exposure to an ERK or JNK inhibitor significantly decreased the nuclear localization of TAZ, indicating that ECM stiffness-induced ERK or JNK activation is important for TAZ-driven osteogenic differentiation. Taken together, these results suggest that ECM stiffness regulates MSC differentiation through ERK or JNK activation.

T-Bet (T-box protein expressed in T cells, also called as TBX21) was originally cloned as a key transcription factor involved in the commitment of T helper (Th) cells to the Th1 lineage. T-Bet directly activates IFN-γ gene transcription and enhances development of Th1 cells. T-Bet simultaneously modulates IL-2 and Th2 cytokines in an IFN-γ-independent manner, resulting in an attenuation of Th2 cell development. Numerous studies have demonstrated that T-bet plays multiple roles in many subtypes of immune cells, including B cell, dendritic cells, natural killer (NK) cells, NK T cells, and innate lymphoid cells. Therefore, T-bet is crucial for the development and coordination of both innate and adaptive immune responses. To fulfill these multiple roles, T-bet undergoes several posttranslational protein modifications, such as phosphorylation at tyrosine, serine, and threonine residues, and ubiquitination at lysine residues, which affect lineage commitment during Th cell differentiation. This review presents a current overview of the progress made in understanding the roles of various types of T-bet protein modifications in the regulation of cytokine production during Th cell differentiation.

Shear stress activates cellular signaling involved in cellular proliferation, differentiation, and migration. However, the mechanisms of mesenchymal stem cell (MSC) differentiation under interstitial flow are not fully understood. Here, we show the increased osteogenic differentiation of MSCs under exposure to constant, extremely low shear stress created by osmotic pressure-induced flow in a microfluidic chip. The interstitial level of shear stress in the proposed microfluidic system stimulated nuclear localization of TAZ (transcriptional coactivator with PDZ-binding motif), a transcriptional modulator of MSCs, activated TAZ target genes such as CTGF and Cyr61, and induced osteogenic differentiation. TAZ-depleted cells showed defects in shear stress-induced osteogenic differentiation. In shear stress induced cellular signaling, Rho signaling pathway was important forthe nuclear localization of TAZ. Taken together, these results suggest that TAZ is an important mediator of interstitial flow-driven shear stress signaling in osteoblast differentiation of MSCs.

It is believed that the inherent differentiation program of melanocytes during embryogenesis predisposes melanoma cells to high frequency of metastasis. Sox10, a transcription factor expressed in neural crest stem cells and a subset of progeny lineages, plays a key role in the development of melanocytes. We show that B16F10 melanoma cells transfected with siRNAs specific for Sox10 display reduced migratory activity which in turn indicated that a subset of transcriptional regulatory target genes of Sox10 is likely to be involved in migration and metastasis of melanoma cells. We carried out a microarray-based gene expression profiling using a Sox10-specific siRNA to identify relevant regulatory targets and found that multiple genes including melanocortin-1 receptor (Mc1r) partake in the regulation of migration. We provide evidences that the effect of Sox10 on migration is mediated in large part by Mitf, a transcription factor downstream to Sox10. Among the mouse melanoma cell lines examined, however, only B16F10 showed robust down-regulation of Sox10 and inhibition of cell migration indicating that further dissection of dosage effects and/or cell line-specific regulatory networks is necessary. The involvement of Mc1r in migration was studied in detail in vivo using a murine metastasis model. Specifically, B16F10 melanoma cells treated with a specific siRNA showed reduced tendency in metastasizing to and colonizing the lung after being injected in the tail vein. These data reveal a cadre of novel regulators and mediators involved in migration and metastasis of melanoma cells that represents potential targets of therapeutic intervention.

Increasing evidence that decreased bone density and increased rates of bone fracture are associated with abnormal metabolic states such as hyperglycemia and insulin resistance indicates that diabetes is a risk factor for osteoporosis. In this study, we observed that TallyHo/JngJ (TH) mice, a polygenic model of type II diabetes, spontaneously developed bone deformities with osteoporotic features. Female and male TH mice significantly gained more body weight than control C57BL/6 mice upon aging. Interestingly, bone density was considerably decreased in male TH mice, which displayed hyperglycemia. The osteoblast-specific bone forming markers osteocalcin and osteoprotegerin were decreased in TH mice, whereas osteoclast-driven bone resorption markers such as IL-6 and RANKL were significantly elevated in the bone marrow and blood of TH mice. In addition, RANKL expression was prominently increased in CD4+ T cells of TH mice upon T cell receptor stimulation, which was in accordance with enhanced IL-17 production. IL-17 production in CD4+ T cells was directly promoted by treatment with leptin while IFN-γ production was not. Moreover, blockade of IFN-γ further increased RANKL expression and IL-17 production in TH-CD4+ T cells. In addition, the osteoporotic phenotype of TH mice was improved by treatment with alendronate. These results strongly indicate that increased leptin in TH mice may act in conjunction with IL-6 to preferentially stimulate IL-17 production in CD4+ T cells and induce RANKL-mediated osteoclastogenesis. Accordingly, we propose that TH mice could constitute a beneficial model for osteoporosis.

BACKGROUND:Translationally Controlled Tumor Protein (TCTP) found in nasal lavage fluids of allergic patients was named IgE-dependent histamine-releasing factor (HRF). Human recombinant HRF (HrHRF) has been recently reported to be much less effective than HRF produced from activated mononuclear cells (HRFmn). METHODS AND FINDINGS:We found that only NH(2)-terminal truncated, but not C-terminal truncated, TCTP shows cytokine releasing activity compared to full-length TCTP. Interestingly, only NH(2)-terminal truncated TCTP, unlike full-length TCTP, forms dimers through intermolecular disulfide bonds. We tested the activity of dimerized full-length TCTP generated by fusing it to rabbit Fc region. The untruncated-full length protein (Fc-HrTCTP) was more active than HrTCTP in BEAS-2B cells, suggesting that dimerization of TCTP, rather than truncation, is essential for the activation of TCTP in allergic responses. We used confocal microscopy to evaluate the affinity of TCTPs to its putative receptor. We detected stronger fluorescence in the plasma membrane of BEAS-2B cells incubated with Del-N11TCTP than those incubated with rat recombinant TCTP (RrTCTP). Allergenic activity of Del-N11TCTP prompted us to see whether the NH(2)-terminal truncated TCTP can induce allergic airway inflammation in vivo. While RrTCTP had no influence on airway inflammation, Del-N11TCTP increased goblet cell hyperplasia in both lung and rhinal cavity. The dimerized protein was found in sera from allergic patients, and bronchoalveolar lavage fluids from airway inflamed mice. CONCLUSIONS:Dimerization of TCTP seems to be essential for its cytokine-like activity. Our study has potential to enhance the understanding of pathogenesis of allergic disease and provide a target for allergic drug development.

BACKGROUND:Extracellular translationally controlled tumor protein (TCTP) is known to play a role in human allergic responses. TCTP has been identified outside of macrophages, in activated mononuclear cells, and in biological fluids from allergic patients. Even TCTP devoid of signal sequences, is secreted to extracellular environment by an yet undefined mechanism. This study is aimed at understanding the mechanism of TCTP release and its regulation. A secondary goal is to see if inhibitors of TCTP release can serve as potential anti-allergic asthmatic drugs. METHODOLOGY/PRINCIPAL FINDINGS:Using Western blotting assay in HEK293 and U937 cells, we found that TCTP secretion is reduced by omeprazole and pantoprazole, both of which are proton pump inhibitors. We then transfected HEK293 cells with proton pump expression vectors to search for the effects of exogeneously overexpressed H(+)/K(+)-ATPase on the TCTP secretion. Based on these in vitro data we checked the in vivo effects of pantoprazole in a murine model of ovalbumin-induced allergy. Omeprazole and pantoprazole reduced TCTP secretion from HEK293 and U937 cells in a concentration-dependent fashion and the secretion of TCTP from HEK293 cells increased when they over-expressed H(+)/K(+)-ATPase. In a murine model of ovalbumin-induced allergy, pretreatment with pantoprazole reduced infiltration of inflammatory cells, increased goblet cells, and increased TCTP secretion induced by OVA challenge. CONCLUSION:Since Omeprazole and pantoprazole decrease the secretion of TCTP which is associated with the development of allergic reaction, they may have the potential to serve as anti-allergic (asthmatic) drugs.

The growth kinetics of nominally one-monolayer (~1-ML)-thick InN wells on/in the +c-GaN matrix fabricated using dynamic atomic layer epitaxy (D-ALEp) by plasma-assisted molecular beam epitaxy were systematically studied, with particular attention given to the impacts of excess In atoms and/or In droplets at a high growth temperature of 650 °C. Even at a constant growth temperature of 650 °C, the thickness of the sheet-island-like InN-well layers could be controlled/varied from 1-ML to 2-ML owing to the effect of excess In atoms and/or In droplets accumulated during growth. The possible growth mechanism is discussed based on the ring-shaped bright cathodoluminescence emissions introduced along the circumference of the In droplets during growth. The effective thermal stability of N atoms below the bilayer adsorbed In atoms was increased by the presence of In droplets, resulting in the freezing of 2-ML-thick InN wells into the GaN matrix. It therefore became possible to study the difference between the emission properties of 1-ML and 2-ML-thick InN wells/GaN matrix quantum wells (QWs) having similar GaN matrix crystallinity grown at the same temperature. InN/GaN QW-samples grown under widely different In+N* supply conditions characteristically separated into two groups with distinctive emission-peak wavelengths originating from 1-ML and 2-ML-thick InN wells embedded in the GaN matrix. Reflecting the growth mechanism inherent to the D-ALEp of InN on/in the +c-GaN matrix at high temperature, either 1-ML or 2-ML-thick "binary" InN well layers tended to be frozen into the GaN matrix rather InGaN random ternary-alloys. Both the structural quality and uniformity of the 1-ML InN well sample were better than those of the 2-ML InN well sample, essentially owing to the quite thin critical thickness of around 1-ML arising from the large lattice mismatch of InN and GaN. [ABSTRACT FROM AUTHOR]

The growth kinetics and properties of nominally 1-ML (monolayer)-thick InN wells on/in +c-GaN matrix fabricated using dynamic atomic layer epitaxy (D-ALEp) by plasma-assisted molecular beam epitaxy were systematically studied, with particular attention given to the effects of growth temperature. Attention was also given to how and where the ∼1-ML-thick InN layers were frozen or embedded on/in the +c-GaN matrix. The D-ALEp of InN on GaN was a two-stage process; in the 1st stage, an "In+N" bilayer/monolayer was formed on the GaN surface, while in the 2nd, this was capped by a GaN barrier layer. Each process was monitored in-situ using spectroscopic ellipsometry. The target growth temperature was above 620 °C and much higher than the upper critical epitaxy temperature of InN (∼500 °C). The "In+N" bilayer/monolayer tended to be an incommensurate phase, and the growth of InN layers was possible only when they were capped with a GaN layer. The InN layers could be coherently inserted into the GaN matrix under self-organizing and self-limiting epitaxy modes. The growth temperature was the most dominant growth parameter on both the growth process and the structure of the InN layers. Reflecting the inherent growth behavior of D-ALEp grown InN on/in +c-GaN at high growth temperature, the embedded InN layers in the GaN matrix were basically not full-ML in coverage, and the thickness of sheet-island-like InN layers was essentially either 1-ML or 2-ML. It was found that these InN layers tended to be frozen at the step edges on the GaN and around screw-type threading dislocations. The InN wells formed type-I band line-up heterostructures with GaN barriers, with exciton localization energies of about 300 and 500meV at 15K for the 1-ML and 2-ML InN wells, respectively. [ABSTRACT FROM AUTHOR]