Abstract
The TMEPAI family, composed of TMEPAI and C18ORF1, is known to inhibit transforming growth factor-β (TGF-β) signalling via its competition for binding of receptor-regulated Smad with Smad ...anchor for receptor activation. However, TMEPAI has also been reported to be involved in androgen receptor signalling, phosphatase and tensin homologue deleted on chromosome 10 signalling, and formation of autophagosomes in addition to degradation of TβRI (TGF-β type I receptor) through lysosomes. Thus, TMEPAI seems to act as a regulator of multiple signalling pathways. A great deal of attention has already been paid to the relationship between the TMEPAI family and tumourigenicity. In this paper, therefore, we describe recent progresses in the understanding of how the TMEPAI family physiologically contributes to cellular functions and diseases.
Approximately 60 years ago in England, phototherapy for neonatal hyperbilirubinemia was used in clinical practice. It was introduced in Japan approximately 50 years ago. At that time, the mechanism ...underlying the serum bilirubin concentration decrease by phototherapy was still unknown. The mechanism was identified by chemists, biochemists, and pediatricians. Clarification started with the report that unconjugated bilirubin was excreted into bile after photoirradiation in Gunn rats. After confirmation of the molecular structure of bilirubin on X‐ray analysis, the mechanism for bile excretion of unconjugated bilirubin was verified based on geometric configurational photoisomers in the Gunn rat. Finally, the reaction and excretion of structural bilirubin photoisomers was proved to be the main mechanism for the decrease in serum bilirubin during phototherapy for neonatal hyperbilirubinemia, which differs from the mechanism in the Gunn rat. The most effective and safest light source and the optimal method to evaluate phototherapy, however, remain unknown. Moreover, as for bronze baby syndrome, which is a well‐known adverse reaction to phototherapy, the etiology is unclear. Hence, we review phototherapy for hyperbilirubinemia including a fundamental understanding of the bilirubin photochemical reactions, and discuss the subclinical carcinogenic risk of phototherapy and the increased mortality rate of extremely low‐birthweight infants due to aggressive phototherapy, which is becoming an increasing problem.
Phototherapy using light-emitting diodes (LEDs) centered on the green spectrum, which has a high cyclobilirubin production rate, was as effective as that centered on the blue spectrum for neonatal ...hyperbilirubinemia. There are no reports of species differences in bilirubin photochemical changes in this spectrum, and the characteristics of bilirubin photochemical changes in humans must be elucidated to proceed with the development of new light sources that include these spectra. This report describes the characteristic photochemical kinetics of bilirubin under green-spectrum LEDs in human, rat, rabbit, dog, pig, sheep, bovine and chicken serum albumin and rhesus monkey serum. These albumin-bilirubin complex solutions were irradiated by green LEDs, and the time-course changes in bilirubin photoisomers were measured by high-performance liquid chromatography. The cyclobilirubin production rates in humans, pigs, and monkeys were significantly higher than those in other species. The rate constant of (EZ)-cyclobilirubin production from (EZ)-bilirubin 'k' was significantly higher in humans and monkeys than in other species. In conclusion, bilirubin photochemical kinetics under green spectrum LEDs in humans were characterized by a high cyclobilirubin production rate at a low substrate concentration. The bilirubin photochemical kinetics in monkeys were similar to those in humans.
Abstract
Dysregulated yes-associated protein (YAP) is involved in several malignant cancers. However, discovering a druggable YAP inhibitor(s) is difficult because YAP itself does not have any ...enzymatic activity. In such cases, targeted protein degradation strategies based on hybrid molecules that bind to the target protein and an E3 ubiquitin ligase are useful for suppressing proteins that exhibit aberrant activation and/or excessive expression. Upon screening YAP-interacting small compounds, we identified HK13, a platanic acid, as a novel compound that interacts with YAP. Next, we synthesized hybrid compounds of platanic acid and LCL-161, which reportedly shows a high affinity for cIAP, one of E3 ubiquitin ligases. Among these compounds, HK24 possessed the ability to inhibit the growth of YAP overexpressing NCI-H290 cells. This inhibitory activity may be mediated by YAP degradation, although HK24 exhibited weak YAP degradation. Furthermore, we confirmed involvement of proteasome pathway in HK24-dependent YAP degradation by culturing NCI-H290 cells in the presence of a proteasome inhibitor. Therefore, it is possible that platanic acid is a potential candidate for molecular medicine targeting YAP.
Graphical Abstract
Graphical Abstract
In Uzbekistan,
Ephedra distachya
L.,
E. equisetina
Bunge,
E. foliata
Boiss. ex C. A. Mey.,
E. lomatolepis
Schrenk, and
E. strobilacea
Bunge show species specificity for habitat environments and ...physical and chemical characteristics of habitat soils. Furthermore, the relationship between soil characteristics and ephedrine and pseudoephedrine contents was examined.
E. distachya
was found growing from 80 to 200 m above sea level (a.s.l) in the Plateau Ustyurt on the desert steppe of cliffs on soil having relatively higher loss on ignition (19.8–33.8%) and water-soluble cations (Ca
2+
, 5.14–133.13; Mg
2+
, 0.85–3.18; and Na
+
, 2.27–8.33 mmol/100 g dry soil weight) than for other
Ephedra
habitats.
E. strobilacea
was found growing on the flat sandy Kyzylkum desert at 94 m a.s.l. and had habitat soil that was the driest with the lowest loss on ignition (2.9%) and highest Na
+
(9.05 mmol/100 g dry soil weight) of all the
Ephedra
habitat soils. On dry steppe from 1054 to 1819 m a.s.l.,
E. foliata
,
E. lomatolepis
, and
E. equisetina
formed not only a single community but also a complex community on constantly collapsing sandy gravel slope with relatively higher Ca
2+
(3.40–17.44 mmol/100 g dry soil weight) soil content. Notably,
E. equisetina
grew on the dry steppe of constantly collapsing sandy gravel slopes, in rocky areas, on sandy gravel floodplains of rivers, and on stable humus soil at the base of coniferous trees in a wide range of habitats from dry steppe to coniferous forest zones at altitudes ranging from 1392 to 1819 m a.s.l., as reflected in the greater variability than for other
Ephedra
habitats in the parameters of loss on ignition (1.4–34.8%), pH (7.1–9.6), NO
3
−
(0.08–35.17 mmol/100 g dry soil weight), Ca
2+
(0.24–17.44 mmol/100 g dry soil weight), Mg
2+
(not detected–1.25 mmol/100 g dry soil weight), and Na
+
(0.13–5.19 mmol/100 g dry soil weight). Ephedrine alkaloids were not detectable in
E. strobilacea
,
E. foliata
, and
E. lomatolepis
. Almost all
E. distachya
contained only pseudoephedrine (1.25–1.59% of dry weight, %DW), while
E. equisetina
contained from 1.31 to 2.05%DW ephedrine and from 1.29 to 2.80%DW pseudoephedrine. Ephedrine and pseudoephedrine in
E. equisetina
showed a statistically significant negative correlation with soil Cl
−
and Mg
2+
, respectively.
The direct aldol reaction between a protected dihydroxyacetone derivative and 4-nitrobenzaldehyde catalyzed by chiral Zn2+ complexes of 1-(n-carboxylalkyl)-7-aminoacyl-1,4,7,10-tetraazacyclododecane ...is reported. New Zn2+ complexes containing l-histidine and carboxylalkyl chains that mimic a class II aldolase, carboxypeptidase A and a serine protease were designed and synthesized. Syn-aldol products were mainly formed by an aldol reaction of acetonide-protected dihydroxyacetone with benzaldehydes and other benzaldehydes in N-methylpyrrolidone (NMP)/alcohol (MeOH, EtOH or 2-PrOH) in good yields with a high degree of diastereo- and enantioselectivity (56%∼quant., 57∼>99% ee). Mechanistic aspect based on ESI-HRMS, elemental analysis and pH titrations of model ligands is also discussed.
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TMEPAI/PMEPA1 is a transmembrane protein that was originally identified as a prostatic RNA, the synthesis of which is induced by testosterone or its derivatives. We have recently identified TMEPAI as ...a direct target gene of transforming growth factor‐β (TGF‐β)/Smad signaling that participates in negative feedback control of the duration and intensity of TGF‐β/Smad signaling. TMEPAI is constitutively and highly expressed in many types of cancer and is associated with poor prognosis. Here, we report that TMEPAI is highly expressed in the lung adenocarcinoma cell lines Calu3, NCI‐H23, and RERF‐LC‐KJ. Expression of TMEPAI in these cancer cells was significantly suppressed by a TGF‐β receptor kinase antagonist, SB208, and by TGF‐β neutralizing antibodies. These results suggest that constitutive expression of TMEPAI in these cancer cells depends on autocrine TGF‐β stimulation. Knockdown of TMEPAI in Calu3 and NCI‐H23 cells enhanced levels of Smad2 phosphorylation and significantly suppressed cell proliferation in the presence of TGF‐β, indicating that highly expressed TMEPAI suppresses levels of Smad phosphorylation in these cancer cells and reduces the growth inhibitory effects of TGF‐β/Smad signaling. Furthermore, knockdown of TMEPAI in Calu3 and NCI‐H23 cells suppressed sphere formation in vitro and tumor formation in s.c. tissues and in lungs after tail vein injection in NOD‐SCID mice in vivo. Together, these experiments indicate that TMEPAI promotes tumorigenic activities in lung cancer cells.
TMEPAI is constitutively expressed in lung adenocarcinoma cell lines. Knockdown of TMEPAI significantly reduced tumorigenic activities of these cells.
Development of novel small molecules that selectively degrade pathogenic proteins would provide an important advance in targeted therapy. Recently, we have devised a series of hybrid small molecules ...named SNIPER (specific and nongenetic IAP-dependent protein ERaser) that induces the degradation of target proteins via the ubiquitin-proteasome system. To understand the localization of proteins that can be targeted by this protein knockdown technology, we examined whether SNIPER molecules are able to induce degradation of cellular retinoic acid binding protein II (CRABP-II) proteins localized in subcellular compartments of cells. CRABP-II is genetically fused with subcellular localization signals, and they are expressed in the cells. SNIPER(CRABP) with different IAP-ligands, SNIPER(CRABP)-4 with bestatin and SNIPER(CRABP)-11 with MV1 compound, induce the proteasomal degradation of wild-type (WT), cytosolic, nuclear, and membrane-localized CRABP-II proteins, whereas only SNIPER(CRABP)-11 displayed degradation activity toward the mitochondrial CRABP-II protein. The small interfering RNA-mediated silencing of cIAP1 expression attenuated the knockdown activity of SNIPER(CRABP) against WT and cytosolic CRABP-II proteins, indicating that cIAP1 is the E3 ligase responsible for degradation of these proteins. Against membrane-localized CRABP-II protein, cIAP1 is also a primary E3 ligase in the cells, but another E3 ligase distinct from cIAP2 and X-linked inhibitor of apoptosis protein (XIAP) could also be involved in the SNIPER(CRABP)-11-induced degradation. However, for the degradation of nuclear and mitochondrial CRABP-II proteins, E3 ligases other than cIAP1, cIAP2, and XIAP play a role in the SNIPER-mediated protein knockdown. These results indicate that SNIPER can target cytosolic, nuclear, membrane-localized, and mitochondrial proteins for degradation, but the responsible E3 ligase is different, depending on the localization of the target protein.
This paper proposes a lossless coding method for HDR color images stored in a floating point format called Radiance RGBE. In this method, three mantissa and a common exponent parts, each of which is ...represented in 8-bit depth, are encoded using the block-adaptive prediction technique with some modifications considering the data structure.
We previously found that TCF7L2 could activate the TMEPAI gene efficiently, whereas LEF1 could not nearly augment its transcription. When we comprehended the functional difference(s) between TCF7L2 ...and LEF1 with respect to the activation of the TMEPAI gene, the C-terminal tail of TCF7L2 was needed to reveal its transcriptional activity as well as its interaction with Smad3. Consistently, both TCF7/TCF7L2 and LEF1/TCF7L2 chimeric proteins exhibited an activity similar to TCF7L2 in transcription and Smad3 binding in contrast with LEF1 and TCF7. Our data elaborated on the diverse activity among TCF/LEF family members with respect to the transcriptional regulation of the TMEPAI gene.
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