Feeding activates FGF15-SHP-TFEB-mediated lipophagy in the gut.

Lysosome-mediated macroautophagy, including lipophagy, is activated under nutrient deprivation but is repressed after feeding. We show that, unexpectedly, feeding activates intestinal autophagy/lipophagy in a manner dependent on both the orphan nuclear receptor, small heterodimer partner (SHP/NR0B2), and the gut hormone, fibroblast growth factor-15/19 (FGF15/19). Furthermore, postprandial intestinal triglycerides (TGs) and apolipoprotein-B48 (ApoB48), the TG-rich chylomicron marker, were elevated in SHP-knockout and FGF15-knockout mice. Genomic analyses of the mouse intestine indicated that SHP partners with the key lysosomal activator, transcription factor-EB (TFEB) to upregulate the transcription of autophagy/lipolysis network genes after feeding. FGF19 treatment activated lipophagy, reducing TG and ApoB48 levels in HT29 intestinal cells, which was dependent on TFEB. Mechanistically, feeding-induced FGF15/19 signaling increased the nuclear localization of TFEB and SHP via PKC beta/zeta-mediated phosphorylation, leading to increased transcription of the TFEB/SHP target lipophagy genes, Ulk1 and Atgl. Collectively, these results demonstrate that paradoxically after feeding, FGF15/19-activated SHP and TFEB activate gut lipophagy, limiting postprandial TGs. As excess postprandial lipids cause dyslipidemia and obesity, the FGF15/19-SHP-TFEB axis that reduces intestinal TGs via lipophagic activation provides promising therapeutic targets for obesity-associated metabolic disease.

Surface termination modulation for superior S-Scheme Bi2WO6/BiOI heterojunction photocatalyst: a hybrid density functional study.

The prevailing theoretical frameworks indicate that depending on the growth conditions, the Bi2WO6(001) surface can manifest in three distinct terminations-DL-O-Bi (DL: double layers), O-Bi, and O-W. In this study, we conduct a comprehensive examination of the interplay between these terminations on Bi2WO6(001) and the 1I-terminated BiOI(001) facet, especially focusing on their impact on the photocatalytic activity of Bi2WO6/BiOI heterostructure, applying hybrid functional calculations. The models formulated for this research are designated as Bi2WO6(O-Bi)/BiOI(1I), Bi2WO6(DL-O-Bi)/BiOI(1I), and Bi2WO6(O-W)/BiOI(1I). Our findings reveal that Bi2WO6(O-Bi)/BiOI(1I) shows a type II band alignment, which facilitates the spatial separation of photo-generated electrons and holes. Notably, the Bi2WO6(DL-O-Bi)/BiOI(1I) configuration has the lowest binding energy and results in an S-scheme (or Step-scheme) heterostructure. In contrast to the type II heterostructure, this particular configuration demonstrates enhanced photocatalytic efficiency due to improved photo-generated carrier separation, augmented oxidation capability, and better visible-light absorption. Conversely, Bi2WO6(O-W)/BiOI(1I) presents a type I projected band structure, which is less conducive for the separation of photo-generated electron-hole pairs. In summation, this investigation points out that one could significantly refine the photocatalytic efficacy of not only Bi2WO6/BiOI but also other heterostructure photocatalysts by modulating the coupling of different terminations via precise crystal synthesis or growth conditions.

The direct Z-scheme character and roles of S vacancy in BiOCl/Bi2S3-(001) heterostructures for superior photocatalytic activity: a hybrid density functional investigation.

Given some current speculations and controversies regarding the type of BiOCl/Bi2S3-(001) heterostructure in experiments, it is of great importance to clarify these controversies and further explain the relevant experimental results. In this work, based on first-principles hybrid density functional calculations, it is verified that the BiOCl/Bi2S3-(001) heterostructure is a direct Z-scheme photocatalyst with high photo-generated carrier separation efficiency and strong redox ability that can react with O2 and OH- to produce photocatalytic active species of superoxide ions (˙O2-) and hydroxyl radicals (˙OH), respectively. This is consistent with the experimental findings and explains the excellent photocatalytic performance of the BiOCl/Bi2S3-(001) heterostructure in experiments. Besides, excitingly, it is found that the optical absorption, built-in electric field intensity, interlayer recombination probability, hydrogen evolution reaction ability, and the difference in electron-hole mobility are further enhanced via S vacancy introduction in BiOCl/Bi2S3-(001). Therefore, the significant roles of S vacancy in further improving the photocatalytic properties of the BiOCl/Bi2S3-(001) heterostructure are profoundly revealed. This work can provide valuable theoretical insights for designing the superior direct Z-scheme BiOCl/VS-Bi2S3-(001) heterostructure with promising photocatalytic properties.

Recent advances in targeted protein degraders as potential therapeutic agents.

Targeted protein degradation (TPD) technology has gradually become widespread in the past 20 years, which greatly boosts the development of disease treatment. Contrary to small inhibitors that act on protein kinases, transcription factors, ion channels, and other targets they can bind to, targeted protein degraders could target "undruggable targets" and overcome drug resistance through ubiquitin-proteasome pathway (UPP) and lysosome pathway. Nowadays, some bivalent degraders such as proteolysis-targeting chimeras (PROTACs) have aroused great interest in drug discovery, and some of them have successfully advanced into clinical trials. In this review, to better understand the mechanism of degraders, we elucidate the targeted protein degraders according to their action process, relying on the ubiquitin-proteasome system or lysosome pathway. Then, we briefly summarize the study of PROTACs employing different E3 ligases. Subsequently, the effect of protein of interest (POI) ligands, linker, and E3 ligands on PROTAC degradation activity is also discussed in detail. Other novel technologies based on UPP and lysosome pathway have been discussed in this paper such as in-cell click-formed proteolysis-targeting chimeras (CLIPTACs), molecular glues, Antibody-PROTACs (Ab-PROTACs), autophagy-targeting chimeras, and lysosome-targeting chimeras. Based on the introduction of these degradation technologies, we can clearly understand the action process and degradation mechanism of these approaches. From this perspective, it will be convenient to obtain the development status of these drugs, choose appropriate degradation methods to achieve better disease treatment and provide basis for future research and simultaneously distinguish the direction of future research efforts.

In vitro induction of tetraploidy and its effects on phenotypic variations in Populus hopeiensis.

BACKGROUND: Artificial induction of polyploidy is the most common and effective way to improve the biological properties of Populus and develop new varieties of this tree. In this study, in order to confirm and expand earlier findings, we established a protocol using colchicine and based on an efficient shoot regeneration system of leaf blades to induce tetraploidy in vitro in three genotypes from diploid Populus hopeiensis. The stomatal characteristics, leaf blade size, and growth were evaluated for diploids and tetraploids of three genotypes. RESULTS: We found that genotype, preculture duration, colchicine concentration, and colchicine exposure time had highly significant effects on the tetraploid induction rate. The optimal protocol for inducing tetraploidy in P. hopeiensis was to preculture leaf blades for 7 days and then treat them for 4 days with 40 mg/L colchicine. The tetraploid induction rates of genotypes BT1, BT3, and BT8 were 21.2, 11.4 and 16.7%, respectively. A total of 136 tetraploids were identified by flow cytometry analysis and somatic chromosome counting. The stomatal length, width, and density of leaf blades significantly differed between diploid and tetraploid plants. Compared with their diploid counterparts, the tetraploids produced larger leaf blades and had a slower growth rate. Our findings further document the modified morphological characteristics of P. hopeiensis following whole-genome duplication (e.g., induced tetraploidy). CONCLUSIONS: We established a protocol for in vitro induction of tetraploidy from diploid leaf blades treated with colchicine, which can be applied to different genotypes of P. hopeiensis.

Microsporogenesis in the triploid hybrid 'Beilinxiongzhu 1#' and detection of primary trisomy in 2x × 3 × Populus hybrids.

BACKGROUND: Primary trisomy is a powerful genetic tool in plants. However, trisomy has not been detected in Populus as a model system for tree and woody perennial plant biology. RESULTS: In the present study, a backcross between Populus alba × Populus glandulosa 'YXY 7#' (2n = 2x = 38) and the triploid hybrid 'Beilinxiongzhu 1#' (2n = 3x = 57) based on the observation of microsporogenesis and an evaluation of the variations in pollen was conducted to create primary trisomy. Many abnormalities, such as premature migration of chromosomes, lagging of chromosomes, chromosome bridges, asymmetric separation, micronuclei, and premature cytokinesis, have been detected during meiosis of the triploid hybrid clone 'Beilinxiongzhu 1#'. However, these abnormal behaviors did not result in completely aborted pollen. The pollen diameter of the triploid hybrid clone 'Beilinxiongzhu 1#' is bimodally distributed, which was similar to the chromosomal number of the backcross progeny. A total of 393 progeny were generated. We provide a protocol for determining the number of chromosomes in aneuploid progeny, and 19 distinct simple sequence repeat (SSR) primer pairs covering the entire Populus genome were developed. Primary trisomy 11 and trisomy 17 were detected in the 2x × 3 x hybrid using the SSR molecular markers and counting of somatic chromosomes. CONCLUSIONS: Nineteen distinct SSR primer pairs for determining chromosomal number in aneuploid individuals were developed, and two Populus trisomies were detected from 2x × 3 x hybrids by SSR markers and somatic chromosome counting. Our findings provide a powerful genetic tool to reveal the function of genes in Populus.

Heat shock-induced failure of meiosis I to meiosis II transition leads to 2n pollen formation in a woody plant.

The formation of diploid gametes through chromosome doubling is a major mechanism of polyploidization, diversification, and speciation in plants. Unfavorable climate conditions can induce or stimulate the production of diploid gametes during meiosis. Here, we demonstrated that heat shock stress (38°C for 3 or 6 h) induced 2n pollen formation, and we generated 42 triploids derived from heat shock-induced 2n pollen of Populus canescens. Meiotic analysis of treated pollen mother cells revealed that induced 2n pollen originated from the complete loss of meiosis II (MII). Among the 42 triploids, 38 triploids derived from second division restitution (SDR)-type 2n pollen and 4 triploids derived from first division restitution-type 2n pollen were verified using simple sequence repeats (SSR) molecular markers. Twenty-two differentially expressed genes related to the cell cycle were identified and characterized by expression profile analysis. Among them was POPTR_0002s08020g (PtCYCA1;2), which encodes a type A Cyclin CYCA1;2 that is required for the meiosis I (MI) to MII transition. After male flower buds were exposed to heat shock, a significant reduction was detected in PtCYCA1;2 expression. We inferred that the failure of MI-to-MII transitions might be associated with downregulated expression of PtCYCA1;2, leading to the formation of SDR-type 2n pollen. Our findings provide insights into mechanisms of heat shock-induced 2n pollen formation in a woody plant and verify that sensitivity to environmental stress has evolutionary importance in terms of polyploidization.

Intrinsic point defects and the n- and p-type dopability in α- and ß-Bi2O3 photocatalysts.

In this work, all kinds of intrinsic point defects, unintentional N and H impurities and possible complex defects between impurities and native defects in α- and ß-Bi2O3 with different growth conditions are systematically investigated using hybrid density functional calculations. And then, the n- or p-type doping mechanisms in α- and ß-Bi2O3 are explored and discussed. It is found that α-Bi2O3 presents the n-type conductivity under O-poor conditions. The unintentional H interstitials as the shallow donors should be majorly responsible for the n-type conductivity character. While under O-rich conditions, α-Bi2O3 displays the p-type conductivity, and the unintentional complex defects VBi1 + 2H as the shallow acceptors should be the primary origins of the p-type conductivity. The hydrogenation of the Bi vacancy in α-Bi2O3 not only significantly lowers the formation energy of the Bi vacancy but also markedly decreases its acceptor transition level. This well explains the experimental observation that α-Bi2O3 changes from n-type to p-type conductivity with increasing O partial pressure. Compared to α-Bi2O3, ß-Bi2O3 always presents the n-type conductivity behaviour regardless of the growth conditions. The native O1 vacancies (VO1) and unintentional H interstitials in ß-Bi2O3 are shallow and excellent donors. They are responsible for the n-type conductivity and further perfectly explain the observed unintentional n-type conductivity character in ß-Bi2O3 experiments. Understanding the defect physics in α- and ß-Bi2O3 could inspire more significant studies on developing Bi2O3-based photocatalysts.

Defect physics of intrinsic point defects in BiPO4 photocatalysts: a hybrid functional study.

In this work, the intrinsic point defect properties of bulk BiPO4 under different growth conditions are intensively investigated and explored using first-principles hybrid functional calculations. It is found that Bi vacancies and O vacancies are the primary native defects in BiPO4. Under O-poor conditions, BiPO4 acts as an intrinsic insulator because the O vacancy defects (donor) and the Bi vacancy defects (acceptor) compensate for each other. Under Bi-poor conditions, good p-type conductivity is observed in BiPO4, which affirms the observed p-type conductivity behavior in experiments. Bi vacancies in BiPO4 are very shallow, which make it an excellent acceptor and are mostly responsible for the p-type character. In addition, it is found that the primary Bi vacancy defects of BiPO4 hardly affect its electronic structure and optical absorption spectrum regardless of the charge states. In contrast, the neutral O vacancy defects in BiPO4 introduce an impurity energy level near the VBM and induce a new optical absorption peak at around 370 nm. Furthermore, the O vacancies should be favorable for enhancing the production and separation efficiencies of the photo-generated electrons and holes in BiPO4. While Bi vacancies easily provide p-type carriers, simultaneously, they could become the active sites for the photocatalytic reactions because of their dominant -3 charge state. Therefore, understanding the defect physics in BiPO4 photocatalysts is believed to be beneficial for more research in developing BiPO4 or BiPO4-based photocatalysts.

SCL14 Inhibits the Functions of the NAC043-MYB61 Signaling Cascade to Reduce the Lignin Content in Autotetraploid Populus hopeiensis.

Whole-genome duplication often results in a reduction in the lignin content in autopolyploid plants compared with their diploid counterparts. However, the regulatory mechanism underlying variation in the lignin content in autopolyploid plants remains unclear. Here, we characterize the molecular regulatory mechanism underlying variation in the lignin content after the doubling of homologous chromosomes in Populus hopeiensis. The results showed that the lignin content of autotetraploid stems was significantly lower than that of its isogenic diploid progenitor throughout development. Thirty-six differentially expressed genes involved in lignin biosynthesis were identified and characterized by RNA sequencing analysis. The expression of lignin monomer synthase genes, such as PAL, COMT, HCT, and POD, was significantly down-regulated in tetraploids compared with diploids. Moreover, 32 transcription factors, including MYB61, NAC043, and SCL14, were found to be involved in the regulatory network of lignin biosynthesis through weighted gene co-expression network analysis. We inferred that SCL14, a key repressor encoding the DELLA protein GAI in the gibberellin (GA) signaling pathway, might inhibit the NAC043-MYB61 signaling functions cascade in lignin biosynthesis, which results in a reduction in the lignin content. Our findings reveal a conserved mechanism in which GA regulates lignin synthesis after whole-genome duplication; these results have implications for manipulating lignin production.

Deep-Learning-Based Mixture Identification for Nuclear Magnetic Resonance Spectroscopy Applied to Plant Flavors.

Nuclear magnetic resonance (NMR) is a crucial technique for analyzing mixtures consisting of small molecules, providing non-destructive, fast, reproducible, and unbiased benefits. However, it is challenging to perform mixture identification because of the offset of chemical shifts and peak overlaps that often exist in mixtures such as plant flavors. Here, we propose a deep-learning-based mixture identification method (DeepMID) that can be used to identify plant flavors (mixtures) in a formulated flavor (mixture consisting of several plant flavors) without the need to know the specific components in the plant flavors. A pseudo-Siamese convolutional neural network (pSCNN) and a spatial pyramid pooling (SPP) layer were used to solve the problems due to their high accuracy and robustness. The DeepMID model is trained, validated, and tested on an augmented data set containing 50,000 pairs of formulated and plant flavors. We demonstrate that DeepMID can achieve excellent prediction results in the augmented test set: ACC = 99.58%, TPR = 99.48%, FPR = 0.32%; and two experimentally obtained data sets: one shows ACC = 97.60%, TPR = 92.81%, FPR = 0.78% and the other shows ACC = 92.31%, TPR = 80.00%, FPR = 0.00%. In conclusion, DeepMID is a reliable method for identifying plant flavors in formulated flavors based on NMR spectroscopy, which can assist researchers in accelerating the design of flavor formulations.

mTORC1 and mTORC2 Converge on the Arp2/3 Complex to Promote KrasG12D-Induced Acinar-to-Ductal Metaplasia and Early Pancreatic Carcinogenesis.

BACKGROUND & AIMS: Oncogenic KrasG12D induces neoplastic transformation of pancreatic acinar cells through acinar-to-ductal metaplasia (ADM), an actin-based morphogenetic process, and drives pancreatic ductal adenocarcinoma (PDAC). mTOR (mechanistic target of rapamycin kinase) complex 1 (mTORC1) and 2 (mTORC2) contain Rptor and Rictor, respectively, and are activated downstream of KrasG12D, thereby contributing to PDAC. Yet, whether and how mTORC1 and mTORC2 impact on ADM and the identity of the actin nucleator(s) mediating such actin rearrangements remain unknown. METHODS: A mouse model of inflammation-accelerated KrasG12D-driven early pancreatic carcinogenesis was used. Rptor, Rictor, and Arpc4 (actin-related protein 2/3 complex subunit 4) were conditionally ablated in acinar cells to deactivate the function of mTORC1, mTORC2 and the actin-related protein (Arp) 2/3 complex, respectively. RESULTS: We found that mTORC1 and mTORC2 are markedly activated in human and mouse ADM lesions, and cooperate to promote KrasG12D-driven ADM in mice and in vitro. They use the Arp2/3 complex as a common downstream effector to induce the remodeling the actin cytoskeleton leading to ADM. In particular, mTORC1 regulates the translation of Rac1 (Rac family small GTPase 1) and the Arp2/3-complex subunit Arp3, whereas mTORC2 activates the Arp2/3 complex by promoting Akt/Rac1 signaling. Consistently, genetic ablation of the Arp2/3 complex prevents KrasG12D-driven ADM in vivo. In acinar cells, the Arp2/3 complex and its actin-nucleation activity mediated the formation of a basolateral actin cortex, which is indispensable for ADM and pre-neoplastic transformation. CONCLUSIONS: Here, we show that mTORC1 and mTORC2 attain a dual, yet nonredundant regulatory role in ADM and early pancreatic carcinogenesis by promoting Arp2/3 complex function. The role of Arp2/3 complex as a common effector of mTORC1 and mTORC2 fills the gap between oncogenic signals and actin dynamics underlying PDAC initiation.

AGR2-Dependent Nuclear Import of RNA Polymerase II Constitutes a Specific Target of Pancreatic Ductal Adenocarcinoma in the Context of Wild-Type p53.

BACKGROUND & AIMS: Promoted by pancreatitis, oncogenic KrasG12D triggers acinar cells' neoplastic transformation through acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia. Anterior gradient 2 (Agr2), a known inhibitor of p53, is detected at early stage of pancreatic ductal adenocarcinoma (PDAC) development. RNA polymerase II (RNAPII) is a key nuclear enzyme; regulation of its nuclear localization in mammalian cells represents a potential therapeutic target. METHODS: A mouse model of inflammation-accelerated KrasG12D-driven ADM and pancreatic intraepithelial neoplasia development was used. Pancreas-specific Agr2 ablation was performed to access its role in pancreatic carcinogenesis. Hydrophobic hexapeptides loaded in liposomes were developed to disrupt Agr2-RNAPII complex. RESULTS: We found that Agr2 is up-regulated in ADM-to-pancreatic intraepithelial neoplasia transition in inflammation and KrasG12D-driven early pancreatic carcinogenesis. Genetic ablation of Agr2 specifically blocks this metaplastic-to-neoplastic process. Mechanistically, Agr2 directs the nuclear import of RNAPII via its C-terminal nuclear localization signal, undermining the ATR-dependent p53 activation in ADM lesions. Because Agr2 binds to the largest subunit of RNAPII in a peptide motif-dependent manner, we developed a hexapeptide to interfere with the nuclear import of RNAPII by competitively disrupting the Agr2-RNAPII complex. This novel hexapeptide leads to dysfunction of RNAPII with concomitant activation of DNA damage response in early neoplastic lesions; hence, it dramatically compromises PDAC initiation in vivo. Moreover, the hexapeptide sensitizes PDAC cells and patient-derived organoids harboring wild-type p53 to RNAPII inhibitors and first-line chemotherapeutic agents in vivo. Of note, this therapeutic effect is efficient across various cancer types. CONCLUSIONS: Agr2 is identified as a novel adaptor protein for nuclear import of RNAPII in mammalian cells. Also, we provide genetic evidence defining Agr2-dependent nuclear import of RNAPII as a pharmaceutically accessible target for prevention and treatment in PDAC in the context of wild-type p53.

In vitro octaploid induction of Populus hopeiensis with colchicine.

BACKGROUND: Autopolyploids, especially artificial lines, provide model systems for understanding the mechanisms of gene dosage effects on trait variation owing to their relatively uniform genetic background. Here, a protocol for in vitro octaploid induction of Populus hopeiensis from leaf blades with colchicine treatment was established through investigation of the effects of different pre-culture durations, colchicine concentrations, and exposure times. RESULTS: We found that pre-culture duration, colchicine concentration, and exposure time had significant effects on the survival rate, shoot regeneration rate, and octaploid induction rate of P. hopeiensis leaf blades. The highest octaploid induction rate (8.61%) was observed when leaf blades pre-cultured for 9 days were treated for 4 days with 100 µM colchicine. The ploidy level of all regenerated plantlets was analyzed by flow cytometry and further confirmed by chromosome counting. A total of 14 octaploids were obtained. The stomatal length, width, and density of leaf blades significantly differed between tetraploid and octaploid plants. Compared with diploid and tetraploid plants, octaploids had a slower growth rate, smaller leaf blade size, and shorter internodes. CONCLUSIONS: We established an effective protocol for inducing octaploids in vitro from autotetraploid P. hopeiensis leaf blades by colchicine treatment.

Effects of Overexpression of Fibroblast Growth Factor 15/19 on Hepatic Drug Metabolizing Enzymes.

Fibroblast growth factors 15 (FGF15) and 19 (FGF19) are endocrine growth factors that play an important role in maintaining bile acid homeostasis. FGF15/19-based therapies are currently being tested in clinical trials for the treatment of nonalcoholic steatohepatitis and cholestatic liver diseases. To determine the physiologic impact of long-term elevations of FGF15/19, a transgenic mouse model with overexpression of Fgf15 (Fgf15 Tg) was used in the current study. The RNA sequencing (RNA-seq) analysis revealed elevations of the expression of several genes encoding phase I drug metabolizing enzymes (DMEs), including Cyp2b10 and Cyp3a11, in Fgf15 Tg mice. We found that the induction of several Cyp2b isoforms resulted in increased function of CYP2B in microsomal metabolism and pharmacokinetics studies. Because the CYP2B family is known to be induced by constitutive androstane receptor (CAR), to determine the role of CAR in the observed inductions, we crossed Fgf15 Tg mice with CAR knockout mice and found that CAR played a minor role in the observed alterations in DME expression. Interestingly, we found that the overexpression of Fgf15 in male mice resulted in a phenotypical switch from the male hepatic expression pattern of DMEs to that of female mice. Differences in secretion of growth hormone (GH) between male and female mice are known to drive sexually dimorphic, STAT5b-dependent expression patterns of hepatic genes. We found that male Fgf15 Tg mice presented with many features similar to GH deficiency, including lowered body length and weight, Igf-1 and Igfals expression, and STAT5 signaling. SIGNIFICANCE STATEMENT: The overexpression of Fgf15 in mice causes an alteration in DMEs at the mRNA, protein, and functional levels, which is not entirely due to CAR activation but associated with lower GH signaling.

Farnesoid X receptor regulates lung macrophage activation and injury following nitrogen mustard exposure.

Nitrogen mustard (NM) is a cytotoxic vesicant known to cause acute lung injury which progresses to fibrosis; this is associated with a sequential accumulation of pro- and anti-inflammatory macrophages in the lung which have been implicated in NM toxicity. Farnesoid X receptor (FXR) is a nuclear receptor involved in regulating lipid homeostasis and inflammation. In these studies, we analyzed the role of FXR in inflammatory macrophage activation, lung injury and oxidative stress following NM exposure. Wild-type (WT) and FXR-/- mice were treated intratracheally with PBS (control) or NM (0.08 mg/kg). Bronchoalveolar lavage fluid (BAL) and lung tissue were collected 3, 14 and 28 d later. NM caused progressive histopathologic alterations in the lung including inflammatory cell infiltration and alveolar wall thickening and increases in protein and cells in BAL; oxidative stress was also noted, as reflected by upregulation of heme oxygenase-1. These changes were more prominent in male FXR-/- mice. Flow cytometric analysis revealed that loss of FXR resulted in increases in proinflammatory macrophages at 3 d post NM; this correlated with upregulation of COX-2 and ARL11, markers of macrophage activation. Markers of anti-inflammatory macrophage activation, CD163 and STAT6, were also upregulated after NM; this response was exacerbated in FXR-/- mice at 14 d post-NM. These findings demonstrate that FXR plays a role in limiting macrophage inflammatory responses important in lung injury and oxidative stress. Maintaining or enhancing FXR function may represent a useful strategy in the development of countermeasures to treat mustard lung toxicity.

Sca-1 is a marker for cell plasticity in murine pancreatic epithelial cells and induced by IFN-ß in vitro.

BACKGROUND & AIMS: Sca-1 is a surface marker for murine hematopoietic stem cells (HSCs) and type-I interferon is a key regulator for Lin-Sca-1+ HSCs expansion through Ifnar/Stat-1/Sca-1-signaling. In this study we aimed to characterize the role and regulation of Sca-1+ cells in pancreatic regeneration. METHODS: To characterize Sca-1 in vivo, immunohistochemistry and immunofluorescence staining of Sca-1 was conducted in normal pancreas, in cerulein-mediated acute pancreatitis, and in Kras-triggered cancerous lesions. Ifnar/Stat-1/Sca-1-signaling was studied in type-I IFN-treated epithelial explants of adult wildtype, Ifnar-/-, and Stat-1-/- mice. Sca-1 induction was analyzed by gene expression and FACS analysis. After isolation of pancreatic epithelial Lin-Sca-1+cells, pancreatosphere-formation and immunofluorescence-assays were carried out to investigate self-renewal and differentiation capabilities. RESULTS: Sca-1+ cells were located in periacinar and periductal spaces and showed an enrichment during cerulein-induced acute pancreatitis (23.2/100 µm2 ± 4.9 SEM) and in early inflammation-mediated carcinogenic lesions of the pancreas of KrasG12D mice (35.8/100 µm2 ± SEM 1.9) compared to controls (3.6/100 µm2 ± 1.3 SEM). Pancreatic Lin-Sca-1+ cells displayed a small population of 1.46% ± 0.12 SEM in FACS. In IFN-ß treated pancreatic epithelial explants, Sca-1 expression was increased, and Lin-Sca-1+ cells were enriched in vitro (from 1.49% ± 0.36 SEM to 3.85% ± 0.78 SEM). Lin-Sca-1+ cells showed a 12 to 51-fold higher capacity for clonal self-renewal compared to Lin-Sca-1- cells and generated cells express markers of the acinar and ductal compartment. CONCLUSIONS: Pancreatic Sca-1+ cells enriched during parenchymal damage showed a significant capacity for cell renewal and in vitro plasticity, suggesting that corresponding to the type I interferon-dependent regulation of Lin-Sca-1+ hematopoietic stem cells, pancreatic Sca-1+ cells also employ type-I-interferon for regulating progenitor-cell-homeostasis.

Evidence of direct Z-scheme triazine-based g-C3N4/BiOI (001) heterostructures: a hybrid density functional investigation.

In this work, we systematically investigate the photocatalytic mechanism of g-C3N4/BiOI (001) through hybrid functional calculations based on first-principles theory. The staggered band structure is observed in the g-C3N4/BiOI (001); meanwhile, a built-in electric field exists from the g-C3N4 monolayer to the BiOI surface at the interface. BiOI has lower band edges, which bend downward at the interface; whereas g-C3N4 has higher band edges, which bend upward. With Coulomb interaction and the built-in electric field, photo-generated electrons in the conduction bands (CB) of BiOI recombine with photo-generated holes in the valence bands (VB) of g-C3N4. Meanwhile, the stronger reduction capacity for photo-excited electrons in the g-C3N4's CB and the stronger oxidation capacity for photo-generated holes in the BiOI (001)'s VB are retained. Therefore, a direct Z-scheme heterostructure character is presented. As a result, the electrons and holes generated by the photons can be separated and migrate highly effectively at the interface. The separated electrons and holes can effectively participate in the redox reactions with water/pollutants to produce the photocatalytically reactive species superoxide ions (˙O2-) and hydroxyl radicals (˙OH), respectively. This is consistent with the experimental results. It is also worth noting that the g-C3N4/BiOI (001) heterostructure shows a larger difference in the effective mass of carriers. Therefore, the direct Z-scheme charge transfer and separation mechanism and the larger effective mass difference of carriers lead to the superior photocatalytic activity of the g-C3N4/BiOI (001) in experiments. A few speculations and controversies that arose from the experiments are clarified.

A novel Cereblon E3 ligase modulator with antitumor activity in gastrointestinal cancer.

Targeted protein degradation offers new opportunities to inactivate cancer drivers and has successfully entered the clinic. Ways to induce selective protein degradation include proteolysis targeting chimera (PROTAC) technology and immunomodulatory (IMiDs) / next-generation Cereblon (CRBN) E3 ligase modulating drugs (CELMoDs). Here, we aimed to develop a MYC PROTAC based on the MYC-MAX dimerization inhibitor 10058-F4 derivative 28RH and Thalidomide, called MDEG-541. We show that a subgroup of gastrointestinal cancer cell lines and primary patient-derived organoids are MDEG-541 sensitive. Although MYC expression was regulated in a CRBN-, proteasome- and ubiquitin-dependent manner, we provide evidence that MDEG-541 induced the degradation of CRBN neosubstrates, including G1 to S phase transition 1/2 (GSPT1/2) and the Polo-like kinase 1 (PLK1). In sum, we have established a CRBN-dependent degrader of relevant cancer targets with activity in gastrointestinal cancers.

Oroxylin A inhibits the migration of hepatocellular carcinoma cells by inducing NAG-1 expression.

Hepatocellular carcinoma (HCC), the most prevalent liver cancer, is considered one of the most lethal malignancies with a dismal outcome mainly due to frequent intrahepatic and distant metastasis. In the present study, we demonstrated that oroxylin A, a natural product extracted from Scutellaria radix, significantly inhibits transforming growth factor-beta1 (TGF-ß1)-induced epithelial-mesenchymal transition (EMT) and metastasis in HCC. Oroxylin A blocked the TGF-ß1/Smad signaling via upregulating the non-steroidal anti-inflammatory drug-activated gene-1 (NAG-1) expression. Oroxylin A promoted NAG-1 transcription by regulating the acetylation of CCAAT/enhancer binding protein ß (C/EBPß), a transcription factor that binds to the NAG-1 promoter. In terms of the underlying mechanism, oroxylin A may interact with histone deacetylase 1 (HDAC1) by forming hydrogen bonds with GLY149 residue and induce proteasome-mediated degradation of HDAC1 subsequently impairing HDAC1-mediated deacetylation of C/EBPß and promoting the expression of NAG-1. Taken together, our findings revealed a previously unknown tumor-suppressive mechanism of oroxylin A. Oroxylin A should be further investigated as a potential clinical candidate for inhibiting HCC metastasis.