Publications by authors named "Chan Zhou"

49 Publications

TGFβ signalling acts as a molecular brake of myoblast fusion.

Nat Commun 2021 02 2;12(1):749. Epub 2021 Feb 2.

Institut NeuroMyoGène (INMG), University Claude Bernard Lyon1, CNRS UMR 5310, INSERM U1217, Lyon, France.

Fusion of nascent myoblasts to pre-existing myofibres is critical for skeletal muscle growth and repair. The vast majority of molecules known to regulate myoblast fusion are necessary in this process. Here, we uncover, through high-throughput in vitro assays and in vivo studies in the chicken embryo, that TGFβ (SMAD2/3-dependent) signalling acts specifically and uniquely as a molecular brake on muscle fusion. While constitutive activation of the pathway arrests fusion, its inhibition leads to a striking over-fusion phenotype. This dynamic control of TGFβ signalling in the embryonic muscle relies on a receptor complementation mechanism, prompted by the merging of myoblasts with myofibres, each carrying one component of the heterodimer receptor complex. The competence of myofibres to fuse is likely restored through endocytic degradation of activated receptors. Altogether, this study shows that muscle fusion relies on TGFβ signalling to regulate its pace.
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http://dx.doi.org/10.1038/s41467-020-20290-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854724PMC
February 2021

Effects of Flag Leaf and Number of Vegetative Ramets on Sexual Reproductive Performance in the Clonal Grass .

Front Plant Sci 2020 30;11:534278. Epub 2020 Oct 30.

Key Laboratory of Vegetation Ecology, Ministry of Education, Institute of Grassland Science, Northeast Normal University, Changchun, China.

Sexual reproduction is vital for population adaptation in clonal plants. The flag leaf is considered to be the primary contributor to sexual reproduction in cereal crops, and there is no unified conclusion on the effect of the number of vegetative ramets on grain yield. However, what effects of the flag leaf and the number of vegetative ramets on sexual reproductive performance of clonal grasses are largely unknown. To test this, under field natural conditions, we grew the rhizomatous grass in a homogeneous environment and conducted studies concerning the growth, reproduction and physiology of reproductive ramets in clonal populations. We measured the growth characteristics of different aged leaves, dynamically measured the net photosynthetic rate of different aged leaves and organ biomass, measured the sexual reproductive characteristics of reproductive ramets that had different numbers of connecting vegetative ramets, and performed isotope (N) labeling of ramet pairs at the seed-filling stage. In clonal populations, from the heading stage, the photosynthetic contribution of the functional leaves to seed production was much greater than that of the flag leaf; the photosynthetic capacity of both the functional leaves and the flag leaf all gradually declined. Vegetative ramets translocated their own resources to the connected reproductive ramets, and a large proportion of translocated resources were allocated to the leaf and stem to sustain life activities; increase in the number of connecting vegetative ramets increased floret number, seed number, seed-setting rate, inflorescence biomass, seed biomass, and reproductive allocation of reproductive ramets, and these parameters significantly and positively correlated with the biomass of connecting vegetative ramets. We conclude that the functional leaf rather than the flag leaf of is the primary contributor to seed production. Reproductive ramets adopt a strategy of growth first and reproduction later to allocate the translocated resources between the organs, but vegetative ramets are very advantageous for sexual reproduction under the tillering node connection form in . Overall, our study implies that vegetative ramets not only play an important role in the spatial expansion but also in the sexual reproduction of clonal plant populations.
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http://dx.doi.org/10.3389/fpls.2020.534278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661390PMC
October 2020

Development of oxygen vacancies enriched CoAl hydroxide@hydroxysulfide hollow flowers for peroxymonosulfate activation: A highly efficient singlet oxygen-dominated oxidation process for sulfamethoxazole degradation.

J Hazard Mater 2020 12 24;400:123297. Epub 2020 Jun 24.

Key Laboratory of Building Safety and Energy Efficiency, Ministry of Education, Department of Water Engineering and Science, College of Civil Engineering, Hunan University, Changsha, Hunan, 410082, PR China.

In this study, oxygen vacancies enriched cobalt aluminum hydroxide@hydroxysulfide (CoAl-LDH@CoS) hollow flowers was synthesized by in-situ etching of CoAl-LDH using sodium sulfide solution. The analysis of SEM, EDS, XRD, and XPS were used to characterize the samples. The as-synthesized 0.2CoAl-LDH@CoS displayed higher catalysis performance of sulfamethoxazole (SMX) degradation via the activation of PMS than the pristine CoAl-LDH. 98.5 % of SMX (40 μM) was eliminated with 0.1 g/L 0.2CoAl-LDH@CoS and 0.3 mM PMS at pH 6.0 in 4 min. The degradation fitted with the pseudo-first-order reaction kinetics well with rate constant of 0.89 min for 0.2CoAl-LDH@CoS/PMS system and 0.55 min for CoAl-LDH/PMS system. Singlet oxygen (O) was verified as dominant reactive oxygen species responsible for SMX degradation via quenching tests. Mechanism investigation suggested that the oxygen vacancies, redox cycles of Co(II)/Co(III) and S/(S and sulfate species) on the surface of 0.2CoAl-LDH@CoS were crucial for PMS activation. In addition, the plausible degradation pathways of SMX were proposed by analysis of the SMX degradation intermediates. This study not only reveals that 0.2CoAl-LDH@CoS is an efficient catalyst to activate PMS for SMX degradation, but also shed a novel insight into development of heterogeneous catalysts with oxygen vacancies.
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http://dx.doi.org/10.1016/j.jhazmat.2020.123297DOI Listing
December 2020

lncRNA DIGIT and BRD3 protein form phase-separated condensates to regulate endoderm differentiation.

Nat Cell Biol 2020 10 7;22(10):1211-1222. Epub 2020 Sep 7.

Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA, USA.

Cooperation between DNA, RNA and protein regulates gene expression and controls differentiation through interactions that connect regions of nucleic acids and protein domains and through the assembly of biomolecular condensates. Here, we report that endoderm differentiation is regulated by the interaction between the long non-coding RNA (lncRNA) DIGIT and the bromodomain and extraterminal domain protein BRD3. BRD3 forms phase-separated condensates of which the formation is promoted by DIGIT, occupies enhancers of endoderm transcription factors and is required for endoderm differentiation. BRD3 binds to histone H3 acetylated at lysine 18 (H3K18ac) in vitro and co-occupies the genome with H3K18ac. DIGIT is also enriched in regions of H3K18ac, and the depletion of DIGIT results in decreased recruitment of BRD3 to these regions. Our findings show that cooperation between DIGIT and BRD3 at regions of H3K18ac regulates the transcription factors that drive endoderm differentiation and suggest that protein-lncRNA phase-separated condensates have a broader role as regulators of transcription.
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http://dx.doi.org/10.1038/s41556-020-0572-2DOI Listing
October 2020

Can CuZnSnS nanoparticles be used as heterogeneous catalysts for sulfadiazine degradation?

J Hazard Mater 2020 08 17;395:122613. Epub 2020 Apr 17.

Key Laboratory of Building Safety and Energy Efficiency, Ministry of Education, Department of Water Engineering and Science, College of Civil Engineering, Hunan University, Changsha, 410082, PR China. Electronic address:

As a quaternary copper-based semiconductor, CuZnSnS (CZTS) is drawing growing attention and is anticipated as a promising photocatalyst, thanks to its large absorption coefficient, exceptional photostability, and theoretical power conversion efficiency. However, CZTS has never been used as an activator of HO for the degradation of refractory organic pollutants. In this study, the synthesis of CZTS nanoparticles obtained with diverse morphologies and crystallinities using solvents of deionized water (CZTS-W) and ethylene glycol (CZTS-EG) was examined in the activation of HO to degrade sulfadiazine (SDZ). The results revealed that CZTS coupled with HO could be an effective system for the degradation of SDZ. Compared to CZTS-EG, CZTS-W presented higher reusability in consecutive cycles with negligible leaching of copper. Reactive oxygen species quenching tests and electron paramagnetic resonance analyses illustrated that •O, •OH, and O contributed to the degradation of SDZ, and O prevailed over •O and •OH. The mechanistic investigation showed that efficient degradation could be associated to the effective recycling of Cu(II)/Cu(I) and low-valent/high-valent sulfur. Also, the degradation pathways of SDZ have been proposed through the detection of intermediate products. This study manifests that CZTS synthesized using deionized water is encouraging for the elimination of organic pollutants.
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http://dx.doi.org/10.1016/j.jhazmat.2020.122613DOI Listing
August 2020

Diverse trajectories of plastome degradation in holoparasitic Cistanche and genomic location of the lost plastid genes.

J Exp Bot 2020 01;71(3):877-892

Ministry of Education Key Laboratory for Biodiversity Science and Ecological Engineering, Institute of Biodiversity Science, School of Life Sciences, Fudan University, Shanghai, China.

The plastid genomes (plastomes) of non-photosynthetic plants generally undergo gene loss and pseudogenization. Despite massive plastomes reported in different parasitism types of the broomrape family (Orobanchaceae), more plastomes representing different degradation patterns in a single genus are expected to be explored. Here, we sequence and assemble the complete plastomes of three holoparasitic Cistanche species (C. salsa, C. mongolica, and C. sinensis) and compare them with the available plastomes of Orobanchaceae. We identified that the diverse degradation trajectories under purifying selection existed among three Cistanche clades, showing obvious size differences in the entire plastome, long single copy region, and non-coding region, and different patterns of the retention/loss of functional genes. With few exceptions of putatively functional genes, massive plastid fragments, which have been lost and transferred into the mitochondrial or nuclear genomes, are non-functional. In contrast to the equivalents of the Orobanche species, some plastid-derived genes with diverse genomic locations are found in Cistanche. The early and initially diverged clades in different genera such as Cistanche and Aphyllon possess obvious patterns of plastome degradation, suggesting that such key lineages should be considered prior to comparative analysis of plastome evolution, especially in the same genus.
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http://dx.doi.org/10.1093/jxb/erz456DOI Listing
January 2020

Myelin sheath structure and regeneration in peripheral nerve injury repair.

Proc Natl Acad Sci U S A 2019 10 14;116(44):22347-22352. Epub 2019 Oct 14.

Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, University of Chicago Medical Center, Chicago, IL 60637.

Observing the structure and regeneration of the myelin sheath in peripheral nerves following injury and during repair would help in understanding the pathogenesis and treatment of neurological diseases caused by an abnormal myelin sheath. In the present study, transmission electron microscopy, immunofluorescence staining, and transcriptome analyses were used to investigate the structure and regeneration of the myelin sheath after end-to-end anastomosis, autologous nerve transplantation, and nerve tube transplantation in a rat model of sciatic nerve injury, with normal optic nerve, oculomotor nerve, sciatic nerve, and Schwann cells used as controls. The results suggested that the double-bilayer was the structural unit that constituted the myelin sheath. The major feature during regeneration was the compaction of the myelin sheath, wherein the distance between the 2 layers of cell membrane in the double-bilayer became shorter and the adjacent double-bilayers tightly closed together and formed the major dense line. The expression level of myelin basic protein was positively correlated with the formation of the major dense line, and the compacted myelin sheath could not be formed without the anchoring of the lipophilin particles to the myelin sheath.
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http://dx.doi.org/10.1073/pnas.1910292116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825268PMC
October 2019

Epigenetic control of embryo-uterine crosstalk at peri-implantation.

Cell Mol Life Sci 2019 Dec 27;76(24):4813-4828. Epub 2019 Jul 27.

Reproductive Medical Center, The First Affiliated Hospital of Xiamen University, Xiamen, 361003, Fujian, People's Republic of China.

Embryo implantation is one of the pivotal steps during mammalian pregnancy, since the quality of embryo implantation determines the outcome of ongoing pregnancy and fetal development. A large number of factors, including transcription factors, signalling transduction components, and lipids, have been shown to be indispensable for embryo implantation. Increasing evidence also suggests the important roles of epigenetic factors in this critical event. This review focuses on recent findings about the involvement of epigenetic regulators during embryo implantation.
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http://dx.doi.org/10.1007/s00018-019-03245-8DOI Listing
December 2019

Culture Change and Affectionate Communication in China and the United States: Evidence From Google Digitized Books 1960-2008.

Front Psychol 2019 22;10:1110. Epub 2019 May 22.

Institute of Developmental Psychology, Beijing Normal University, Beijing, China.

Humans are born with the ability and the need for affection, but communicating affection as a social behavior is historically bound. Based on the digitized books of Google Ngram Viewer from 1960 through 2008, the present research investigated affectionate communication (AC) in China and the United States, and its changing landscape along with social changes from collectivist to individualistic environments. In particular, we analyzed the frequency in terms of verbal affection (e.g., love you, like you), non-verbal affection (e.g., hug, kiss), and individualism (indicated by the use of first-person singular pronouns such as I, me, and myself) in Chinese and American books. The results revealed an increasing trend for AC in recent decades, although the frequency of affection words was lower in Chinese than in American books. Further, individualism was positively related to the frequency of affection words in both Chinese and American books. These results demonstrate the effect of cultural changes on AC, in that affection exchange becomes popular in adaptation to individualistic urban environments. These findings exemplify a cross-cultural difference in the expression of love and the cultural universality of social change in Eastern and Western societies.
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http://dx.doi.org/10.3389/fpsyg.2019.01110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6540734PMC
May 2019

Spatiotemporal coordination of trophoblast and allantoic Rbpj signaling directs normal placental morphogenesis.

Cell Death Dis 2019 06 5;10(6):438. Epub 2019 Jun 5.

Reproductive Medical Center, The First Affiliated Hospital of Xiamen University, 361003, Xiamen, Fujian, People's Republic of China.

The placenta, responsible for the nutrient and gas exchange between the mother and fetus, is pivotal for successful pregnancy. It has been shown that Rbpj, the core transcriptional mediator of Notch signaling pathway, is required for normal placentation in mice. However, it remains largely unclear how Rbpj signaling in different placental compartments coordinates with other important regulators to ensure normal placental morphogenesis. In this study, we found that systemic deletion of Rbpj led to abnormal chorioallantoic morphogenesis and defective trophoblast differentiation in the ectoplacental cone (EPC). Employing mouse models with selective deletion of Rbpj in the allantois versus trophoblast, combining tetraploid aggregation assay, we demonstrated that allantois-expressed Rbpj is essential for chorioallantoic attachment and subsequent invagination of allantoic blood vessels into the chorionic ectoderm. Further studies uncovered that allantoic Rbpj regulates chorioallantoic fusion and morphogenesis via targeting Vcam1 in a Notch-dependent manner. Meanwhile, we also revealed that trophoblast-expressed Rbpj in EPC facilitates Mash2's transcriptional activity, promoting the specification of Tpbpα-positive trophoblasts, which differentiate into trophoblast subtypes responsible for interstitial and endovascular invasion at the later stage of placental development. Collectively, our study further shed light on the molecular network governing placental development and functions, highlighting the necessity of a spatiotemporal coordination of Rbpj signaling for normal placental morphogenesis.
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http://dx.doi.org/10.1038/s41419-019-1683-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549187PMC
June 2019

Ubiquitin-specific protease 7 (USP7) is essential for endometrial stromal cell decidualization in mice.

Dev Growth Differ 2019 Feb 9;61(2):176-185. Epub 2019 Jan 9.

Reproductive Medical Center, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.

Ubiquitin-specific protease 7 (USP7), a member of the deubiquitinating (DUB) enzyme family, regulates protein stability and has a well-characterized function in tumorigenesis. Given its critical role in growth and development, it was speculated to be involved in modulating processes in the female reproductive system but its exact role has not been elucidated. Decidualization is one of the key processes in pregnancy and aberrant decidualization is a cause of pregnancy failure. The uterine endometrium layer undergoes significant structural and functional changes during decidualization in preparation for and after embryo implantation. Here, we hypothesized that USP7 could be involved in mediating endometrial stromal cell (ESC) decidualization and set out to determine its function with a primary stromal cell culture. Using in situ hybridization and immunohistochemical techniques, we observed increased USP7 expression during uterine decidualization and found that it was predominantly localized to the decidual zone in the post-implantation uterus. Since the ovarian hormones, progesterone (P4) and estrogen (E2), function in promoting stroma decidualization, we investigated their relationship with USP7 expression and found that they exert minimal influence. Moreover, increased USP7 expression observed during deciduoma development was found to be independent of blastocyst attachment. Using a specific USP7 inhibitor, HBX19818, we demonstrated an additional novel role for USP7 in endometrial stroma decidualization in mice during early pregnancy. Our findings could potentially be applied towards future research and development in female infertility.
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http://dx.doi.org/10.1111/dgd.12594DOI Listing
February 2019

In situ gelation of rhEGF-containing liquid crystalline precursor with good cargo stability and system mechanical properties: a novel delivery system for chronic wounds treatment.

Biomater Sci 2019 Feb;7(3):995-1010

School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, Guangdong, P. R. China.

The objective of this study was to develop a novel delivery system for recombinant human epidermal growth factor (rhEGF) for chronic wound treatment. Such a delivery system should be of good cargo stability and system mechanical properties in order to guarantee a satisfactory wound-healing effect. rhEGF-containing lyotropic liquid crystalline precursors (rhEGF-LLCPs) with in situ gelation capability were considered as a promising candidate to achieve this aim. Various properties of the optimal formulations (rhEGF-LLCP1 and rhEGF-LLCP2) were characterized, including apparent viscosity, gelation time, in vitro release and phase behavior. The stability of rhEGF and system mechanical properties (i.e. mechanical rigidity and bioadhesive force) were verified. Interestingly, rhEGF-LLCP2 with a larger internal water channel diameter exhibited faster release rate in vitro and then better bioactivity in Balb/c 3T3 and HaCaT cell models. Moreover, rhEGF-LLCP2 showed distinct promotion effects on wound closure, inflammatory recovery and re-epithelization process in Sprague-Dawley rat models. In conclusion, rhEGF-LLCP emerged as a prospective candidate to preserve the stability and enhance the wound-healing effect of rhEGF, which might serve as a new delivery system for chronic wound therapies.
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http://dx.doi.org/10.1039/c8bm01196fDOI Listing
February 2019

Whole genome sequencing puts forward hypotheses on metastasis evolution and therapy in colorectal cancer.

Nat Commun 2018 11 14;9(1):4782. Epub 2018 Nov 14.

Department of Experimental Surgery-Cancer Metastasis, Medical Faculty Mannheim, Ruprecht Karls University Heidelberg, 69120 Mannheim, Germany.

Incomplete understanding of the metastatic process hinders personalized therapy. Here we report the most comprehensive whole-genome study of colorectal metastases vs. matched primary tumors. 65% of somatic mutations originate from a common progenitor, with 15% being tumor- and 19% metastasis-specific, implicating a higher mutation rate in metastases. Tumor- and metastasis-specific mutations harbor elevated levels of BRCAness. We confirm multistage progression with new components ARHGEF7/ARHGEF33. Recurrently mutated non-coding elements include ncRNAs RP11-594N15.3, AC010091, SNHG14, 3' UTRs of FOXP2, DACH2, TRPM3, XKR4, ANO5, CBL, CBLB, the latter four potentially dual protagonists in metastasis and efferocytosis-/PD-L1 mediated immunosuppression. Actionable metastasis-specific lesions include FAT1, FGF1, BRCA2, KDR, and AKT2-, AKT3-, and PDGFRA-3' UTRs. Metastasis specific mutations are enriched in PI3K-Akt signaling, cell adhesion, ECM and hepatic stellate activation genes, suggesting genetic programs for site-specific colonization. Our results put forward hypotheses on tumor and metastasis evolution, and evidence for metastasis-specific events relevant for personalized therapy.
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http://dx.doi.org/10.1038/s41467-018-07041-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235880PMC
November 2018

Cultural value mismatch in urbanizing China: A large-scale analysis of collectivism and happiness based on social media and nationwide survey.

Int J Psychol 2018 Dec 21;53 Suppl 2:54-63. Epub 2018 Sep 21.

Independent Researcher, Rochester, NY, USA.

Throughout history, collectivism has contributed much to social bonding and human wellness. However, it remains unclear whether the collectivism-wellness equation still applies, when there is a mismatch between the collectivistic values and the ecological environment of urbanisation. Testing the hypothesis of cultural value mismatch (e.g., high urbanised & high collectivistic, or low urbanised & low collectivistic), two studies were designed to examine the relationship between collectivism and emotional wellbeing in China, with urbanisation as moderator. Based on the emotion analysis of tweets among 1.6 millions of Weibo users, Study 1 found that the province-level collectivism scores were significantly and positively related to negative emotions in high urbanised provinces, but this relationship was not significant in low or middle urbanised provinces. Using a nationwide survey dataset, Study 2 showed that, on the individual level, those with higher collectivism reported less negative emotions, but only in low- and middle-urbanised provinces, not in high-urbanised provinces. On positive emotions in all areas, the positive effect of collectivism was observed on individual level, but not on province level. These findings support the value mismatch hypothesis of urbanisation, suggesting that the purchasing power of collectivism on wellbeing is compromised in urbanising China.
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http://dx.doi.org/10.1002/ijop.12523DOI Listing
December 2018

Cell activity during peripheral nerve defect repair process using a nerve scaffold.

Oncotarget 2017 Dec 5;8(69):113828-113836. Epub 2017 Dec 5.

Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, School of Life Sciences, Southwest University, Chongqing 400715, China.

Peripheral nerve defects, but not artificial nerves, are repaired by endogenous cells. We examined cell activity during the repair process in the presence of autologous nerves and artificial preparations in order to guide future artificial nerve fabrication. PLGA tubes, nerve scaffolds comprising a PLGA tube plus 6,000 fibroin fibers, or autologous nerves were implanted into 10 mm rat sciatic nerve defects ( 60 per group). Over a period of 1-20 weeks after nerve grafting, sections were stained and imaged to distinguish the cell types present and we quantified the recovery of motor and sensory function in the surgically implanted limb. We observed a decreasing trend in inflammatory cell and fibroblast counts over time which ranked in magnitude as: (PLGA group > nerve scaffold > autologous nerve> sham) and an opposite trend in Schwann cell counts. Differences in withdrawal time from hot water and static sciatic index (SSI) indicated that, after repair, sensory and motor function were best in the sham group, followed by the autologous group, the nerve scaffold group, and the PLGA group. These findings indicate that the inflammatory reaction is significant in the first two weeks after nerve grafting, followed by the rebirth of fibroblasts and Schwann cells, which guide axon regeneration. This inflammatory response was a fundamental stage of peripheral defect repair, but a weaker inflammatory response corresponded to better recovery of sensorimotor functional.
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http://dx.doi.org/10.18632/oncotarget.22978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768366PMC
December 2017

Polycomb subunit BMI1 determines uterine progesterone responsiveness essential for normal embryo implantation.

J Clin Invest 2018 01 20;128(1):175-189. Epub 2017 Nov 20.

Reproductive Medical Center, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China.

Natural and synthetic progestogens have been commonly used to prevent recurrent pregnancy loss in women with inadequate progesterone secretion or reduced progesterone sensitivity. However, the clinical efficacy of progesterone and its analogs for maintaining pregnancy is variable. Additionally, the underlying cause of impaired endometrial progesterone responsiveness during early pregnancy remains unknown. Here, we demonstrated that uterine-selective depletion of BMI1, a key component of the polycomb repressive complex-1 (PRC1), hampers uterine progesterone responsiveness and derails normal uterine receptivity, resulting in implantation failure in mice. We further uncovered genetic and biochemical evidence that BMI1 interacts with the progesterone receptor (PR) and the E3 ligase E6AP in a polycomb complex-independent manner and regulates the PR ubiquitination that is essential for normal progesterone responsiveness. A close association of aberrantly low endometrial BMI1 expression with restrained PR responsiveness in women who had previously had a miscarriage indicated that the role of BMI1 in endometrial PR function is conserved in mice and in humans. In addition to uncovering a potential regulatory mechanism of BMI1 that ensures normal endometrial progesterone responsiveness during early pregnancy, our findings have the potential to help clarify the underlying causes of spontaneous pregnancy loss in women.
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http://dx.doi.org/10.1172/JCI92862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5749512PMC
January 2018

Genome-Wide Maps of m6A circRNAs Identify Widespread and Cell-Type-Specific Methylation Patterns that Are Distinct from mRNAs.

Cell Rep 2017 Aug;20(9):2262-2276

Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address:

N-methyladenosine (mA) is the most abundant internal modification of mRNAs and is implicated in all aspects of post-transcriptional RNA metabolism. However, little is known about mA modifications to circular (circ) RNAs. We developed a computational pipeline (AutoCirc) that, together with depletion of ribosomal RNA and mA immunoprecipitation, defined thousands of mA circRNAs with cell-type-specific expression. The presence of mA circRNAs is corroborated by interaction between circRNAs and YTHDF1/YTHDF2, proteins that read mA sites in mRNAs, and by reduced mA levels upon depletion of METTL3, the mA writer. Despite sharing mA readers and writers, mA circRNAs are frequently derived from exons that are not methylated in mRNAs, whereas mRNAs that are methylated on the same exons that compose mA circRNAs exhibit less stability in a process regulated by YTHDF2. These results expand our understanding of the breadth of mA modifications and uncover regulation of circRNAs through mA modification.
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http://dx.doi.org/10.1016/j.celrep.2017.08.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705222PMC
August 2017

Maintenance of macrophage transcriptional programs and intestinal homeostasis by epigenetic reader SP140.

Sci Immunol 2017 Mar 3;2(9). Epub 2017 Mar 3.

Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

Epigenetic "readers" that recognize defined posttranslational modifications on histones have become desirable therapeutic targets for cancer and inflammation. SP140 is one such bromodomain- and plant homeodomain (PHD)-containing reader with immune-restricted expression, and single-nucleotide polymorphisms (SNPs) within associate with Crohn's disease (CD). However, the function of SP140 and the consequences of disease-associated SNPs have remained unclear. We show that SP140 is critical for transcriptional programs that uphold the macrophage state. SP140 preferentially occupies promoters of silenced, lineage-inappropriate genes bearing the histone modification H3K27me3, such as the cluster in human macrophages, and ensures their repression. Depletion of SP140 in mouse or human macrophages resulted in severely compromised microbe-induced activation. We reveal that peripheral blood mononuclear cells (PBMCs) or B cells from individuals carrying CD-associated SNPs within have defective messenger RNA splicing and diminished SP140 protein levels. Moreover, CD patients carrying SNPs displayed suppressed innate immune gene signatures in a mixed population of PBMCs that stratified them from other CD patients. Hematopoietic-specific knockdown of in mice resulted in exacerbated dextran sulfate sodium (DSS)-induced colitis, and low levels in human CD intestinal biopsies correlated with relatively lower intestinal innate cytokine levels and improved response to anti-tumor necrosis factor (TNF) therapy. Thus, the epigenetic reader SP140 is a key regulator of macrophage transcriptional programs for cellular state, and a loss of SP140 due to genetic variation contributes to a molecularly defined subset of CD characterized by ineffective innate immunity, normally critical for intestinal homeostasis.
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http://dx.doi.org/10.1126/sciimmunol.aag3160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5549562PMC
March 2017

The effect of four types of artificial nerve graft structures on the repair of 10-mm rat sciatic nerve gap.

J Biomed Mater Res A 2017 Nov 21;105(11):3077-3085. Epub 2017 Aug 21.

Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, School of Life Sciences, Southwest University, Chongqing, 400715, China.

Investigating the effect of four types of artificial nerve graft (ANG) structures on rat sciatic nerve defect repair will aid future ANG designs. In this study, fibroin fibers and polylactic acid were used to prepare four ANGs with differing structures: nerve conduit with micron-sized pores (Conduit with pore group), nerve conduit without micron-sized pores (Conduit group), nerve scaffold comprising Conduit with pore group material plus silk fibers (Scaffold with pore group), and nerve scaffold comprising Conduit group material plus silk fibers (Scaffold group). ANGs or autologous nerves (Autologous group) were implanted into 10 mm rat sciatic nerve defects (n = 50 per group). Twenty weeks after nerve grafting, the time required to retract the surgical limb from the hot water was ranked as follows: Conduit with pore group > Scaffold with pore group > Conduit group > Scaffold group > Autologous group. The static sciatic index was ranked in descending order: Autologous group > Scaffold group > Conduit group > Scaffold with pore group > Conduit with pore group. Immunofluorescence staining identified significant differences in the distribution and number of axons, Schwann cells, and fibroblasts. These findings indicate that ANGs with micron-sized pores had a negative impact on the repair of peripheral nerve defects, while internal microchannels were beneficial. © 2017 The Authors. Journal of Biomedical Materials Research Part A Published by Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3077-3085, 2017.
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http://dx.doi.org/10.1002/jbm.a.36172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5659138PMC
November 2017

PR-Set7 deficiency limits uterine epithelial population growth hampering postnatal gland formation in mice.

Cell Death Differ 2017 12 21;24(12):2013-2021. Epub 2017 Jul 21.

Reproductive Medical Center, The First Affiliated Hospital of Xiamen University, Xiamen 361003, People's Republic of China.

Formation of secretary endometrial glands in the uterus known as adenogenesis is a typical process of branching morphogenesis involving dynamic epithelial growth and differentiation. Unsuccessful adenogenesis often leads to female infertility. However, it remains largely unexplored so far regarding the epigenetic machinery governing normal endometrial gland formation. Here, we demonstrated that PR-Set7, an epigenetic regulator for H4K20me1 modification, was extensively expressed in the postnatal uteri, and its conditional deletion resulted in a complete lack of endometrial glands and infertility in mice. Subsequent analysis revealed that uterine PR-Set7 deficiency abolishes the dynamic endometrial epithelial population growth during the short span of gland formation from postnatal days 3 to 9. This markedly reduced epithelial population growth in PR-Set7-null mutant uteri is well associated with DNA damage accumulation and massive apoptotic death in the epithelium, due to blockade of 53BP1 recruitment to DNA damage sites upon reduced levels of H4K20me1/2. Using Pgr/Rosa26 mouse line and postnatal progesterone injection mouse model, we further confirmed that an impaired epithelial cell population growth either by inducing epithelial death in the diphtheria toxin-A (DTA)-mouse model or attenuating epithelial growth upon postnatal progesterone treatment similarly hampers uterine adenogenesis. Collectively, we establish here a novel 'epithelial population growth threshold' model for successful gland development. Besides further shedding light on the regulatory machinery governing uterine gland formation, our findings raise a safety concern on progesterone supplementation to prevent preterm birth in women bearing a female fetus, as exogenous progesterone may hamper uterine adenogenesis via attenuating epithelial population growth.
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http://dx.doi.org/10.1038/cdd.2017.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5686342PMC
December 2017

Nuclear Shp2 directs normal embryo implantation via facilitating the ERα tyrosine phosphorylation by the Src kinase.

Proc Natl Acad Sci U S A 2017 05 19;114(18):4816-4821. Epub 2017 Apr 19.

Reproductive Medical Center, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, People's Republic of China;

Estrogen and progesterone coupled with locally produced signaling molecules are essential for embryo implantation. However, the hierarchical landscape of the molecular pathways that governs this process remains largely unexplored. Here we show that the protein tyrosine phosphatase Shp2, a positive transducer of RTK signaling, is predominately localized in the nuclei in the periimplantation mouse uterus. Uterine-specific deletion of Shp2 exhibits reduced progesterone receptor (PR) expression and progesterone resistance, which derails normal uterine receptivity, leading to complete implantation failure in mice. Notably, the PR expression defects are attributed to the limited estrogen receptor α (ERα) activation in uterine stroma. Further analysis reveals that nuclear Shp2, rather than cytosolic Shp2, promotes the ERα transcription activity. This function is achieved by enhancing the Src kinase-mediated ERα tyrosine phosphorylation, which facilitates ERα binding to promoter in an ERK-independent manner in periimplantation uteri. Besides uncovering a regulatory mechanism, this study could be clinically relevant to dysfunctional ERα-caused endometrial disorders in women.
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http://dx.doi.org/10.1073/pnas.1700978114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5422785PMC
May 2017

Tricyclic Antidepressants Promote Ceramide Accumulation to Regulate Collagen Production in Human Hepatic Stellate Cells.

Sci Rep 2017 03 21;7:44867. Epub 2017 Mar 21.

Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA USA.

Activation of hepatic stellate cells (HSCs) in response to injury is a key step in hepatic fibrosis, and is characterized by trans-differentiation of quiescent HSCs to HSC myofibroblasts, which secrete extracellular matrix proteins responsible for the fibrotic scar. There are currently no therapies to directly inhibit hepatic fibrosis. We developed a small molecule screen to identify compounds that inactivate human HSC myofibroblasts through the quantification of lipid droplets. We screened 1600 compounds and identified 21 small molecules that induce HSC inactivation. Four hits were tricyclic antidepressants (TCAs), and they repressed expression of pro-fibrotic factors Alpha-Actin-2 (ACTA2) and Alpha-1 Type I Collagen (COL1A1) in HSCs. RNA sequencing implicated the sphingolipid pathway as a target of the TCAs. Indeed, TCA treatment of HSCs promoted accumulation of ceramide through inhibition of acid ceramidase (aCDase). Depletion of aCDase also promoted accumulation of ceramide and was associated with reduced COL1A1 expression. Treatment with B13, an inhibitor of aCDase, reproduced the antifibrotic phenotype as did the addition of exogenous ceramide. Our results show that detection of lipid droplets provides a robust readout to screen for regulators of hepatic fibrosis and have identified a novel antifibrotic role for ceramide.
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http://dx.doi.org/10.1038/srep44867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5359599PMC
March 2017

Correction: Detecting the Differences in Responses of Stomatal Conductance to Moisture Stresses between Deciduous Shrubs and Artemisia Subshrubs.

PLoS One 2016;11(12):e0169382. Epub 2016 Dec 29.

[This corrects the article DOI: 10.1371/journal.pone.0084200.].
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0169382PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5199078PMC
December 2016

[REGULATORY EFFECT OF OLFACTORY ENSHEATHING CELLS ON INFLAMMATORY CYTOKINES IN REPAIR OF RAT SCIATIC NERVE DEFECT].

Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2016 Dec;30(12):1538-1544

School of Life Sciences, Southwest University, Chongqing, 400715, P. R. China.

Objective: To investigate the expression regulation of inflammation cytokines interleukin 4 (IL-4), IL-6, IL-13, and tumor necrosis factor α (TNF-α) in rats with sciatic nerve defect following olfactory ensheathing cell (OEC) transplantation.

Methods: The primary OEC for cell culture and identification was dissociated from the olfactory bulb of the green fluorescent protein-Sprague Dawley (GFP-SD) rat. One hundred SD rats were randomly divided into 2 groups, and the right sciatic nerve defect (10 mm in length) model was made, then repaired with poly (lactic acid-co-glycolic acid) (PLGA). The mixture of equivalent cultured GFP-OEC and extracellular matrix (ECM) was injected into both ends of PLGA nerve conduit in the experimental group (=55), and the mixture of DMEM and ECM in the control group (=45). The general situation of rats was observed after operation. At 6 hours, 1 day, 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks, and 6 weeks, the inflammatory cytokines were detected by Western blot. At 2, 4, and 6 weeks, the survival of GFP-OEC was observed in the experimental group. At 9 weeks, HE staining was used to observe the morphology of nerve tissue, and the sensory and motor function and the electrophysiological index were detected.

Results: The cultured primary cells were GFP-OECs by immunofluorescence staining. Compared with the control group, the experimental group showed significantly increased expression level of IL-4 at 2-6 weeks (<0.05), significantly decreased expression level of IL-6 and TNF-α at 3 days and 1 week (<0.05) and significantly increased expression level of IL-13 at 1 day and 3-6 weeks (<0.05) by Western blot detection. At 2, 4, and 6 weeks, the surviving GFP-OEC of regenerative nerve end was observed in the experimental group under the fluorescence microscope. At 9 weeks, regenerative nerve tissue was loose, and cell morphology was irregular in the experimental group, while the regenerative nerve tissue had vesicular voids and the cell number decreased significantly in the control group. At 9 weeks, the functional recovery of sciatic nerve in the experimental group was better than that of the control group, showing significant difference in the lateral foot retraction time, sciatic nerve function index, muscle action potential latency, and the amplitude of compound muscle action potential (<0.05).

Conclusions: OEC can promote the anti-inflammation cytokines expression of IL-4 and IL-13 and inhibit the pro-inflammatory cytokines expression of IL-6 and TNF-α, which can improve the local inflammatory microenvironment of sciatic nerve and effectively promote the structure and function recovery of sciatic nerve.
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http://dx.doi.org/10.7507/1002-1892.20160317DOI Listing
December 2016

Significance of different response evaluation criteria in predicting progression-free survival of lung cancer with certain imaging characteristics.

Thorac Cancer 2016 Sep 21;7(5):535-542. Epub 2016 Jun 21.

Department of Thoracic Oncology, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.

Background: Certain radiographic signs of a treatment response, such as cavitation, changes in density, or tumor change along a short axis, are not considered by Response Evaluation Criteria in Solid Tumors (RECIST). This study evaluates what additional prognostic information can be obtained by including these criteria in tumor assessment.

Methods: Data of 105 patients were included. Tumor cavitation was observed in 51 patients at baseline. An additional 23 patients developed tumor cavitation during treatment. A change in tumor density was the only radiographic treatment response observed in 22 patients. The only measureable treatment response in nine patients was a decrease along the short axis size of the tumor. Tumor response was assessed using various criteria.

Results: In patients with basic tumor cavitation, RECIST1.1 scores accurately predicted differences in progression-free survival (PFS; P = 0.076) while modified (m) RECIST did not (P = 0.550). mRECIST detected a significant difference between PFS in patients with post-therapeutic cavitation with different responses, but no significant difference using RECIST1.1 (P = 0.004 vs. P = 0.477). In patients with only tumor density changes, there was no significant difference in PFS when either RECIST1.1 or density criteria were used (P = 0.419). In patients with a change in size along the tumor's short axis, short axis criteria could predict significant difference in PFS (P = 0.004).

Conclusions: RECIST1.1 provides the best assessment of tumor response and prediction of PFS in patients with basic tumor cavitation. mRECIST provides better PFS prognostic information in patients with post-therapeutic cavitation. Short axis criteria provides better PFS prognostic information in patients with changes in the short axis of tumor diameter. Changes in tumor density were not a useful prognostic sign.
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http://dx.doi.org/10.1111/1759-7714.12363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5130210PMC
September 2016

DIGIT Is a Conserved Long Noncoding RNA that Regulates GSC Expression to Control Definitive Endoderm Differentiation of Embryonic Stem Cells.

Cell Rep 2016 10;17(2):353-365

Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address:

Long noncoding RNAs (lncRNAs) exhibit diverse functions, including regulation of development. Here, we combine genome-wide mapping of SMAD3 occupancy with expression analysis to identify lncRNAs induced by activin signaling during endoderm differentiation of human embryonic stem cells (hESCs). We find that DIGIT is divergent to Goosecoid (GSC) and expressed during endoderm differentiation. Deletion of the SMAD3-occupied enhancer proximal to DIGIT inhibits DIGIT and GSC expression and definitive endoderm differentiation. Disruption of the gene encoding DIGIT and depletion of the DIGIT transcript reveal that DIGIT is required for definitive endoderm differentiation. In addition, we identify the mouse ortholog of DIGIT and show that it is expressed during development and promotes definitive endoderm differentiation of mouse ESCs. DIGIT regulates GSC in trans, and activation of endogenous GSC expression is sufficient to rescue definitive endoderm differentiation in DIGIT-deficient hESCs. Our study defines DIGIT as a conserved noncoding developmental regulator of definitive endoderm.
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http://dx.doi.org/10.1016/j.celrep.2016.09.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120872PMC
October 2016

Long noncoding RNAs expressed in human hepatic stellate cells form networks with extracellular matrix proteins.

Genome Med 2016 Mar 23;8(1):31. Epub 2016 Mar 23.

Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.

Background: Hepatic fibrosis is the underlying cause of cirrhosis and liver failure in nearly every form of chronic liver disease, and hepatic stellate cells (HSCs) are the primary cell type responsible for fibrosis. Long noncoding RNAs (lncRNAs) are increasingly recognized as regulators of development and disease; however, little is known about their expression in human HSCs and their function in hepatic fibrosis.

Methods: We performed RNA sequencing and ab initio assembly of RNA transcripts to define the lncRNAs expressed in human HSC myofibroblasts. We analyzed chromatin immunoprecipitation data and expression data to identify lncRNAs that were regulated by transforming growth factor beta (TGF-β) signaling, associated with super-enhancers and restricted in expression to HSCs compared with 43 human tissues and cell types. Co-expression network analyses were performed to discover functional modules of lncRNAs, and principle component analysis and K-mean clustering were used to compare lncRNA expression in HSCs with other myofibroblast cell types.

Results: We identified over 3600 lncRNAs that are expressed in human HSC myofibroblasts. Many are regulated by TGF-β, a major fibrotic signal, and form networks with genes encoding key components of the extracellular matrix (ECM), which is the substrate of the fibrotic scar. The lncRNAs directly regulated by TGF-β signaling are also enriched at super-enhancers. More than 400 of the lncRNAs identified in HSCs are uniquely expressed in HSCs compared with 43 other human tissues and cell types and HSC myofibroblasts demonstrate different patterns of lncRNA expression compared with myofibroblasts originating from other tissues. Co-expression analyses identified a subset of lncRNAs that are tightly linked to collagen genes and numerous proteins that regulate the ECM during formation of the fibrotic scar. Finally, we identified lncRNAs that are induced during progression of human liver disease.

Conclusions: lncRNAs are likely key contributors to the formation and progression of fibrosis in human liver disease.
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http://dx.doi.org/10.1186/s13073-016-0285-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804564PMC
March 2016

MCM2 mediates progesterone-induced endometrial stromal cell proliferation and differentiation in mice.

Endocrine 2016 Aug 24;53(2):595-606. Epub 2016 Feb 24.

State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, People's Republic of China.

Uterine decidualization characterized by stromal cell proliferation and differentiation is critical to the establishment of pregnancy in many species. Progesterone is a key factor in regulating endometrial cell decidualization, however, the molecular basis involved in mediating the effects of progesterone during decidualization remains largely unknown. We report here that the DNA replication licensing factor MCM2, one of the conserved set of six-related proteins (MCM complex: MCM2-7) essential for eukaryotic DNA replication, is dynamically expressed in both proliferative and differentiated stromal cells during mouse periimplantation uterus. Applying PR-knockout mouse model and pharmacological strategy, we further found that the expression of Mcm2 is induced by progesterone action in the mouse uterine stroma. Employing a primary cell culture system, we further demonstrated that siRNA-mediated silencing of MCM2 arrests the cell cycle at G1-S transition during stromal cell proliferation. Moreover, the downregulation of Mcm2 could also compromise stromal cell differentiation. Collectively, our studies uncovered the role of a unique DNA replication licensing molecule MCM2 in mediating Progesterone-induced stromal cell decidualization in mouse uterus.
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http://dx.doi.org/10.1007/s12020-016-0894-9DOI Listing
August 2016

Enhancing in vitro dissolution and in vivo bioavailability of fenofibrate by solid self-emulsifying matrix combined with SBA-15 mesoporous silica.

Colloids Surf B Biointerfaces 2016 May 8;141:476-482. Epub 2016 Feb 8.

School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China; Research and Development Center of Pharmaceutical Engineering, Sun Yat-sen University, Guangzhou 510006, PR China. Electronic address:

Mesoporous silica Santa Barbara amorphous-15 (SBA-15), derived from supermolecular assemblies of surfactant Pluronic(®) P123 with well-ordered 2-D hexagonal pores, was investigated as a reservoir to construct a novel solid self-emulsifying matrix for enhancing the oral bioavailability of fenofibrate (FNB). The emulsification rate and droplet size of a liquid self-emulsifying delivery system (SEDDS) were analyzed for optimization. SBA-15 was then added to the ethanol solution containing liquid SEDDS, and the obtained suspension changed into solid SEDDS matrix via solvent evaporation. The characterizations by SEM and XRD revealed that the solid matrix consisted of particles with smooth surface and FNB was completely transformed into molecular or amorphous state in the formulation. When introduced to aqueous media under gentle agitation, the solid matrix exhibited excellent self-emulsification properties and formed a uniform microemulsion with mean diameter of 117.35 ± 2.33 nm. The solid SEDDS matrix showed faster in vitro release rate than the raw powder and commercial capsule. The absorption of FNB delivered by solid SEDDS matrix was significantly improved in beagle dogs, and its Cmax and AUC values were about 8- and 4-fold greater than those of commercial products, respectively. In conclusion, SBA-15 emerged as a promising reservoir for SEDDS to enhance the bioavailability of poorly water-soluble drugs, which may provide a new strategy for advanced therapies.
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http://dx.doi.org/10.1016/j.colsurfb.2016.02.013DOI Listing
May 2016

A honeycomb composite of mollusca shell matrix and calcium alginate.

Colloids Surf B Biointerfaces 2016 Mar 4;139:100-6. Epub 2015 Dec 4.

Key Laboratory of Freshwater Fish Reproduction and Development (Southwest University), Ministry of Education, Chongqing 400715, China; School of Life Science, Southwest University, Chongqing 400715, China.

A honeycomb composite is useful to carry cells for application in bone, cartilage, skin, and soft tissue regenerative therapies. To fabricate a composite, and expand the application of mollusca shells as well as improve preparing methods of calcium alginate in tissue engineering research, Anodonta woodiana shell powder was mixed with sodium alginate at varying mass ratios to obtain a gel mixture. The mixture was frozen and treated with dilute hydrochloric acid to generate a shell matrix/calcium alginate composite. Calcium carbonate served as the control. The composite was transplanted subcutaneously into rats. At 7, 14, 42, and 70 days after transplantation, frozen sections were stained with hematoxylin and eosin, followed by DAPI, β-actin, and collagen type-I immunofluorescence staining, and observed using laser confocal microscopy. The composite featured a honeycomb structure. The control and composite samples displayed significantly different mechanical properties. The water absorption rate of the composite and control group were respectively 205-496% and 417-586%. The composite (mass ratio of 5:5) showed good biological safety over a 70-day period; the subcutaneous structure of the samples was maintained and the degradation rate was lower than that of the control samples. Freezing the gel mixture afforded control over chemical reaction rates. Given these results, the composite is a promising honeycomb scaffold for tissue engineering.
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http://dx.doi.org/10.1016/j.colsurfb.2015.12.006DOI Listing
March 2016