Nanoparticle formulation of mycophenolate mofetil achieves enhanced efficacy against hepatocellular carcinoma by targeting tumour-associated fibroblast

Hepatocellular carcinoma (HCC) is one of the most aggressive tumours with marked fibrosis. Mycophenolate mofetil (MMF) was well-established to have antitumour and anti-fibrotic properties. To overcome the poor bioavailability of MMF, this study constructed two MMF nanosystems, MMF-LA@DSPE-PEG and MMF-LA@PEG-PLA, by covalently conjugating linoleic acid (LA) to MMF and then loading the conjugate into polymer materials, PEG_5k-PLA_8k and DSPE- PEG_2k, respectively. Hepatocellular carcinoma cell lines and C57BL/6 xenograft model were used to examine the anti-HCC efficacy of nanoparticles (NPs), whereas NIH-3T3 fibroblasts and highly-fibrotic HCC models were used to explore the anti-fibrotic efficacy. Administration of NPs dramatically inhibited the proliferation of HCC cells and fibroblasts in vitro. Animal experiments revealed that MMF-LA@DSPE-PEG achieved significantly higher anti-HCC efficacy than free MMF and MMF-LA@PEG-PLA both in C57BL/6 HCC model and highly-fibrotic HCC models. Immunohistochemistry further confirmed that MMF-LA@DSPE-PEG dramatically reduced cancer-associated fibroblast (CAF) density in tumours, as the expression levels of alpha-smooth muscle actin (α-SMA), fibroblast activation protein (FAP) and collagen IV were significantly downregulated. In addition, we found the presence of CAF strongly correlated with increased HCC recurrence risk after liver transplantation. MMF-LA@DSPE-PEG might act as a rational therapeutic strategy in treating HCC and preventing post-transplant HCC recurrence.     

New Phenylpropanoid Glycosides from Illicium majus and Their Radical Scavenging Activities

Chemical investigation of the ethanol extract of the branch and leaves of Illicium majus resulted in the isolation of four new phenylpropanoid glycosides ( 1 – 4 ) and one new phenolic glycoside ( 9 ), along with 13 known ones. Spectroscopic techniques were used to elucidate the structures of the new isolates such as 3-[(2R,3S)-7-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-3-(hydroxymethyl)-2,3-dihydro-1-benzofuran-5-yl]propyl β-D-glucopyranoside ( 1 ), [(2R,3S)-7-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-5-(3-hydroxypropyl)-2,3-dihydro-1-benzofuran-3-yl]methyl 2-O-α-L-rhamnopyranosyl-β-D-glucopyranoside ( 2 ), [(2R,3S)-7-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-5-(3-hydroxypropyl)-2,3-dihydro-1-benzofuran-3-yl]methyl 2-O-α-L-rhamnopyranosyl-β-D-xylopyranoside ( 3 ), 3-[(2R,3S)-3-({[2-O-(4-O-acetyl-α-L-rhamnopyranosyl)-β-D-xylopyranosyl]oxy}methyl)-7-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-2,3-dihydro-1-benzofuran-5-yl]propyl acetate ( 4 ), and 4-(2-hydroxyethyl)phenyl 3-O-β-D-glucopyranosyl-β-D-glucopyranoside ( 9 ). Free radical scavenging activities of the isolates were elucidated through the DPPH assay method. The most active compounds, 1-O-caffeoyl-β-D-glucopyranose ( 17 ) and soulieana acid 1 ( 18 ), exhibited moderate radical scavenging activities (IC₅₀=37.7±4.4 μM and IC₅₀=97.2±3.4 μM, respectively). The antibacterial activities of the isolates against Staphylococcus aureus and Escherichia coli were also assessed, and no activity was shown at the measured concentration (<32 μg/mL).     

PRPF6 promotes androgen receptor/androgen receptor-variant 7 actions in castration-resistant prostate cancer cells

Androgen receptor (AR) and its variants play vital roles in development and progression of prostate cancer. To clarify the mechanisms involved in the enhancement of their actions would be crucial for understanding the process in prostate cancer and castration-resistant prostate cancer transformation. Here, we provided the evidence to show that pre-mRNA processing factor 6 (PRPF6) acts as a key regulator for action of both AR full length (AR-FL) and AR variant 7 (AR-V7), thereby participating in the enhancement of AR-FL and AR-V7-induced transactivation in prostate cancer. In addition, PRPF6 is recruited to cis-regulatory elements in AR target genes and associates with JMJD1A to enhance AR-induced transactivation. PRPF6 also promotes expression of AR-FL and AR-V7. Moreover, PRPF6 depletion reduces tumor growth in prostate cancer-derived cell lines and results in significant suppression of xenograft tumors even under castration condition in mouse model. Furthermore, PRPF6 is obviously highly expressed in human prostate cancer samples. Collectively, our results suggest PRPF6 is involved in enhancement of oncogenic AR signaling, which support a previously unknown role of PRPF6 during progression of prostate cancer and castration-resistant prostate cancers.     

Advancement and properties of circular RNAs in prostate cancer: An emerging and compelling frontier for discovering

Prostate cancer (PC) is the most common carcinoma among men worldwide which results in 26% of leading causes of cancer-related death. However, the ideal and effective molecular marker remains elusive. CircRNA, initially observed in plant-infected viruses and Sendai virus in 1979, is generated from pre-mRNA back-splicing and comes in to play by adequate expression. The differential expression in prostate tissues compared with the control reveals the promising capacity in modulating processes including carcinogenesis and metastasis. However, the biological mechanisms of regulatory network in PC needs to systemically concluded. In this review, we enlightened the comprehensive studies on the definite mechanisms of circRNAs affecting tumor progression and metastasis. What''s more, we validated the potential clinical application of circRNAs serving as diagnostic and prognostic biomarker. The discussion and analysis in circRNAs will broaden our knowledge of the pathogenesis of PC and further optimize the current therapies against different condition.     

The involvement of α-proteobacteria Phenylobacterium in maintaining the dominance of toxic Microcystis blooms in Lake Taihu,China

Lake Taihu in China has suffered serious harmful cyanobacterial blooms for decades. The algal blooms threaten the ecological sustainability, drinking water safety, and human health. Although the roles of abiotic factors (such as water temperature and nutrient loading) in promoting Microcystis blooms have been well studied, the importance of biotic factors (e.g. bacterial community) in promoting and meditating Microcystis blooms remains unclear. In this study, we investigated the ecological dynamics of bacterial community, the ratio of toxic Microcystis, as well as microcystin in Lake Taihu. High-throughput 16S rRNA sequencing and principal component analysis (PCA) revealed that the bacteria community compositions (BCCs) clustered into three groups, the partitioning of which corresponded to that of groups according to the toxic profiles (the ratio of toxic Microcystis to total Microcystis, and the microcystin concentrations) of the samples. Further Spearman's correlation network showed that the α-proteobacteria Phenylobacterium strongly positively correlated with the toxic profiles. Subsequent laboratory chemostats experiments demonstrated that three Phenylobacterium strains promoted the dominance of the toxic Microcystis aeruginosa PCC7806 when co-culturing with the non-toxic PCC7806 mcyB⁻ mutant. Taken together, our data suggested that the α-proteobacteria Phenylobacterium may play a vital role in the maintenance of toxic Microcystis dominance in Lake Taihu.     

Possible pharmaceutical applications can be developed from naturally occurring phenanthroindolizidine and phenanthroquinolizidine alkaloids

Naturally occurring phenanthroindolizidine and phenanthroquinolizidine alkaloids (PIAs and PQAs) are two small groups of herbal metabolites sharing a similar pentacyclic structure with a highly oxygenated phenanthrene moiety fused with a saturated or an unsaturated N-heterocycle (indolizidine/quinolizidine moieties). Natural PIAs and PQAs only could be obtained from finite plant families (such as Asclepiadaceae, Lauraceae and Urticaceae families, etc.). Up to date, more than one hundred natural PIAs, while only nine natural PQAs had been described. PIA and PQA analogues have been applied to the development of potent anticancer agents all along because of their excellent cytotoxic activity. However, in the last two decades, other great biological properties, such as anti-inflammatory and antiviral activities were revealed successively by different pharmacological assays. Especially because of their potent antiviral activity against coronavirus (TGEV, SARS CoV and MHV) and tobacco mosaic virus, PIA and PQA analogues have attracted much pharmaceutical attention again, some of them have been used to present interesting targets for total or semi synthesis, and structure–activity relationship (SAR) study for the development of antiviral agents. In this review, natural PIA and PQA analogues obtained in the last two decades with their herbal origins, key spectroscopic characteristics for structural identification, biological activity with possible SARs and application prospects were systematically summarized. We hope this paper can stimulate further investigations on PIA and PQA analogues as an important source for potential drug discovery.

     

Nuclear-localized eukaryotic translation initiation factor 1A is involved in mouse preimplantation embryo development

Journal of Molecular Histology - Preimplantation embryo development is characterized by drastic nuclear reprogramming and dynamic stage-specific gene expression. Key regulators of this earliest...     

Loss of longitudinal superiority marks the microarchitecture deterioration of osteoporotic cancellous bones

Biomechanics and Modeling in Mechanobiology - Osteoporosis (OP), a skeletal disease making bone mechanically deteriorate and easily fracture, is a global public health issue due to its high...