Unraveling the role of CD24 in Hepatocellular carcinoma: Involvement of inactivated Hippo signaling and SOX4-mediated regulation.

Hepatocellular carcinoma (HCC) is a prevalent type of liver cancer, and CD24 gene is reportedly involved in HCC progression. However, the precise regulatory mechanisms of CD24 in HCC remain unclear. In this study, we established a primary HCC mouse model and observed that CD24, induced by inactivation of the Hippo pathway, was highly expressed in HCC.

Immunogenic chemotherapy: great potential for improving response rates.

The activation of anti-tumor immunity is critical in treating cancers. Recent studies indicate that several chemotherapy agents can stimulate anti-tumor immunity by inducing immunogenic cell death and durably eradicate tumors. This suggests that immunogenic chemotherapy holds great potential for improving response rates.

Identification and characterization of novel compound heterozygous variants in causing primary ovarian insufficiency with resistant ovary syndrome.

Primary ovarian insufficiency (POI) is among the foremost causes of women infertility due to premature partial or total loss of ovarian function. Resistant ovary syndrome (ROS) is a subtype of POI manifested as normal ovarian reserve but insensitive to gonadotropin stimulation. Inactivating variants of follicle-stimulating hormone receptor (FSHR), a class A G-protein coupled receptor, have been associated with POI and are inherited an autosomal recessive pattern.

Discovery of Dual TAF1-ATR Inhibitors and Ligand-Induced Structural Changes of the TAF1 Tandem Bromodomain.

Bromodomains regulate chromatin remodeling and gene transcription through recognition of acetylated lysines on histones and other proteins. Bromodomain-containing protein TAF1, a subunit of general transcription factor TFIID, initiates preinitiation complex formation and cellular transcription. TAF1 serves as a cofactor for certain oncogenic transcription factors and is implicated in regulating the p53 tumor suppressor.

Rational Design of Right-Handed Heterogeneous Peptidomimetics as Inhibitors of Protein-Protein Interactions.

Peptidomimetics have gained great attention for their function as protein-protein interaction (PPI) inhibitors. Herein, we report the design and investigation of a series of right-handed helical heterogeneous 1:1 α/Sulfono-γ-AA peptides as unprecedented inhibitors for p53-MDM2 and p53-MDMX. The most potent helical heterogeneous 1:1 α/Sulfono-γ-AA peptides were shown to bind tightly to MDM2 and MDMX, with of 19.

Islet-cell autoantigen 69 accelerates liver regeneration by downregulating Tgfbr1 and attenuating Tgfβ signaling in mice.

Regeneration is a unique defense mechanism of liver tissue in response to functional cell loss induced by toxic chemicals or surgical resection. In this study, we found that Islet-cell autoantigen 69 (Ica69) accelerates liver regeneration in mice. Following 70% partial hepatectomy, both Ica69 mRNA and protein are significantly upregulated in mouse hepatocytes at the early stage of liver regeneration.

α-Helix-Mimicking Sulfono-γ-AApeptide Inhibitors for p53-MDM2/MDMX Protein-Protein Interactions.

The use of peptidomimetic scaffolds is a promising strategy for the inhibition of protein-protein interactions (PPIs). Herein, we demonstrate that sulfono-γ-AApeptides can be rationally designed to mimic the p53 α-helix and inhibit p53-MDM2 PPIs. The best inhibitor, with and IC values of 26 nM and 0.

Mutant p53 Sequestration of the MDM2 Acidic Domain Inhibits E3 Ligase Activity.

Missense p53 mutants often accumulate in tumors and drive progression through gain of function. MDM2 efficiently degrades wild-type p53 but fails to degrade mutant p53 in tumor cells. Previous studies revealed that mutant p53 inhibits MDM2 autoubiquitination, suggesting that the interaction inhibits MDM2 E3 activity.

MDMX acidic domain inhibits p53 DNA binding in vivo and regulates tumorigenesis.

The MDM2 homolog MDMX oncoprotein is indispensable for inhibition of p53 during normal embryonic development and malignant transformation, yet how MDMX harnesses p53 functions is unclear. In addition to a canonical N-terminal p53-binding domain, recent work suggests the central acidic domain of MDMX regulates p53 interaction through intramolecular mimicry and engages in second-site interaction with the p53 core domain in vitro. To test the physiological relevance of these interactions, we generated an MDMX knockin mouse having substitutions in a conserved WW motif necessary for these functions (W201S/W202G).

Tumor cell senescence response produces aggressive variants.

Tumors often respond favorably to initial chemotherapy but eventually relapse with drug resistance and increased metastatic potential. Cellular senescence is a major therapeutic outcome of cancer chemotherapy, which leads to tumor stasis or regression through immune clearance of senescent cells. However, senescent tumor cells have been shown to resume proliferation at low frequency.

Nucleolar repression facilitates initiation and maintenance of senescence.

Tumor cells with defective apoptosis pathways often respond to chemotherapy by entering irreversible cell cycle arrest with features of senescence. However, rare cells can bypass entry to senescence, or re-enter cell cycle from a senescent state. Deficiency in senescence induction and maintenance may contribute to treatment resistance and early relapse after therapy.

hMOF acetylation of DBC1/CCAR2 prevents binding and inhibition of SirT1.

The NAD(+)-dependent deacetylase SirT1 regulates gene silencing and genomic stability in response to nutrient deprivation and DNA damage. An important regulator of SirT1 in mammalian cells is DBC1 (deleted in breast cancer 1; KIAA1967 or CCAR2), which binds to SirT1 and inhibits the deacetylation of substrates. Recent studies have revealed that ATM/ATR-mediated phosphorylation of DBC1 promotes binding to SirT1.

Regulation of SirT1-nucleomethylin binding by rRNA coordinates ribosome biogenesis with nutrient availability.

Nucleomethylin (NML), a novel nucleolar protein, is important for mediating the assembly of the energy-dependent nucleolar silencing complex (eNoSC), which also contains SirT1 and SUV39H1. eNoSC represses rRNA transcription during nutrient deprivation, thus reducing energy expenditure and improving cell survival. We found that NML is an RNA binding protein that copurifies with 5S, 5.

The NAD+ synthesis enzyme nicotinamide mononucleotide adenylyltransferase (NMNAT1) regulates ribosomal RNA transcription.

The chromosomal region encoding the nuclear NAD(+) synthesis enzyme nicotinamide mononucleotide adenylyltransferase (NMNAT1) is frequently deleted in human cancer. We describe evidence that NMNAT1 interacts with the nucleolar repressor protein nucleomethylin and is involved in regulating rRNA transcription. NMNAT1 binds to nucleomethylin and is recruited into a ternary complex containing the NAD(+)-dependent deacetylase SirT1.

Reactive astrocytes contribute to increased epileptic susceptibility induced by subthreshold dose of pilocarpine.

Seizures may influence epileptogenesis, but it is not yet clearly established whether subthreshold stimulations that are not sufficient to induce visible behavioral seizures change epileptic susceptibility, and the possible underlying mechanisms have not been completely understood. We assessed the susceptibility to epilepsy after subthreshold dose of pilocarpine, as well as glial fibrillary acidic protein (GFAP) expression using immunohistochemistry. An increase in the susceptibility to pentylenetetrazole (PTZ)-induced seizures was observed in rats previously subjected to subthreshold dose of pilocarpine.

Synthesis and structure-activity relationship studies of cytotoxic cinnamic alcohol derivatives.

Three series of di- and trisubstituted derivatives of cinnamic alcohol and its conjugated dienol analogues were designed and synthesised. The derivatives were screened for cytotoxicity against nine tumour cell lines: KB, A549, Hela, CNE, PC-3, BEL-7404, HL-60, BGC823 and P388D1. Most of the cinnamic alcohol derivatives showed cytotoxic activity.

Preparation of C-23 esterified silybin derivatives and evaluation of their lipid peroxidation inhibitory and DNA protective properties.

A diverse series of C-23 esterified silybin derivatives (1a-n) were designed and synthesized. The antioxidative properties of these compounds were evaluated by 1,1-diphenyl-2-picrylhydrazyl (DPPH) and superoxide anion radical scavenging, ferrous ion chelation, and inhibition of rat liver homogenate lipid peroxidation. Their protective effects on the prevention of hydrogen peroxide induced DNA damage were also investigated.

[Antioxidative and cytotoxic properties of diarylheptanoids isolated from Zingiber officinale].

Objective: To investigate the antioxidant and cytotoxic properties of five diarylheptanoids (1-5) isolated from the rhizomes of Zingiber officinale.

Method: Various models such as scavenging superoxide anions and 1,1-diphenyl-2- picrylhydrazyl (DPPH) radicals, inhibiting lipid peroxidation, as well as protecting of rat pheochromocytoma (PC12) cells induced by hydrogen peroxide (H2O2) were employed to assay the antioxidative effects of the diarylheptanoids. The cytotoxicities of compounds 1-5 were measured with MTT assays.

Preparation of two sets of 5,6,7-trioxygenated dihydroflavonol derivatives as free radical scavengers and neuronal cell protectors to oxidative damage.

An unusual class of 5,6,7-trioxygenated dihydroflavonols (3a-e and 4a-j) were designed and prepared. Their antioxidative properties were assessed by examining their capacities in several in vitro models, including superoxide anion and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging, rat liver homogenate lipid peroxidation inhibition, PC12 cells protection from oxidative damage, and xanthine oxidase inhibition. These dihydroflavonols displayed positive quenching abilities towards O(2)(-) and DPPH free radicals, in which the majority exhibited superior antioxidant properties to Vitamin C.

Preparation of ferulic acid derivatives and evaluation of their xanthine oxidase inhibition activity.

Several ferulic acid ethyl esters (3a-h) were synthesized under the Knoevengel reaction condition and they were further reduced to afford the respective allylic alcohol derivatives (4a-g). Some of them were evaluated for the xanthine oxidase (XO) inhibitory activity. Among them, 3h exhibited a significant inhibitory activity with an IC50 value of 1.

Hepatoprotective and antioxidative effects of total phenolics from Laggera pterodonta on chemical-induced injury in primary cultured neonatal rat hepatocytes.

Although Laggera pterodonta as a folk medicine has been widely used for several centuries to ameliorate some inflammatory ailments as hepatitis in China, there have been no studies of the hepatoprotective and antioxidative effects of this plant. In this paper, the hepatoprotective effect of total phenolics from L. pterodonta (TPLP) against CCI4-, D-GalN-, TAA-, and t-BHP-induced injury was examined in primary cultured neonatal rat hepatocytes.

Synthesis and biological evaluation of novel compounds related to 1-arylnaphthalene lignans and isoquinolines.

Novel compounds designed as hybrids of 1-arylnaphthalene lignans with isoquinoline alkaloids were prepared and evaluated for their cytotoxicities on human tumor cell lines, such as A549, Hela, PC-3, CNE, BEL-7404, and KB. Some of the synthetic compounds exhibited their IC50 values on selected cell lines at 10(-6) M scale. The preliminary CoMFA molecular-modelling studies of these synthetic analogues were also performed.

Design, synthesis, and biological evaluation of new territrem B analogues.

Some 23 analogues of the potent acetylcholinesterase (AChE) inhibitor territrem B (1) were designed, synthesized, and tested for their biological activities. Some of the new synthetic derivatives exhibited IC50 values for AChE inhibition in the upper micromolar range. Molecular-modeling studies indicated that a planar conformation seems to be crucial for AChE inhibition.