Fms-like tyrosine kinase 3 (FLT3) has been validated as a therapeutic target for acute myeloid leukemia (AML). While a number of FLT3 kinase inhibitors have been approved for AML treatment, the ...clinical data revealed that they cannot achieve complete and sustained suppression of FLT3 signaling at the tolerated dose. Here we report a series of new, potent and selective FLT3 proteolysis targeting chimera degraders. The optimal compound LWY713 potently induced the degradation of FLT3 with a DC
value of 0.64 nM and a D
value of 94.8% in AML MV4-11 cells with FLT3-internal tandem duplication (ITD) mutation. Mechanistic studies demonstrated that LWY713 selectively induced FLT3 degradation in a cereblon- and proteasome-dependent manner. LWY713 potently inhibited FLT3 signaling, suppressed cell proliferation, and induced cell G0/G1-phase arrest and apoptosis in MV4-11 cells. Importantly, LWY713 displayed potent in vivo antitumor activity in MV4-11 xenograft models.
NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3), a member of the nucleotide-binding domain (NOD) and leucine-rich repeat sequence (LRR) protein (NLR) family, plays an essential role in the ...inflammation initiation and inflammatory mediator secretion, and thus is also associated with many disease progressions. Food-derived bioactive peptides (FDBP) exhibit excellent anti-inflammatory activity in both
and
models. They are encrypted in plant, meat, and milk proteins and can be released under enzymatic hydrolysis or fermentation conditions, thereby hindering the progression of hyperuricemia, inflammatory bowel disease, chronic liver disease, neurological disorders, lung injury and periodontitis by inactivating the NLRP3. However, there is a lack of systematic review around FDBP, NLRP3, and NLRP3-related diseases. Therefore, this review summarized FDBP that exert inhibiting effects on NLRP3 inflammasome from different protein sources and detailed their preparation and purification methods. Additionally, this paper also compiled the possible inhibitory mechanisms of FDBP on NLRP3 inflammasomes and its regulatory role in NLRP3 inflammasome-related diseases. Finally, the progress of cutting-edge technologies, including nanoparticle, computer-aided screening strategy and recombinant DNA technology, in the acquisition or encapsulation of NLRP3 inhibitory FDBP was discussed. This review provides a scientific basis for understanding the anti-inflammatory mechanism of FDBP through the regulation of the NLRP3 inflammasome and also provides guidance for the development of therapeutic adjuvants or functional foods enriched with these FDBP.
Abstract Wheat germ agglutinin-modified lipid-polymer hybrid nanoparticles (WGA-LPNs) promote cellular uptake after oral delivery via receptor-mediated endocytosis and bioadhesion. Understanding the ...mucosal transport of WGA-LPNs would help to improve bioavailability and ensure therapeutic efficacy. In this study, WGA-LPNs interacted with mucin, forming larger agglomerates with intact core-shell structure. The interaction of WGA-LPNs with mucin improved enterocyte endocytosis in Caco-2 cells. An in situ intestinal diffusion study in mice confirmed that WGA-LPNs reached enterocytes and underwent endocytosis, despite interference from mucin. Importantly, oral bioavailability of oridonin-loaded WGA-LPNs increased by 1.96-fold compared with that of LPNs. Furthermore, oral administration of WGA-LPNs inhibited tumor growth in HepG2 xenograft nude mice. In addition to elucidating interactions between WGA-LPNs and mucin, these results indicated WGA-LPNs might act as promising nanocarriers for oral delivery of drugs.
The mechanism of RASSF1A in DNA damage repair remains to be further clarified for applying to synthetic lethal strategy.
Eight esophageal cancer cell lines, 181 cases of esophageal dysplasia and 1066 ...cases of primary esophageal squamous cell carcinoma (ESCC) were employed. Methylation-specific PCR, the CRISPR/Cas9 technique, immunoprecipitation assay and a xenograft mouse model were used.
was methylated in 2.21% of esophageal dysplasia and 11.73% of ESCC. RASSF1A was also involved in DNA damage repair through activating Hippo signaling. Loss of
expression sensitized esophageal cancer cell lines to ataxia telangiectasia mutated and rad3-related (ATR) inhibitor (VE-822) both
and
.
methylation is a synthetic lethal marker for ATR inhibitors.
Key message
A novel rice resistance gene,
Xo2
, influencing pathogenesis of the bacterial leaf streak disease, has been identified, and candidate genes for
Xo2
in the fine mapping region have been ...shown to be involved in bacterial leaf streak resistance.
Rice (
Oryza sativa
) bacterial leaf streak, caused by
Xanthomonas oryzae
pv.
oryzicola
(
Xoc
), is one of the most serious rice bacterial diseases. The deployment of host resistance genes is an effective approach for controlling this disease. The cultivar BHADOIA 303 (X455) from Bangladesh is resistant to most of Chinese
Xoc
races. To identify and map the resistance gene(s) involved in
Xoc
resistance, we examined the association between phenotypic and genotypic variations in two F
2
populations derived from crosses between X455/Jingang 30 and X455/Wushansimiao. The segregation ratios of the F
2
progeny were consistent with the action of a single dominant resistance gene, which was designated as
Xo2
. Based on rice SNP chip (GSR40K) assays of X455, Jingang 30, and resistant and susceptible pools thereof, we mapped
Xo2
to the region from 10 Mb to 12.5 Mb on chromosome 2. The target gene was further finely mapped between the markers RM12941 and D6-1 within an approximately 110-kb region. The de novo sequencing and gene annotation of X455 and Jingang 30 revealed nineteen predicted genes within the target region. RNA-seq and expression analysis showed that four candidate genes, including
Osa002T0115800
, encoding an NLR resistance protein, were distinctly upregulated. Differential sequence and synteny analysis between X455 and Jingang 30 suggested that
Osa002T0115800
is likely the functional
Xo2
gene. This study lays a foundation for marker-assisted selection resistance breeding against rice bacterial leaf streak and the further cloning of
Xo2
.
To determine whether human anti-LRP4/agrin antibodies are pathogenic in mice and to investigate underpinning pathogenic mechanisms.
Immunoglobulin (Ig) was purified from a patient with myasthenia ...gravis (MG) with anti-LRP4/agrin antibodies and transferred to mice. Mice were characterized for body weight, muscle strength, twitch and tetanic force, neuromuscular junction (NMJ) functions including compound muscle action potential (CMAP) and endplate potentials, and NMJ structure. Effects of the antibodies on agrin-elicited muscle-specific tyrosine kinase (MuSK) activation and AChR clustering were studied and the epitopes of these antibodies were identified.
Patient Ig-injected mice had MG symptoms, including weight loss and muscle weakness. Decreased CMAPs, reduced twitch and tetanus force, compromised neuromuscular transmission, and NMJ fragmentation and distortion were detected in patient Ig-injected mice. Patient Ig inhibited agrin-elicited MuSK activation and AChR clustering. The patient Ig recognized the β3 domain of LRP4 and the C-terminus of agrin and reduced agrin-enhanced LRP4-MuSK interaction.
Anti-LRP4/agrin antibodies in the patient with MG is pathogenic. It impairs the NMJ by interrupting agrin-dependent LRP4-MuSK interaction.
Adipocyte differentiation involves a series of highly synergistic processes, including clone amplification, proliferation arrest, and terminal differentiation. However, the mechanisms that control ...these different steps remain unclear. Emerging studies support that miRNAs play an important role in regulating adipogenesis. In this study, we found that the expression of miR-345-5p decreased during adipogenic differentiation, and overexpression of miR-345-5p reduced lipid accumulation in adipocytes and the expression of adipocyte related genes essential to lipogenic transcription, fatty acid synthesis and fatty acid transport. In addition, miR-345-5p directly targeted the 3'UTR of vascular endothelial growth factor B, and miR-345-5p mimic inhibited the expression of vascular endothelial growth factor B at both mRNA and protein levels. In conclusion, our results demonstrate that miR-345-5p inhibits adipocyte differentiation via targeting vascular endothelial growth factor B.
Six steroidal saponins were isolated from
Anemarrhena asphodeloides Bunge (Liliaceae), a traditional chinese medicine, and named anemarrhenasaponin I (An-I), anemarrhenasaponin Ia (An-Ia), ...timosaponin B-I (TB-I), timosaponin B-II (TB-II), timosaponin B-III (TB-III), and timosaponin A-III (TA-III). The effects of these six compounds on platelet aggregation and hemolysis in human blood were studied. All these compounds provoked remarkable inhibiting effect on platelet aggregation, and activated partial thromboplastin times (APTT) are sensitive to the presence of these six compounds. Using an in vitro system, APTT was delayed with the increment of the concentrations of these six compounds. In these six compounds, only timosaponin A-III appeared a strong effect on hemolysis, and anemarrhenasaponin Ia had a slight effect on hemolysis, other had no effect on hemolysis. These results suggested that these steroidal saponins isolated from
Anemarrhena asphodeloides Bunge (Liliaceae) might be used as a novel antithrombotic therapeutic agents in post-myocardial infarction.
The binding mode and stoichiometry of the cationic porphyrin TMPyP4 to G-quadruplex structure are still controversial to date, mainly due to the intricate polymorphism of G-rich sequences in the ...different conditions of solution. Here in the presence of the molecular crowding agent PEG, the binding interaction of TMPyP4 and another porphyrin derivative TPrPyP4 with four-stranded parallel (G(4)T(4)G(4))4 G-quadruplex was studied systematically using circular dichroism, visible absorption titration, and steady-state and time-resolved fluorescence spectroscopies. The results show that each (G(4)T(4)G(4))4 molecule is able to bind four TMPyP4 or TPrPyP4 molecules. Two types of independent and nonequivalent binding sites with the higher and lower binding affinity are confirmed, and the stronger and weaker binding constants are 2.74 x 10(8) and 8.21 x 10(5)M(-1) for (G(4)T(4)G(4))4-TMPyP4, 2.05 x 10(8) and 1.05 x 10(6)M(-1) for (G(4)T(4)G(4))4-TPrPyP4, respectively. The two porphyrin molecules stack on the two ends of G-quadruplex with the higher binding affinity, another two porphyrins bind weakly to the two external grooves.
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