Bromodomain
and extraterminal (BET) proteins bind acetylated lysine
residues in histones and nonhistone proteins via tandem bromodomains
and regulate chromatin dynamics, cellular processes, and disease procession.
Thus targeting BET proteins is a promising strategy for treating various
diseases, especially malignant tumors and chronic inflammation. Many
pan-BET small-molecule inhibitors have been described, and some of
them are in clinical evaluation. Nevertheless, the limited clinical
efficacy of the current BET inhibitors is also evident and has inspired
the development of new technologies to improve their clinical outcomes
and minimize unwanted side effects. In this Review, we summarize the
latest protein characteristics and biological functions of BRD4 as
an example of BET proteins, analyze the clinical development status
and preclinical resistance mechanisms, and discuss recent advances
in BRD4-selective inhibitors, dual-target BET inhibitors, proteolysis
targeting chimera degraders, and protein–protein interaction
inhibitors.
Background Modic changes are the MRI signal changes of degenerative lumbar vertebral endplate and which lead to or accelerate intervertebral disc degeneration. NLRP3, caspase-1, and interleukin-1b (IL-1b) play a pivotal role in the pathogenesis of many inflammatory diseases, such as osteoarthritis. However, the roles of IL-1b and its activators caspase-1 and NLRP3 are unclear in the degenerative endplate.Questions/purposes We asked: (1) What are the degenerative changes of the histologic features and chondrogenic markers' gene expressions between the cartilaginous endplates of patients with Modic changes and trauma (control)? (2) How does the NLRP3/caspase-1/IL-1b axis in the cartilaginous endplates of patients with Modic changes compare with control (trauma) specimens? Methods Surgical specimens of cartilaginous endplates were divided into Modic changes (n = 56) and the trauma control (n = 16) groups. Hematoxylin and eosin and safranin O staining of cartilaginous endplate tissues were done to evaluate the extracellular matrix. Reverse transcription-polymerase chain reaction was performed on these tissues to investigate mRNA expression of type II collagen (Col II), SOX-9, matrix metalloproteinase-3, and a disintegrin like and metalloproteinase thrombospondin type I motifs-5. NLRP3, caspase-1, and IL-1b were evaluated by reverse transcription-polymerase chain reaction and immunohistochemistry. Results Hematoxylin and eosin and safranin O staining showed the extracellular matrix degraded in the cartilaginous endplates of patients with Modic changes but not in the control cartilaginous endplates. Chondrogenic Col II (p = 0.024) and SOX9 (p = 0.053) were downregulated in the Modic changes group compared with the control group. In contrast to the control group, the transcriptional levels of
In the southern Sichuan Basin, China, the recent increase in the seismic activity has been suspected to be related to hydraulic fracturing stimulation for producing the shale gas. In this study, we used the monitoring data from a local seismic network within the shale gas blocks to study the earthquakes near the shale gas production wells that have detailed injection data. Comparison of the timing of earthquakes and stimulation schedule of the studied well pads indicates an apparent correlation between the seismic activity and hydraulic fracturing. The results of seismic velocity tomography reveal that the reactivation of preexisting faults due to fluid diffusion is the primary cause of the observed earthquakes. Focal mechanism analysis combined with geomechanical modeling indicates that the increased pore pressures resulted from hydraulic fracturing are sufficient to trigger seismic slip on the faults.
Data-independent acquisition mass spectrometry (DIA-MS) is a powerful technique that enables relatively deep proteomic profiling with superior quantification reproducibility. DIA data mining predominantly relies on a spectral library of sufficient proteome coverage that, in most cases, is built on datadependent acquisition-based analysis of the same sample. To expand the proteome coverage for a pre-determined protein family, we report herein on the construction of a hybrid spectral library that supplements a DIA experiment-derived library with a protein family-targeted virtual library predicted by deep learning. Leveraging this DIA hybrid library substantially deepens the coverage of three transmembrane protein families (G protein-coupled receptors, ion channels, and transporters) in mouse brain tissues with increases in protein identification of 37%-87% and peptide identification of 58%-161%. Moreover, of the 412 novel GPCR peptides exclusively identified with the DIA hybrid library strategy, 53.6% were validated as present in mouse brain tissues based on orthogonal experimental measurement.
Blocking the interactions between
bromodomain and extraterminal
(BET) proteins and acetylated lysines of histones by small molecules
has important implications for the treatment of cancers and other
diseases. Many pan-BET inhibitors have shown satisfactory results
in clinical trials, but their potential for poor tolerability and
toxicity persist. However, recently reported studies illustrate that
some BET bromodomain (BET-BD1 or BET-BD2)-selective inhibitors have
advantage over pan-inhibitors, including reduced toxicity concerns.
Furthermore, some selective BET inhibitors have similar or even better
therapeutic efficacy in inflammatory diseases or cancers. Therefore,
the development of selective BET inhibitors has become a hot spot
for medicinal chemists. Here, we summarize the known selective BET-BD1
and BET-BD2 inhibitors and review the methods for enhancing the selectivity
and potency of these inhibitors based on their different modes of
interactions with BET-BD1 or BET-BD2. Finally, we discuss prospective
strategies that selectively target the bromodomains of BET proteins.
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