Azaindole derivatives as potential kinase inhibitors and their SARs elucidation.

Currently, heterocycles have occupied an important position in the fields of drug design. Among them, azaindole moiety is regarded as one privileged scaffold to develop therapeutic agents. Since two nitrogen atoms of azaindole increase the possibility to form hydrogen bonds in the adenosine triphosphate (ATP)-binding site, azaindole derivatives are important sources of kinase inhibitors. Moreover, some of them have been on the market or in clinical trials for the treatment of some kinase-related diseases (e.g., vemurafenib, pexidartinib, decernotinib). In this review, we focused on the recent development of azaindole derivatives as potential kinase inhibitors based on kinase targets, such as adaptor-associated kinase 1 (AAK1), anaplastic lymphoma kinase (ALK), AXL, cell division cycle 7 (Cdc7), cyclin-dependent kinases (CDKs), dual-specificity tyrosine (Y)-phosphorylation regulated kinase 1A (DYRK1A), fibroblast growth factor receptor 4 (FGFR4), phosphatidylinositol 3-kinase (PI3K) and proviral insertion site in moloney murine leukemia virus (PIM) kinases. Meanwhile, the structure-activity relationships (SARs) of most azaindole derivatives were also elucidated. In addition, the binding modes of some azaindoles complexed with kinases were also investigated during the SARs elucidation. This review may offer an insight for medicinal chemists to rationally design more potent kinase inhibitors bearing the azaindole scaffold.

CRISPR FISHer enables high-sensitivity imaging of nonrepetitive DNA in living cells through phase separation-mediated signal amplification.

The dynamic three-dimensional structures of chromatin and extrachromosomal DNA molecules regulate fundamental cellular processes and beyond. However, the visualization of specific DNA sequences in live cells, especially nonrepetitive sequences accounting for most of the genome, is still vastly challenging. Here, we introduce a robust CRISPR-mediated fluorescence in situ hybridization amplifier (CRISPR FISHer) system, which exploits engineered sgRNA and protein trimerization domain-mediated, phase separation-based exponential assembly of fluorescent proteins in the CRISPR-targeting locus, conferring enhancements in both local brightness and signal-to-background ratio and thus achieving single sgRNA-directed visualization of native nonrepetitive DNA loci in live cells. In one application, by labeling and tracking the broken ends of chromosomal fragments, CRISPR FISHer enables real-time visualization of the entire process of chromosome breakage, separation, and subsequent intra- or inter-chromosomal ends rejoining in a single live cell. Furthermore, CRISPR FISHer allows the movement of small extrachromosomal circular DNAs (eccDNAs) and invading DNAs to be recorded, revealing substantial differences in dynamic behaviors between chromosomal and extrachromosomal loci. With the potential to track any specified self or non-self DNA sequences, CRISPR FISHer dramatically broadens the scope of live-cell imaging in biological events and for biomedical diagnoses.

PBPK Modeling on Organs-on-Chips: An Overview of Recent Advancements.

Organ-on-a-chip (OoC) is a new and promising technology, which aims to improve the efficiency of drug development and realize personalized medicine by simulating in vivo environment in vitro. Physiologically based pharmacokinetic (PBPK) modeling is believed to have the advantage of better reflecting the absorption, distribution, metabolism and excretion process of drugs in vivo than traditional compartmental or non-compartmental pharmacokinetic models. The combination of PBPK modeling and organ-on-a-chip is believed to provide a strong new tool for new drug development and have the potential to replace animal testing. This article provides the recent development of organ-on-a-chip technology and PBPK modeling including model construction, parameter estimation and validation strategies. Application of PBPK modeling on Organ-on-a-Chip (OoC) has been emphasized, and considerable progress has been made. PBPK modeling on OoC would become an essential part of new drug development, personalized medicine and other fields.

Sulfonamide derivatives as potential anti-cancer agents and their SARs elucidation.

Currently, the arise of drug resistance and undesirable off-target effects of anti-cancer agents are major challenges for cancer treatment, which energizes medicinal chemists to develop more anti-cancer agents with high efficiency and low toxicity continuously. Sulfonamide derivatives are a class of promising compounds with diverse biological activities including anti-cancer, and parts of them have been marketed for cancer therapy, such as Belinostat, ABT-199 and Amsacrine. In this review, we summed up the recent advances of sulfonamide derivatives as potential anti-cancer agents based on the anti-cancer targets, such as aromatase, carbonic anhydrase (CA), anti-apoptotic B-cell lymphoma-2 (Bcl-2) proteins, topoisomerase and phosphatidylinositol 3-kinase (PI3K), and elucidated the corresponding structure-activity relationships (SARs) of most sulfonamide derivatives. We hope this review could provide a clear insight for medicinal chemists in the rational design of more potent and bio-target specific anti-cancer agents.

Relationship Between Plasma Copper Concentration and Body Fat Distribution in Children in China: a Cross-Sectional Study.

This study aimed to explore the association of the plasma copper concentration with body fat distribution and the potential mediating effect of inflammation status in children. A total of 454 children were recruited in this study. Dual-energy X-ray absorptiometry was applied to measure the fat mass (FM) and fat mass percentages (FM%) at whole body, trunk, appendicular, android, and gynoid regions. Android to gynoid fat mass ratio and fat mass to lean mass (FM/LM) ratio at whole body, trunk, and appendicular sites were calculated. Plasma copper concentration was measured via inductively coupled plasma mass spectrometry. C-reactive protein (CRP) was determined by ELISA. After adjusting for covariates, multiple linear regression analyses showed that, for every additional unit increase in the plasma copper concentration, the FM, FM%, and FM/LM at whole body and subregions increased by 0.030-0.472 kg (P < 0.001-0.019), 0.013-1.04% (P = 0.007-0.042), and 0.021-0.030 (P < 0.001), respectively. Mediating analysis suggested that CRP significantly mediated 22.0-30.6% (P < 0.001) of the estimated association of copper with FM% and FM/LM at whole body and limbs. Thus, children with higher plasma levels of copper tended to have a higher regional and overall body fat deposition, and this relationship was partly mediated by inflammatory status.

Caffeic Acid Prevented LPS-Induced Injury of Primary Bovine Mammary Epithelial Cells through Inhibiting NF-κB and MAPK Activation.

In our previous study, lipopolysaccharide (LPS) significantly reduced the cell viability of primary bovine mammary epithelial cells (bMEC) leading to cell apoptosis, which were prevented by caffeic acid (CA) through inhibiting NF-κB activation and reducing proinflammatory cytokine expression. While the underlying mechanism remains unclear, here, we determined that LPS induced the extensive microstructural damage of bMEC, especially the mitochondria and endoplasmic reticulum. Then, the obvious reduction of mitochondrial membrane potential and expression changes of apoptosis-associated proteins (Bcl-2, Bax, and casepase-3) indicated that apoptosis signaling through the mitochondria should be responsible for the cell viability decrease. Next, the high-throughput cDNA sequencing (RNA-Seq) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were employed to verify that the MAPK and JAK-STAT signaling pathways also were the principal targets of LPS. Following, the critical proteins (ERK, JNK, p38, and c-jun) of the MAPK signaling pathways were activated, and the release of proinflammatory cytokines (TNF-α, IL-1ß, IL-6, and IL-8) regulated by NF-κB and MAPKs was significantly increased, which can promote a cascade of inflammation that induces cell injury and apoptosis. Meanwhile, CA significantly inhibited the activation of MAPKs and the release of proinflammatory cytokines in a dose-dependent manner, which were similar to its effects on the NF-κB activation that we previously published. So we concluded that CA regulates the proteins located in the upstream of multiple cell signal pathways which can reduce the LPS-induced activation of NF-κB and MAPKs, thus weakening the inflammatory response and maintaining cell structure and function, which accordingly inhibit apoptosis.