Small molecules as inhibitors of PCSK9: current status and future challenges

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in regulating lipoprotein metabolism by binding to low-density lipoprotein receptors (LDLRs), leading to their degradation. LDL cholesterol (LDL-C) lowering drugs that operate through the inhibition of PCSK9 are being pursued for the management of hypercholesterolemia and reducing its associated atherosclerotic cardiovascular disease (CVD) risk. Two PCSK9-blocking monoclonal antibodies (mAbs), alirocumab and evolocumab, were approved in 2015. However, the high costs of PCSK9 antibody drugs impede their prior authorization practices and reduce their long-term adherence. Given the potential of small-molecule drugs, the development of small-molecule PCSK9 inhibitors has attracted considerable attention. This article provides an overview of the recent development of small-molecule PCSK9 inhibitors disclosed in the literature and patent applications, and different approaches that have been pursued to modulate the functional activity of PCSK9 using small molecules are described. Challenges and potential strategies in developing small-molecule PCSK9 inhibitors are also discussed

Space charge modulated electrical breakdown

Electrical breakdown is one of the most important physical phenomena in electrical and electronic engineering. Since the early 20th century, many theories and models of electrical breakdown have been proposed, but the origin of one key issue, that the explanation for dc breakdown strength being twice or higher than ac breakdown strength in insulating materials, remains unclear. Here, by employing a bipolar charge transport model, we investigate the space charge dynamics in both dc and ac breakdown processes. We demonstrate the differences in charge accumulations under both dc and ac stresses and estimate the breakdown strength, which is modulated by the electric field distortion induced by space charge. It is concluded that dc breakdown initializes in the bulk whereas ac breakdown initializes in the vicinity of the sample-electrode interface. Compared with dc breakdown, the lower breakdown strength under ac stress and the decreasing breakdown strength with an increase in applied frequency, are both attributed to the electric field distortion induced by space charges located in the vicinity of the electrodes

Hypothesis: Caco‐2 cell rotational 3D mechanogenomic turing patterns have clinical implications to colon crypts

Colon crypts are recognized as a mechanical and biochemical Turing patterning model. Colon epithelial Caco‐2 cell monolayer demonstrated 2D Turing patterns via force analysis of apical tight junction live cell imaging which illuminated actomyosin meshwork linking the actomyosin network of individual cells. Actomyosin forces act in a mechanobiological manner that alters cell/nucleus/tissue morphology. We observed the rotational motion of the nucleus in Caco‐2 cells that appears to be driven by actomyosin during the formation of a differentiated confluent epithelium. Single‐ to multi‐cell ring/torus‐shaped genomes were observed prior to complex fractal Turing patterns extending from a rotating torus centre in a spiral pattern consistent with a gene morphogen motif. These features may contribute to the well‐described differentiation from stem cells at the crypt base to the luminal colon epithelium along the crypt axis. This observation may be useful to study the role of mechanogenomic processes and the underlying molecular mechanisms as determinants of cellular and tissue architecture in space and time, which is the focal point of the 4D nucleome initiative. Mathematical and bioengineer modelling of gene circuits and cell shapes may provide a powerful algorithm that will contribute to future precision medicine relevant to a number of common medical disorders.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146665/1/jcmm13853.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146665/2/jcmm13853_am.pd

Culture Change and Affectionate Communication in China and the United States: Evidence From Google Digitized Books 1960–2008

Humans are born with the ability and the need for affection, but communicating affection as a social behavior is historically bound. Based on the digitized books of Google Ngram Viewer from 1960 through 2008, the present research investigated affectionate communication (AC) in China and the United States, and its changing landscape along with social changes from collectivist to individualistic environments. In particular, we analyzed the frequency in terms of verbal affection (e.g., love you, like you), non-verbal affection (e.g., hug, kiss), and individualism (indicated by the use of first-person singular pronouns such as I, me, and myself) in Chinese and American books. The results revealed an increasing trend for AC in recent decades, although the frequency of affection words was lower in Chinese than in American books. Further, individualism was positively related to the frequency of affection words in both Chinese and American books. These results demonstrate the effect of cultural changes on AC, in that affection exchange becomes popular in adaptation to individualistic urban environments. These findings exemplify a cross-cultural difference in the expression of love and the cultural universality of social change in Eastern and Western societies

Synthesis, Biological Evaluation of Fluorescent 23-Hydroxybetulinic Acid Probes, and Their Cellular Localization Studies

© 2018 American Chemical Society. 23-Hydroxybetulinic acid (23-HBA) is a complex lupane triterpenoid, which has attracted increasing attention as an anticancer agent. However, its detailed mechanism of anticancer action remains elusive so far. To reveal its anticancer mode of action, a series of fluorescent 23-HBA derivatives conjugated with coumarin dyes were designed, synthesized, and evaluated for their antiproliferative activities. Subcellular localization and uptake profile studies of representative fluorescent 23-HBA probe 26c were performed in B16F10 cells, and the results suggested that probe 26c was rapidly taken up into B10F10 cells in a dose-dependent manner and mitochondrion was the main site of its accumulation. Further mode of action studies implied that the mitochondrial pathway was involved in 23-HBA-mediated apoptosis. Together, our results provided new clues for revealing the molecular mechanism of natural product 23-HBA for its further development into an antitumor agent

6,7-seco-ent-kauranoids derived from oridonin as potential anticancer agents

Structurally unique 6,7-seco-ent-kaurenes, which are widely distributed in the genus Isodon, have attracted considerable attention because of their antitumor activities. Previously, a convenient conversion of commercially available oridonin (1) to 6,7-seco-ent-kaurenes was developed. Herein, several novel spiro-lactone-type ent-kaurene derivatives bearing various substituents at the C-1 and C-14 positions were further designed and synthesized from the natural product oridonin. Moreover, a number of seven-membered C-ring-expanded 6,7-seco-ent-kaurenes were also identified for the first time. It was observed that most of the spiro-lactone-type ent-kaurenes tested markedly inhibited the proliferation of cancer cells, with an IC50 value as low as 0.55 μM. An investigation on its mechanism of action showed that the representative compound 7b affected the cell cycle and induced apoptosis at a low micromolar level in MCF-7 human breast cancer cells. Furthermore, compound 7b inhibited liver tumor growth in an in vivo mouse model and exhibited no observable toxic effects. Collectively, the results warrant further preclinical investigations of these spiro-lactone-type ent-kaurenes as potential novel anticancer agents

Design, synthesis, and biological evaluation of truncated deguelin derivatives as Hsp90 inhibitors

A series of novel B and C-rings truncated deguelin derivatives have been designed and synthesized in the present study as heat shock protein 90 (Hsp90) inhibitors. The synthesized compounds exhibited micromolar antiproliferative potency toward a panel of human cancer cell lines. Their structure-activity relationships (SARs) were investigated in a systematic manner. Compound 21c was identified to have high Hsp90 binding potency (60 nM) and caused degradation of client proteins through ubiquitin proteasome system. Further biological studies showed that compound 21c induced a dose-dependent S and G2-phase cell cycle arrest on human breast cancer MCF-7 cells. Flow cytometry and Western blot analyses confirmed that compound 21c caused apoptosis of MCF-7 cells. In addition, compound 21c showed much potent inhibition on the migration and invasion of MCF-7 cells. Taken together, these results suggest that 21c might be a promising lead compound for further development of Hsp90 inhibitors