Pharmacal Research

Preventive approach for overcoming dementia Abstract Dementia is used as a general term to describe chronic disorders of mental processes caused by the deterioration of cognitive functions to the extent that one’s ability to perform daily activities is impaired. Currently, age is known to be the main risk factor for dementia, suggesting that the risk of being diagnosed with dementia significantly increases later in one’s life. Therefore, there are two approaches one can take when confronting dementia: to cure it when it occurs in late adulthood or to prevent the onset of symptoms beforehand. Recently, the latter strategy of delaying and preventing Alzheimer’s disease, the most prevalent form and most studied type of dementia, through both pharmaceutical and nonpharmaceutical interventions is becoming increasingly recognized. In this review, we discuss studies conducted in various fields that addresses nonpharmaceutical lifestyle interventions, including diet, physical activity, cognitive stimulation, and social engagement, and their effects in preventing and inhibiting dementia.

Phosphatidylserine receptor-targeting therapies for the treatment of cancer Abstract Asymmetric distribution of phospholipids across the plasma membrane is a unique characteristic of eukaryotic cells. Phosphatidylcholine and sphingomyelin are exposed in the outer leaflet, and phosphatidylserine (PS) is predominantly located in the inner leaflet. Redistribution of PS to the cell surface can be observed in several physiological conditions, such as apoptosis and platelet activation, or in pathological conditions, such as the release of microvesicles/exosomes from tumor tissues. PS binding to the phosphatidylserine receptor (PSR) on immune cells initiates immunosuppressive pathways that can lead to immune evasion by cancer cells. Conversely, PSR activation of cancer cells plays an important role in their survival, proliferation and metastasis. Herein, we briefly summarize both recent advances in our understanding of the pathological roles of PS and its receptor in cancer biology, as well as relevant pharmacological approaches.

Idelalisib inhibits osteoclast differentiation and pre-osteoclast migration by blocking the PI3Kδ-Akt-c-Fos/NFATc1 signaling cascade Abstract Since increased number of osteoclasts could lead to impaired bone structure and low bone mass, which are common characteristics of bone disorders including osteoporosis, the pharmacological inhibition of osteoclast differentiation is one of therapeutic strategies for preventing and/or treating bone disorders and related facture. However, little data are available regarding the functional relevance of phosphoinositide 3-kinase (PI3K) isoforms in the osteoclast differentiation process. To elucidate the functional involvement of PI3Kδ in osteoclastogenesis, here we investigated how osteoclast differentiation was influenced by idelalisib (also called CAL-101), which is p110δ-selective inhibitor approved for the treatment of specific human B cell malignancies. Here, we found that receptor activator of nuclear factor kappa B ligand (RANKL) induced PI3Kδ protein expression, and idelalisib inhibited RANKL-induced osteoclast differentiation. Next, the inhibitory effect of idelalisib on RANKL-induced activation of the Akt-c-Fos/NFATc1 signaling cascade was confirmed by western blot analysis and real-time PCR. Finally, idelalisib inhibited pre-osteoclast migration in the last stage of osteoclast differentiation through down-regulation of the Akt-c-Fos/NFATc1 signaling cascade. It may be possible to expand the clinical use of idelalisib for controlling osteoclast differentiation. Together, the present results contribute to our understanding of the clinical value of PI3Kδ as a druggable target and the efficacy of related therapeutics including osteoclastogenesis.

Applications of deep learning for the analysis of medical data Abstract Over the past decade, deep learning has demonstrated superior performances in solving many problems in various fields of medicine compared with other machine learning methods. To understand how deep learning has surpassed traditional machine learning techniques, in this review, we briefly explore the basic learning algorithms underlying deep learning. In addition, the procedures for building deep learning-based classifiers for seizure electroencephalograms and gastric tissue slides are described as examples to demonstrate the simplicity and effectiveness of deep learning applications. Finally, we review the clinical applications of deep learning in radiology, pathology, and drug discovery, where deep learning has been actively adopted. Considering the great advantages of deep learning techniques, deep learning will be increasingly and widely utilized in a wide variety of different areas in medicine in the coming decades.

Targeting ROCK/LIMK/cofilin signaling pathway in cancer Abstract Rho-associated coiled-coil-containing protein kinase (ROCK)/Lin11, Isl-1 and Mec-3 kinase (LIMK)/cofilin-signaling cascades are stimulated by receptor tyrosine kinases, G protein-coupled receptors, integrins and its ligands, growth factors, hormones, fibronectin, collagen, and laminin. Activated signaling cascades can cause transit from normal cells to cancer cells by modulating actin/filament dynamics. In various cancers including breast, prostate, and colorectal cancers, high expression or activity of each cascade protein is significantly associated with poor survival rate of patients as well as aggressive metastasis. Silencing ROCK, LIMK, or cofilin can abrogate their activities and inhibit cancer cell growth, invasion, and metastasis. Therefore ROCK/LIMK/cofilin signaling proteins might be good candidates to develop cancer prevention strategies or therapeutics. Currently, netarsudil, a ROCK inhibitor, is only used in clinical patients for glaucoma or ocular hypertension, but not for cancer. In this review, we will discuss comprehensive ROCK/LIMK/cofilin signaling pathway in cancers and its inhibitors for developing cancer therapy.

Flavonoid morin inhibits proliferation and induces apoptosis of melanoma cells by regulating reactive oxygen species, Sp1 and Mcl-1 Abstract Reactive oxygen species (ROS) is associated with cancer progression in different cancers, including melanoma. It also affects specificity protein (Sp1), a transcription factor. Flavonoid morin is known to inhibit growth of cancer cells, including lung cancer and breast cancer. Herein, we hypothesized that morin can inhibit cancer activities in melanoma by altering ROS generation. The aim of this study is to determine the effects of morin and its underlying mechanisms in melanoma cells. Effects of morin on cell proliferation and apoptosis were determined using standardized assays. Changes in pro-apoptotic and anti-apoptotic proteins were analyzed by western blot analysis. Cellular ROS levels and mitochondrial function were evaluated by measuring DCF-DA fluorescence and rhodamine-123 fluorescence intensities, respectively. Morin induced ROS production and apoptosis, as presented by increased proportion of cells with Annexin V-PE(+) staining and sub-G0/G1 peak in cell cycle analysis. It also downregulated Sp1, Mcl-1, Bcl-2, and caspase-3 but upregulated cleaved caspase-3, Bax, and PUMA. In immunohistochemical staining, Sp1 was overexpressed in melanoma tissues compared to normal skin tissues. Collectively, our data suggest that morin can induce apoptosis of melanoma cells by regulating pro-apoptotic and anti-apoptotic proteins through ROS, and may be a potential substance for treatment of melanoma.

A new anti- Helicobacter pylori juglone from Reynoutria japonica Abstract A 70% ethanol extract from the root portion of Reynoutria japonica afforded one new and three known juglone derivatives, namely, 2-methoxy-6-acetyl-7-methyljuglone (1), 2-ethoxy-6-acetyl-7-methyljuglone (2), 2-methoxy-7-acetonyljuglone (3), and 3-acetyl-7-methoxy-2-methyljuglone (4) together with two phenolics (5 and 6), an anthraquinone (7), a stilbene (8) and a phthalide (9). Their structures were elucidated on the basis of comprehensive spectroscopic studies including IR, MS, and 1H, 13C, 2D NMR spectra. Compound 3 is a new compound in nature, and compounds 4–6 have been isolated for the first time from R. japonica. The isolates were evaluated for their antibacterial activity against three strains (43504, 51, and 26695) of Helicobacter pylori. The four isolated juglone derivatives (1–4) showed potent growth inhibitory activity. Among them, compounds 1–3 exhibited stronger inhibitory activity than those of the positive controls, juglone and metronidazole, for the three strains and that of another reference, clarithromycin, for the 43504 and 51 strains. Specifically, the new juglone compound 3 displayed the most potent antibacterial activity against all three strains, 43504, 51, and 26695, with MIC values of 0.06, 0.06 and 0.13 μM, respectively, and MIC50 values of 0.14, 0.11 and 0.15 μM, respectively.

The YB-1/EZH2/amphiregulin signaling axis mediates LPA-induced breast cancer cell invasion Abstract Lysophosphatidic acid (LPA) has been known to induce epithelial-mesenchymal transition (EMT) to stimulate cancer cell invasion, and resveratrol (3,5,4′-trans-trihydroxystilbene; REV) suppresses the invasion and metastasis of various cancers. The current study aimed to identify the underlying mechanism by which LPA aggravates breast cancer cell invasion and the reversal of this phenomenon. Immunoblotting and quantitative RT-PCR analysis revealed that LPA induces amphiregulin (AREG) expression. Silencing of Y-box binding protein 1 (YB-1) or enhancer of zeste homolog 2 (EZH2) expression efficiently inhibited LPA-induced AREG expression. In addition, transfection of the cells with YB-1 siRNA abrogated LPA-induced EZH2 and AREG expression, leading to attenuation of breast cancer cell invasion. Furthermore, we observed that both REV and 5-fluorouracil (5-Fu) significantly reduce LPA-induced YB-1 phosphorylation and subsequent breast cancer invasion. Importantly, combined treatment of REV with 5-Fu showed more significant inhibition of LPA-induced breast cancer invasion compared to single treatment. Therefore, our data demonstrate that the YB-1/EZH2 signaling axis mediates LPA-induced AREG expression and breast cancer cell invasion and its inhibition by REV and 5-Fu, providing potential therapeutic targets and inhibition of breast cancer.

Three new ent -abietane diterpenoids from the roots of Euphorbia fischeriana and their cytotoxicity in human tumor cell lines Abstract Three new ent-abietane diterpenoids, termed fischerianoids A–C (1–3), were isolated and identified from the ethyl acetate extracts of roots of the medicinally valuable plant Euphorbia fischeriana. The planar and relative structures of 1–3 were established via high-resolution electrospray ionisation mass spectrometry and one- and two-dimensional nuclear magnetic resonance spectroscopic analyses, and the absolute configuration of 1 was further established via X-ray crystallography experiment. Compounds 1–3 showed selective inhibitory potency against certain human tumor cell lines with IC50 values ranging from 8.50 ± 0.13 to 35.52 ± 0.08 μM. Graphical abstract

Bookmarking by histone methylation ensures chromosomal integrity during mitosis Abstract The cell cycle is an orchestrated process that replicates DNA and transmits genetic information to daughter cells. Cell cycle progression is governed by diverse histone modifications that control gene transcription in a timely fashion. Histone modifications also regulate cell cycle progression by marking specific chromatic regions. While many reviews have covered histone phosphorylation and acetylation as regulators of the cell cycle, little attention has been paid to the roles of histone methylation in the faithful progression of mitosis. Indeed, specific histone methylations occurring before, during, or after mitosis affect kinetochore assembly and chromosome condensation and segregation. In addition to timing, histone methylations specify the chromatin regions such as chromosome arms, pericentromere, and centromere. Therefore, spatiotemporal programming of histone methylations ensures epigenetic inheritance through mitosis. This review mainly discusses histone methylations and their relevance to mitotic progression.