ROS-Mediated Anti-Tumor Effect of Coptidis Rhizoma against Human Hepatocellular Carcinoma Hep3B Cells and Xenografts

Coptidis Rhizoma is the dried rhizome from the Coptis chinensis Franch. that has been shown to have a number of beneficial pharmacological properties including antioxidant, anti-inflammatory, and anti-cancer effects. However, the anti-cancer effects of Coptidis Rhizoma on hepatocellular carcinoma (HCC) remain unclear. In this study, we investigated the anti-cancer properties of Coptidis Rhizoma ethanol extract (CR) in HCC Hep3B cells and in a xenograft mouse model. Our results showed that the CR significantly inhibited cell growth and induced apoptosis in Hep3B cells through increased expression of Bcl-2 associated x-protein (Bax) and cleavage of poly-ADP ribose polymerase (PARP), reduced expression of Bcl-2, and activated caspases. CR also increased the generation of intracellular reactive oxygen species (ROS), which caused a loss of mitochondrial membrane potential (MMP, ΔΨm) and activation of the mitochondria-mediated intrinsic apoptosis pathway. Moreover, N-acetylcysteine (NAC), a ROS inhibitor, markedly blocked the effects of CR on apoptotic pathways. CR also induced the expression of light chain 3 (LC3)-I/II, a key autophagy regulator, whereas CR-mediated autophagy was significantly suppressed by NAC. In addition, pre-treatment with NAC perfectly attenuated the inhibition of cell invasion and migration of CR-stimulated Hep3B cells. Furthermore, oral administration of CR suppressed Hep3B tumor growth in xenograft mice without toxicity, alterations to body weight, or changes in hematological and biochemical profiles. Taken together, our findings suggest that CR has anti-tumor effects that result from ROS generation, and may be a potential pharmacological intervention for HCC.     

E7766, a Macrocycle-Bridged Stimulator of Interferon Genes (STING) Agonist with Potent Pan-Genotypic Activity

A strategy for creating potent and pan-genotypic stimulator of interferon genes (STING) agonists is described. Locking a bioactive U-shaped conformation of cyclic dinucleotides by introducing a transannular macrocyclic bridge between the nucleic acid bases leads to a topologically novel macrocycle-bridged STING agonist (MBSA). In addition to substantially enhanced potency, the newly designed MBSAs, exemplified by clinical candidate E7766 , exhibit broad pan-genotypic activity in all major human STING variants. E7766 is shown to have potent antitumor activity with long lasting immune memory response in a mouse liver metastatic tumor model. Two complementary stereoselective synthetic routes to E7766 are also described.     

Effects of Electromagnetic Waves with LTE and 5G Bandwidth on the Skin Pigmentation In Vitro

With the rapid growth of wireless communication devices, the influences of electromagnetic fields (EMF) on human health are gathering increasing attention. Since the skin is the largest organ of the body and is located at the outermost layer, it is considered a major target for the health effects of EMF. Skin pigmentation represents one of the most frequent symptoms caused by various non-ionizing radiations, including ultraviolet radiation, blue light, infrared, and extremely low frequency (ELF). Here, we investigated the effects of EMFs with long-term evolution (LTE, 1.762 GHz) and 5G (28 GHz) bandwidth on skin pigmentation in vitro. Murine and Human melanoma cells (B16F10 and MNT-1) were exposed to either LTE or 5G for 4 h per day, which is considered the upper bound of average smartphone use time. It was shown that neither LTE nor 5G exposure induced significant effects on cell viability or pigmentation. The dendrites of MNT-1 were neither lengthened nor regressed after EMF exposure. Skin pigmentation effects of EMFs were further examined in the human keratinocyte cell line (MNT-1-HaCaT) co-culture system, which confirmed the absence of significant hyper-pigmentation effects of LTE and 5G EMFs. Lastly, MelanoDerm™, a 3D pigmented human epidermis model, was irradiated with LTE (1.762 GHz) or 5G (28 GHz), and image analysis and special staining were performed. No changes in the brightness of MelanoDerm™ tissues were observed in LTE- or 5G-exposed tissues, except for only minimal changes in the size of melanocytes. Collectively, these results imply that exposure to LTE and 5G EMFs may not affect melanin synthesis or skin pigmentation under normal smartphone use condition.     

Lithiophilic MXene-Guided Lithium Metal Nucleation and Growth Behavior

The positive effects of a lithiophilic substrate on the electrochemical performance of lithium metal anodes are confirmed in several reports, while the understanding of lithiophilic substrate-guided lithium metal nucleation and growth behavior is still insufficient. In this study, the effect of a lithiophilic surface on lithium metal nucleation and growth behaviors is investigated using a large-area Ti₃C₂T_x MXene substrate with a large number of oxygen and fluorine dual heteroatoms. The use of the MXene substrate results in a high lithium-ion concentration as well as the formation of uniform solid–electrolyte-interface (SEI) layers on the lithiophilic surface. The solid–solid interface (MXene-SEI layer) significantly affects the surface tension of the deposited lithium metal nuclei as well as the nucleation overpotential, resulting in the formation of uniformly dispersed lithium nanoparticles ( ≈ 10–20 nm in diameter) over the entire MXene surface. The primary lithium nanoparticles preferentially coalesce and agglomerate into larger secondary particles while retaining their primary particle shapes. Subsequently, they form close-packed structures, resulting in a dense metal layer composed of particle-by-particle microstructures. This distinctive lithium metal deposition behavior leads to highly reversible cycling performance with high Columbic efficiencies >  99.0% and long cycle lives of over 1000 cycles.     

Idiosyncratic Drug-Induced Liver Injury: Mechanistic and Clinical Challenges

Idiosyncratic drug-induced liver injury (IDILI) remains a significant problem for patients and drug development. The idiosyncratic nature of IDILI makes mechanistic studies difficult, and little is known of its pathogenesis for certain. Circumstantial evidence suggests that most, but not all, IDILI is caused by reactive metabolites of drugs that are bioactivated by cytochromes P450 and other enzymes in the liver. Additionally, there is overwhelming evidence that most IDILI is mediated by the adaptive immune system; one example being the association of IDILI caused by specific drugs with specific human leukocyte antigen (HLA) haplotypes, and this may in part explain the idiosyncratic nature of these reactions. The T cell receptor repertoire likely also contributes to the idiosyncratic nature. Although most of the liver injury is likely mediated by the adaptive immune system, specifically cytotoxic CD8+ T cells, adaptive immune activation first requires an innate immune response to activate antigen presenting cells and produce cytokines required for T cell proliferation. This innate response is likely caused by either a reactive metabolite or some form of cell stress that is clinically silent but not idiosyncratic. If this is true it would make it possible to study the early steps in the immune response that in some patients can lead to IDILI. Other hypotheses have been proposed, such as mitochondrial injury, inhibition of the bile salt export pump, unfolded protein response, and oxidative stress although, in most cases, it is likely that they are also involved in the initiation of an immune response rather than representing a completely separate mechanism. Using the clinical manifestations of liver injury from a number of examples of IDILI-associated drugs, this review aims to summarize and illustrate these mechanistic hypotheses.     

How latecomers catch up to leaders in high-energy physics as Big Science: transition from national system to international collaboration

Scientometrics - This study describes the increase of research productivity of latecomer countries (latecomers) in the high-energy physics (HEP) community by research strategies based on a national...     

Correlations between histopathologic and dermoscopic findings in Korean actinic keratosis

Skin biopsy for AK diagnosis is usually performed on only a limited part of the whole lesion. Therefore, a clinical diagnosis is important. According to a study, there is no significant correlation between histopathological and clinical classification system. We examined the correlation between microscopic information and dermoscopic findings to deduce if dermoscopic information reflects histopathologic grade severity. Forty seven patients with histologically confirmed AK were enrolled and positive ratio of red pseudonetwork, rosette, red background and targetoid signs, white‐to‐yellow scale, white structureless area, and pigmentation from dermoscopic findings were investigated. Furthermore, viable epidermal thickness, vessel lumen dimensions, existence and thickness of ortho‐ and parakeratosis, degree of sola elastosis, flag sign existence, and Roewert‐Huber classification were measured as histologic findings. Red background did not show a significant correlation with vascular dimension or viable epidermal thickness. When targetoid sign was present, vascular dimension was significantly larger but showed no correlation with viable epidermal thickness, parakeratosis or orthokeratosis. Solar elastosis level was significantly higher when white‐to‐yellow scale was present. According to Spearman's correlation analysis, ortho/parakeratotic thickness showed correlations with each other. The negative correlation between viable epidermal thickness and vascular dimension was also shown. Roewert‐Huber histologic AK classification showed no correlation with any factors we checked. Factors considered to be characteristic features of AK in dermoscopy seemed unassociated with histologic AK classification and additional research is needed to determine degree of dysplasia of AK lesions using dermoscopy.     

Environmental Enrichment Enhances Cav 2.1 Channel-Mediated Presynaptic Plasticity in Hypoxic–Ischemic Encephalopathy

Hypoxic–ischemic encephalopathy (HIE) is a devastating neonatal brain condition caused by lack of oxygen and limited blood flow. Environmental enrichment (EE) is a classic paradigm with a complex stimulation of physical, cognitive, and social components. EE can exert neuroplasticity and neuroprotective effects in immature brains. However, the exact mechanism of EE on the chronic condition of HIE remains unclear. HIE was induced by a permanent ligation of the right carotid artery, followed by an 8% O₂ hypoxic condition for 1 h. At 6 weeks of age, HIE mice were randomly assigned to either standard cages or EE cages. In the behavioral assessments, EE mice showed significantly improved motor performances in rotarod tests, ladder walking tests, and hanging wire tests, compared with HIE control mice. EE mice also significantly enhanced cognitive performances in Y-maze tests. Particularly, EE mice showed a significant increase in Ca_v 2.1 (P/Q type) and presynaptic proteins by molecular assessments, and a significant increase of Ca_v 2.1 in histological assessments of the cerebral cortex and hippocampus. These results indicate that EE can upregulate the expression of the Ca_v 2.1 channel and presynaptic proteins related to the synaptic vesicle cycle and neurotransmitter release, which may be responsible for motor and cognitive improvements in HIE.     

Thermal treatment effect on the magnetoelectric properties of (Ni0.5Zn0.5)Fe2O4/Pt/Pb(Zr0.3Ti0.7)O3 heterostructured thin films

Magnetoelectric (ME) property modulation in heterostructured (Ni_0.5Zn_0.5)Fe₂O₄/Pt/Pb(Zr_0.3Ti_0.7)O₃ (NZFO/Pt/PZT) thin films on platinized Si substrate by thermal annealing condition variation was studied. In an attempt to prevent interfacial reaction between NZFO and PZT layers during high temperature annealing, thin Pt layer was deposited which can serve as inter-diffusion barrier as well as electrode. The ferroelectric, magnetic, and ME properties of the heterostructured film were noticeably modulated due to microstructural evolution and clamping relaxation developed during thermal annealing process. Room temperature ME voltage coefficient of the heterostructured thin films was enhanced with increasing annealing temperature and reached to 29 mV/cm·Oe when annealed at 650 °C.