Withaferin A: A Pleiotropic Anticancer Agent from the Indian Medicinal Plant Withania somnifera (L.) Dunal.

Cancer represents the second most deadly disease and one of the most important public health concerns worldwide. Surgery, chemotherapy, radiation therapy, and immune therapy are the major types of treatment strategies that have been implemented in cancer treatment. Unfortunately, these treatment options suffer from major limitations, such as drug-resistance and adverse effects, which may eventually result in disease recurrence. Many phytochemicals have been investigated for their antitumor efficacy in preclinical models and clinical studies to discover newer therapeutic agents with fewer adverse effects. Withaferin A, a natural bioactive molecule isolated from the Indian medicinal plant Withania somnifera (L.) Dunal, has been reported to impart anticancer activities against various cancer cell lines and preclinical cancer models by modulating the expression and activity of different oncogenic proteins. In this article, we have comprehensively discussed the biosynthesis of withaferin A as well as its antineoplastic activities and mode-of-action in in vitro and in vivo settings. We have also reviewed the effect of withaferin A on the expression of miRNAs, its combinational effect with other cytotoxic agents, withaferin A-based formulations, safety and toxicity profiles, and its clinical potential.

Elucidating Role of Reactive Oxygen Species (ROS) in Cisplatin Chemotherapy: A Focus on Molecular Pathways and Possible Therapeutic Strategies.

The failure of chemotherapy is a major challenge nowadays, and in order to ensure effective treatment of cancer patients, it is of great importance to reveal the molecular pathways and mechanisms involved in chemoresistance. Cisplatin (CP) is a platinum-containing drug with anti-tumor activity against different cancers in both pre-clinical and clinical studies. However, drug resistance has restricted its potential in the treatment of cancer patients. CP can promote levels of free radicals, particularly reactive oxygen species (ROS) to induce cell death. Due to the double-edged sword role of ROS in cancer as a pro-survival or pro-death mechanism, ROS can result in CP resistance. In the present review, association of ROS with CP sensitivity/resistance is discussed, and in particular, how molecular pathways, both upstream and downstream targets, can affect the response of cancer cells to CP chemotherapy. Furthermore, anti-tumor compounds, such as curcumin, emodin, chloroquine that regulate ROS and related molecular pathways in increasing CP sensitivity are described. Nanoparticles can provide co-delivery of CP with anti-tumor agents and by mediating photodynamic therapy, and induce ROS overgeneration to trigger CP sensitivity. Genetic tools, such as small interfering RNA (siRNA) can down-regulate molecular pathways such as HIF-1α and Nrf2 to promote ROS levels, leading to CP sensitivity. Considering the relationship between ROS and CP chemotherapy, and translating these findings to clinic can pave the way for effective treatment of cancer patients.

Viral hijacking of the TENT4-ZCCHC14 complex protects viral RNAs via mixed tailing.

TENT4 enzymes generate 'mixed tails' of diverse nucleotides at 3' ends of RNAs via nontemplated nucleotide addition to protect messenger RNAs from deadenylation. Here we discover extensive mixed tailing in transcripts of hepatitis B virus (HBV) and human cytomegalovirus (HCMV), generated via a similar mechanism exploiting the TENT4-ZCCHC14 complex. TAIL-seq on HBV and HCMV RNAs revealed that TENT4A and TENT4B are responsible for mixed tailing and protection of viral poly(A) tails. We find that the HBV post-transcriptional regulatory element (PRE), specifically the CNGGN-type pentaloop, is critical for TENT4-dependent regulation. HCMV uses a similar pentaloop, an interesting example of convergent evolution. This pentaloop is recognized by the sterile alpha motif domain-containing ZCCHC14 protein, which in turn recruits TENT4. Overall, our study reveals the mechanism of action of PRE, which has been widely used to enhance gene expression, and identifies the TENT4-ZCCHC14 complex as a potential target for antiviral therapeutics.

Flexible Cu2ZnSn(S,Se)4 solar cells with over 10% efficiency and methods of enlarging the cell area.

For kesterite copper zinc tin sulfide/selenide (CZTSSe) solar cells to enter the market, in addition to efficiency improvements, the technological capability to produce flexible and large-area modules with homogeneous properties is necessary. Here, we report a greater than 10% efficiency for a cell area of approximately 0.5 cm2 and a greater than 8% efficiency for a cell area larger than 2 cm2 of certified flexible CZTSSe solar cells. By designing a thin and multi-layered precursor structure, the formation of defects and defect clusters, particularly tin-related donor defects, is controlled, and the open circuit voltage value is enhanced. Using statistical analysis, we verify that the cell-to-cell and within-cell uniformity characteristics are improved. This study reports the highest efficiency so far for flexible CZTSSe solar cells with small and large areas. These results also present methods for improving the efficiency and enlarging the cell area.

Secondary Phase Formation Mechanism in the Mo-Back Contact Region during Sulfo-Selenization Using a Metal Precursor: Effect of Wettability between a Liquid Metal and Substrate on Secondary Phase Formation.

Recently, highly efficient CZTS solar cells using pure metal precursors have been reported, and our group created a cell with 12.6% efficiency, which is equivalent to the long-lasting world record of IBM. In this study, we report a new secondary phase formation mechanism in the back contact interface. Previously, CZTSSe decomposition with Mo has been proposed to explain the secondary phase and void formation in the Mo-back contact region. In our sulfo-selenization system, the formation of voids and secondary phases is well explained by the unique wetting properties of Mo and the liquid metal above the peritectic reaction (η-Cu6Sn5 → ε-Cu3Sn + liquid Sn) temperature. Good wetting between the liquid Sn and the Mo substrate was observed because of strong metallic bonding between the liquid metal and Mo layer. Thus, some ε-Cu3Sn and liquid Sn likely remained on the Mo layer during the sulfo-selenization process, and Cu-SSe and Cu-Sn-SSe phases formed on the Mo side. When bare soda lime glass (SLG) was used as a substrate, nonwetting adhesion was observed because of weak van der Walls interactions between the liquid metal and substrate. The Cu-Sn alloy did not remain on the SLG surface, and Cu-SSe and Cu-Sn-SSe phases were not observed after the final sulfo-selenization process. Additionally, Mo/SLG substrates coated with a thin Al2O3 layer (1-5 nm) were used to control secondary phase formation by changing the wetting properties between Mo and the liquid metal. A 1 nm Al2O3 layer was enough to control secondary phase formation at the CZTSSe/Mo and void/Mo interfaces, and a 2 nm Al2O3 layer was enough to perfectly control secondary phase formation at the Mo interface and Mo-SSe formation.

Antihyperglycemic and Antiobesity Effects of JAL2 on db/db Mice.

Lonicera japonica Thunb. (LJT) and Rehmannia glutinosa Libosch. (RGL) have been used traditionally as a herbal medicine in Korean medicine. Using LC/Q-TOF was performed to profile the two herbal medicines and the mixture of LJR and RGL (JAL2, ratio 1 : 1). We performed oral glucose tolerance test (OGTT) and plasma GLP-1 and insulin secretion by multiplex assays to investigate antidiabetic effects of LJT, RGL, and JAL2 in db/db mice, the mice model of type 2 diabetes mellitus (T2DM). Also, the antiobesity-related factors such as plasma peptide YY (PYY), triglyceride, total cholesterol, HDL, LDL, and weight of liver, epididymal, and retroperitoneal fat tissue were investigated. Through the multiplex assay, it was found that JAL2 treatment more efficiently attenuated high levels of blood glucose by stimulating GLP-1 secretion and reduced LDL concentration and weight of liver and retroperitoneal fat tissue compared to LJT or RGL treated separately. These results suggest that the JAL2 has antidiabetes and antiobesity effects in T2DM mice model.

Temperature-Dependent Evolution of Poly(3-Hexylthiophene) Type-II Phase in a Blended Thin Film.

The structure of P3HT in P3HT:PCBM films is examined on a poly(3,4-ethylenedioxythiophene) polystyrene sulfonate ( PEDOT: PSS) substrate subjected to cryo-cooling to low temperature (-143 °C) followed by gradual heating to 50 °C. The behavior of these systems is examined in the absence and presence of an Al electrode on top of the P3HT:PCBM film. At temperatures below -10 °C, only the type-I phase of P3HT is observed. However, the type-II phase of P3HT starts to form near -10 °C, in both the presence and absence of the Al layer. In the system without an Al layer, the type-II phase disappears at 30 °C, but this phase persists to 50 °C in the presence of the Al layer. Concomitant with the formation of the type-II phase, a 1:3 ordered P3HT type-II (1/3,0,0) superlattice peak emerged. The type-II domains tend to form near the Al electrode layer and show a higher degree of alignment than the type-I crystals.

Nanostructures of small-molecule organic crystals on capillary wave surfaces with controllable capillary lengths.

We report on the nanostructures of organic small-molecule pentacene crystals that have been vapor-deposited onto the capillary wave surfaces of thin liquid films. The characteristic lateral length of the capillary wave surface or the capillary length can be controlled by changing the thickness of the liquid films and, thus, the van der Waals interaction with the substrate. We find that the morphology of the organic crystals gradually varies from fractals to compact islands as the liquid film thickness increases. The square of average distance between organic crystal grains was also found to be proportional to the liquid film thickness. We discuss the possibility that these effects are driven by capillary fluctuations at the air-liquid interface.

Herbal compound farnesiferol C exerts antiangiogenic and antitumor activity and targets multiple aspects of VEGFR1 (Flt1) or VEGFR2 (Flk1) signaling cascades.

Farnesiferol C (FC) is one of the major compounds isolated from Ferula assafoetida, an Asian herbal spice used for cancer treatment as a folk remedy. Here, we examined the hypothesis that novel antiangiogenic activities of FC contribute to anticancer efficacy. In human umbilical vein endothelial cells (HUVEC), exposure to the 10 to 40 mumol/L concentration range of FC inhibited vascular endothelial growth factor (VEGF)-induced cell proliferation, migration, invasion, tube formation, and the expression of matrix metalloproteinase-2. In addition, FC inhibited the angiogenic sprouting of VEGF-treated rat aorta in an ex vivo model. Furthermore, FC inhibited the in vivo growth of mouse Lewis lung cancer allograft model by 60% (P < 0.001) at a daily i.p. dosage of 1 mg/kg body weight without any negative effect on the weight of the host mice. Immunohistochemistry staining showed decreased microvessel density (CD34) and proliferative index (Ki-67) without affecting the apoptotic (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) index. Mechanistically, FC decreased the binding of VEGF to VEGFR1/Flt-1, but not to VEGFR2/KDR/Flk-1. In terms of early signaling, FC exerted a rapid inhibitory action (examined within 10 minutes) on VEGF-induced autophosphorylation of VEGFR1 without affecting that of VEGFR2. Nevertheless, FC decreased the phosphorylation of most of the kinases downstream of VEGFR2: focal adhesion kinase, Src, extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, and c-jun-NH(2)-kinase without affecting AKT. Computer simulation suggests that FC may inhibit Src or focal adhesion kinase protein activities directly through its docking to their ATP-binding sites. Taken together, the multitargeting actions of FC, particularly VEGFR1 inhibition, may make it a novel drug candidate to complement current VEGF/VEGFR2-targeting antiangiogenic modalities for cancer.