Manzamine A reduces androgen receptor transcription and synthesis by blocking E2F8-DNA interactions and effectively inhibits prostate tumor growth in mice.

The androgen receptor (AR) is the main driver in the development of castration-resistant prostate cancer, where the emergence of AR splice variants leads to treatment-resistant disease. Through detailed molecular studies of the marine alkaloid manzamine A (MA), we identified transcription factor E2F8 as a previously unknown regulator of AR transcription that prevents AR synthesis in prostate cancer cells. MA significantly inhibited the growth of various prostate cancer cell lines and was highly effective in inhibiting xenograft tumor growth in mice without any pathophysiological perturbations in major organs. MA suppressed the full-length AR (AR-FL), its spliced variant AR-V7, and the AR-regulated prostate-specific antigen (PSA; also known as KLK3) and human kallikrein 2 (hK2; also known as KLK2) genes. RNA sequencing (RNA-seq) analysis and protein modeling studies revealed E2F8 interactions with DNA as a potential novel target of MA, suppressing AR transcription and its synthesis. This novel mechanism of blocking AR biogenesis via E2F8 may provide an opportunity to control therapy-resistant prostate cancer over the currently used AR antagonists designed to target different parts of the AR gene.

Short term biodistribution and in vivo toxicity assessment of intravenously injected pristine graphene oxide nanoflakes in SD rats.

The present study aimed to elucidate the short term biodistribution of nano sized graphene oxide (GO) along with the toxicological assessment under in-vivo condition with an intent to analyse the toxic effects of sudden accidental exposure of GO The synthesised GO was characterized using UV-Visible spectroscopy, XRD, FTIR, Raman spectroscopy, TGA and DLS. The morphological imaging was performed using SEM, TEM and AFM. With a lateral size of less than 300 nm, these nanoparticles exhibit significant organ barrier permeability of up to 20%. Upon acute exposure to 10 mg/kg dose of ICG-tagged GO nanoflakes through intravenous route, various organs such as kidney, spleen and liver were observed, and the nanoparticles predominantly accumulated in the liver upon 24 h of exposure. Upon confirming the accumulation of these particles in liver through IVIS imaging, our next attempt was to analyse various biochemical and serum parameters. An elevation in various serum parameters such as ALT, AST, Creatinine and Bilirubin was observed. Similarly, in the case of biochemical parameters tested in liver homogenates, an increase in NO, Catalase, GSH, SOD, ROS, LPO, GR, GPx, and GST was observed. This study highlights the potential toxicological risk associated with GO exposure which must be taken into account for any risk analysis associated with GO based consumer products and the occupational hazards.

Enhanced Visible-Light Photodetection with Undoped and Doped ZnO Thin-Film Self-Powered Photodetectors.

Photodetection plays an essential role in the visible-light zone and is important in modern science and technology owing to its potential applications in various fields. Fabrication of a stable photodetector remains a challenge for researchers. We demonstrated a high-response/recovery and self-powered undoped ZnO (UZO) and Cu-doped ZnO (CZO) thin film-based visible-light photodetector fabricated on a cost-effective Si substrate using reactive cosputtering. The structural, morphological, and optical properties of CZO and UZO thin films have been examined using X-ray diffraction, field emission scanning electron microscopy, X-ray photoelectron spectroscopy, atomic force microscopy, and photoluminescence spectroscopy. The results of the CZO/n-Si photodetector compared with those of the undoped ZnO (UZO)/n-Si photodetector show that the CZO/n-Si exhibits a higher on/off ratio, responsivity, and detectivity than UZO/n-Si. Also, the CZO/n-Si photodetector shows high stability and reproducibility over 20 cycles after 180 days. A relative study of CZO/n-Si- and UZO/n-Si-based photodetectors reveals the enhanced performance of the CZO/n-Si photodetector, which has a high on/off ratio of ∼300 with a high specific detectivity of 2.8 × 1010 Jones for 75 mW visible light. The prepared self-powered CZO/n-Si/Ag thin film-based visible-light photodetector paves the way for the development of high-performance photodetector designs.

Ocimum sanctum Leaf Extract-Assisted Green Synthesis of Pd-Doped CuO Nanoparticles for Highly Sensitive and Selective NO2 Gas Sensors.

In view of facile, cost-effective, and environmentally friendly synthetic methods, palladium-doped copper oxide (Pd-CuO) nanoparticles have been synthesized from Ocimum sanctum (commonly known as "Tulsi") phytoextract for gas-sensing applications. The structural, morphological, and compositional properties of Pd-doped CuO nanoparticles were studied using various techniques such as XRD, FESEM, XPS, and EDX. The characterization results confirmed the doping of Pd on CuO nanoparticles, and Pd-CuO nanostructures appear as nanoflakes in FESEM analysis. The gas-sensing response of Pd (1.12 wt %)-CuO nanoflake-based sensor was measured at 5-100 ppm concentration of different gases, NO2, H2S, NH3, and H2, at 125 °C. Gas-sensing tests reveal that the sensitivity of the sensor were 81.7 and 38.9% for 100 and 5 ppm concentrations of NO2, respectively, which was significantly greater than that of pure CuO. The response and recovery times of the sensor were 72 and 98 s for 100 ppm of NO2 gas, while they were 90 and 50 s for 5 ppm NO2. The calculated limit of detection (LOD) value of the sensor is 0.8235. This appealing LOD is suitable for real-time gas detection. The gas sensor was found to exhibit excellent selectivity toward NO2 gas and repeatability and stability in humid (80%) conditions. The Pd doping in CuO nanostructures plays a significant role in escalating the sensitivity and selectivity of CuO-based NO2 gas sensor suitable to work at low operating temperatures.

DNA Methyltransferase 1 Targeting Using Guadecitabine Inhibits Prostate Cancer Growth by an Apoptosis-Independent Pathway.

Epigenetic alterations such as DNA methylation and histone modifications are implicated in repressing several tumor suppressor genes in prostate cancer progression. In this study, we determined the anti-prostate cancer effect of a small molecule drug guadecitabine (gDEC) that inhibits/depletes the DNA methylation writer DNA methyltransferase 1 (DNMT1). gDEC inhibited prostate cancer cell growth and proliferation in vitro without activating the apoptotic cascade. Molecular studies confirmed DNMT1 depletion and modulated epithelial-mesenchymal transition markers E-cadherin and ß-catenin in several prostate cancer cell lines (LNCaP, 22Rv1, and MDA PCa 2b). gDEC treatment also significantly inhibited prostate tumor growth in vivo in mice (22Rv1, MDA PCa 2b, and PC-3 xenografts) without any observed toxicities. gDEC did not impact the expression of androgen receptor (AR) or AR-variant 7 (AR-V7) nor sensitize the prostate cancer cells to the anti-androgen enzalutamide in vitro. In further investigating the mechanism of cytoreduction by gDEC, a PCR array analyses of 84 chromatin modifying enzymes demonstrated upregulation of several lysine-specific methyltransferases (KMTs: KMT2A, KMT2C, KMT2E, KMT2H, KMT5A), confirmed by additional expression analyses in vitro and of harvested xenografts. Moreover, gDEC treatment increased global histone 3 lysine 4 mono-and di-methylation (H3K4me1 and H3K4me2). In sum, gDEC, in addition to directly depleting the corepressor DNMT1, upregulated KMT activating epigenetic enzymes, activating terminal epithelial program activation, and prostate cancer cell cycling exits independent of apoptosis.

A Perspective on Withania somnifera Modulating Antitumor Immunity in Targeting Prostate Cancer.

Medicinal plants serve as a lead source of bioactive compounds and have been an integral part of day-to-day life in treating various disease conditions since ancient times. Withaferin A (WFA), a bioactive ingredient of Withania somnifera, has been used for health and medicinal purposes for its adaptogenic, anti-inflammatory, and anticancer properties long before the published literature came into existence. Nearly 25% of pharmaceutical drugs are derived from medicinal plants, classified as dietary supplements. The bioactive compounds in these supplements may serve as chemotherapeutic substances competent to inhibit or reverse the process of carcinogenesis. The role of WFA is appreciated to polarize tumor-suppressive Th1-type immune response inducing natural killer cell activity and may provide an opportunity to manipulate the tumor microenvironment at an early stage to inhibit tumor progression. This article signifies the cumulative information about the role of WFA in modulating antitumor immunity and its potential in targeting prostate cancer.

Efficient hydrolytic cleavage of DNA and antiproliferative effect on human cancer cells by two dinuclear Cu(II) complexes containing a carbohydrazone ligand and 1,10-phenanthroline as a coligand.

We report the synthesis, crystal structures and biological activities of two dinuclear Cu(II) complexes [Cu(o-phen)LCu(OAc)] (1) and [Cu(o-phen)LCu(o-phen)](OAc) (2), where o-phen = 1,10-phenanthroline, H3L = o-HOC6H4C(H)=N-NH-C(OH)=N-N=C(H)-C6H4OH-o, and OAc=CH3COO-. Both compounds display strong and broad X-band EPR spectra at RT in their powder state confirming that these are paramagnetic. The intercalative DNA binding of the compounds as revealed from spectrophotometric studies was found to be consistent with the results of fluorescence spectroscopic studies for ethidium bromide displacement assay as well as enhanced viscosity of DNA in the presence of these compounds. The compounds effectively catalyze hydrolytic cleavage of supercoiled pUC19 DNA and show remarkable cytotoxicity toward human lung cancer A549 cell line (IC50 values are 4.34 and 8.46 µM for 1 and 2, respectively) and breast cancer MCF7 cell line (IC50 values are 6.50 and 8.68 µM for 1 and 2, respectively) and are found to be relatively less toxic toward keratinocyte HaCaT normal cell line (IC50 values are 11.19 and 16.01 µM for 1 and 2, respectively). Annexin-V/PI dual staining results analyzed by flow cytometry strongly suggest the induction of apoptotic pathway for the anticancer activity of these complexes. Flow cytometry experiment for cell cycle analysis showed considerable increase in the G2/M phase in both A549 and MCF7 cell lines by these two compounds. On the other hand, compounds 1 and 2 activate reactive oxygen species (ROS) level in A549 cells, but act as scavengers or inhibitors of ROS in MCF7 cell line as analyzed by DCFDA staining using flow cytometry. Two dinuclear Cu(II) complexes exhibit efficient hydrolytic cleavage of DNA and display remarkable cytotoxicity against human lung cancer A549 and breast cancer MCF7cells. The ROS level in A549 cells is activated, but the ROS level in MCF7 cells is decreased in the presence of these complexes. Cell cycle analysis by flow cytometry shows G2/M phase arrest in both these cell lines.

DNA binding, cleavage and cytotoxicity studies of three mononuclear Cu(II) chloro-complexes containing N-S donor Schiff base ligands.

We report the biological activity of three Cu(II) complexes [Cu(pabt)Cl] (1), [Cu(pma)Cl] (2), and [Cu(pdta)Cl]Cl (3) (pabt = N-(2-mercaptophenyl)-2'-pyridylmethylenimine, pma = N-(2-pyridylmethyl)-2-mercaptoaniline, pdta = 2,2'-di(pyridyl-2-methyleneimine)diphenyl disulfide). 1-3 display four-line EPR multiplet in solution at RT suggesting that these are mononuclear. DNA-binding studies using spectrophotometric titration of these complexes with calf thymus DNA showed binding through intercalation mode which was found to be consistent with the observation of increased viscosity of DNA and quenching of fluorescence of ethidium bromide bound DNA in the presence of these complexes. All three complexes were found to be efficient in bringing about oxidative and hydrolytic cleavage of DNA. The proposed mechanism of hydrolytic DNA cleavage has been discussed. MTT assay showed remarkable cytotoxicity on cervical cancer HeLa cell line and the IC50 values were 1.27, 4.13, and 3.92 µM for 1, 2 and 3, respectively, as compared to the IC50 value (13 µM) reported for cisplatin in HeLa cells. AO/PI and Annexin-V/PI assay suggest the induction of cell death primarily via apoptotic pathway. Nuclear staining using DAPI was used to assess changes in nuclear morphology during apoptotic cell death. The role of reactive oxygen species (ROS) for induction of apoptotic cell death was studied using H2DCF-DA assay and the result suggests that the generation of ROS by the complexes may be a possible cause for their antiproliferative activity. TUNEL assay showed DNA fragmentation in apoptotic cells. Cell cycle analysis using flow cytometry showed significant increase in the G2/M phase in HeLa cells by the compounds 1-3. Mononuclear Cu(II) complexes display remarkable cytotoxicity against cervical cancer HeLa cell line. The generation of ROS by the complexes may be a cause of their antiproliferative activity. Fluorescent images from DAPI staining assay revealed that the cells undergoing apoptosis displayed typical features like cell shrinkage, membrane blebbing, chromatin condensation and nuclear fragmentation. TUNEL assay showed DNA fragmentation in apoptotic cells.