Multi-functional copper oxide nanoparticles synthesized using Lagerstroemia indica leaf extracts and their applications.

Developing multifunctional nanomaterials through environmentally friendly and efficient approaches is a pivotal focus in nanotechnology. This study aimed to employ a biogenic method to synthesize multifunctional copper oxide nanoparticles (LI-CuO NPs) with diverse capabilities, including antibacterial, antioxidant, and seed priming properties, as well as photocatalytic organic dye degradation and wastewater treatment potentials using Lagerstroemia indica leaf extract. The synthesized LI-CuO NPs were extensively characterized using UV-vis spectroscopy, dynamic light scattering (DLS), X-ray diffraction (XRD), scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM-EDX), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), and Fourier transform-infrared spectroscopy (FT-IR). The colloid displayed surface plasmon resonance peaks at 320 nm, characteristic of LI-CuO NPs. DLS analysis revealed an average particle size of 93.5 nm and a negative zeta potential of -20.3 mV. FTIR and XPS analyses demonstrated that LI-CuO NPs possessed abundant functional groups that acted as stabilizing agents. XRD analysis indicated pure crystalline and spherical LI-CuO NPs measuring 36 nm in size. Antibacterial tests exhibited significant differential activity of LI-CuO NPs against both gram-negative (Escherichia coli, Salmonella typhimurium) and gram-positive (Staphylococcus aureus and Listeria monocytogenes) bacteria. In antioxidant tests, the LI-CuO NPs demonstrated a remarkable radical scavenging activity of 97.6 % at a concentration of 400 µg mL-1. These nanoparticles were also found to enhance mustard seed germination at low concentrations. With a remarkable reusability, LI-CuO NPs exhibited excellent photocatalytic performance, with a degradation efficiency of 97.6 % at 150 µg/mL as well as a 95.6 % reduction in turbidity when applied to wastewater treatment. In conclusion, this study presents environmentally friendly method for the facile synthesis of LI-CuO NPs that could potentially offer promising applications in biomedicine, agriculture, and environmental remediation due to their multifunctional properties.

Green Synthesis of Novel Silver Nanoparticles Using Salvia blepharophylla and Salvia greggii: Antioxidant and Antidiabetic Potential and Effect on Foodborne Bacterial Pathogens.

In the face of evolving healthcare challenges, the utilization of silver nanoparticles (AgNPs) has emerged as a compelling solution due to their unique properties and versatile applications. The aim of this study was the synthesis and characterization of novel AgNPs (SB-AgNPs and SG-AgNPs, respectively) using Salvia blepharophylla and Salvia greggii leaf extracts and the evaluation of their antimicrobial, antioxidant, and antidiabetic activities. Several analytical instrumental techniques were utilized for the characterization of SB-AgNPs and SG-AgNPs, including UV-visible (UV-Vis) spectroscopy, transmission electron microscopy (TEM), dynamic light scattering (DLS), Fourier transmission infrared (FT-IR) spectroscopy, energy-dispersive X-ray analysis (EDX), and X-ray diffraction (XRD). FTIR analysis identified various functional groups in the leaf extracts and nanoparticles, suggesting the involvement of phytochemicals as reducing and stabilizing agents. High-resolution TEM images displayed predominantly spherical nanoparticles with average sizes of 52.4 nm for SB-AgNPs and 62.5 nm for SG-AgNPs. Both SB-AgNPs and SG-AgNPs demonstrated remarkable antimicrobial activity against Gram-positive bacteria Staphylococcus aureus and Listeria monocytogenes and Gram-negative bacteria Salmonella typhimurium and Escherichia coli. SB-AgNPs and SG-AgNPs also exhibited 90.2 ± 1.34% and 89.5 ± 1.5% DPPH scavenging and 86.5 ± 1.7% and 80.5 ± 1.2% α-amylase inhibition, respectively, at a concentration of 100 µg mL-1. Overall, AgNPs synthesized using S. blepharophylla and Salvia greggii leaf extracts may serve as potential candidates for antibacterial, antioxidant, and antidiabetic agents. Consequently, this study provides viable solutions to mitigate the current crisis of antibiotic resistance and to efficiently combat antimicrobial infections and Type 2 diabetes.

Therapeutic targeting of EP300/CBP by bromodomain inhibition in hematologic malignancies.

CCS1477 (inobrodib) is a potent, selective EP300/CBP bromodomain inhibitor which induces cell-cycle arrest and differentiation in hematologic malignancy model systems. In myeloid leukemia cells, it promotes rapid eviction of EP300/CBP from an enhancer subset marked by strong MYB occupancy and high H3K27 acetylation, with downregulation of the subordinate oncogenic network and redistribution to sites close to differentiation genes. In myeloma cells, CCS1477 induces eviction of EP300/CBP from FGFR3, the target of the common (4; 14) translocation, with redistribution away from IRF4-occupied sites to TCF3/E2A-occupied sites. In a subset of patients with relapsed or refractory disease, CCS1477 monotherapy induces differentiation responses in AML and objective responses in heavily pre-treated multiple myeloma. In vivo preclinical combination studies reveal synergistic responses to treatment with standard-of-care agents. Thus, CCS1477 exhibits encouraging preclinical and early-phase clinical activity by disrupting recruitment of EP300/CBP to enhancer networks occupied by critical transcription factors.

Effect of zinc oxide nanoparticles synthesized from Carya illinoinensis leaf extract on growth and antioxidant properties of mustard (Brassica juncea).

Background: The sustainability of crop production is impacted by climate change and land degradation, and the advanced application of nanotechnology is of paramount importance to overcome this challenge. The development of nanomaterials based on essential nutrients like zinc could serve as a basis for nanofertilizers and nanocomposite synthesis for broader agricultural applications and quality human nutrition. Therefore, this study aimed to synthesize zinc oxide nanoparticles (ZnO NPs) using pecan (Carya illinoinensis) leaf extract and investigate their effect on the growth, physiology, nutrient content, and antioxidant properties of mustard (Brassica juncea). Methods: The ZnO NPs were characterized by UV-Vis spectrophotometry, Dynamic Light Scattering (DLS), X-ray diffractometer (XRD), Scanning Electron Microscopy (SEM), and Fourier Transform Infra-Red Spectroscopy (FTIR). Mustard plants were subjected to different concentrations of ZnONPs (0, 20, 40, 60, 80, 100 and 200 mg L-1) during the vegetative growth stage. Results: The UV-Vis spectra of ZnO NPs revealed the absorption maxima at 362 nm and FTIR identified numerous functional groups that are responsible for capping and stabilizing ZnO NPs. DLS analysis presented monodispersed ZnO NPs of 84.5 nm size and highly negative zeta potential (-22.4 mV). Overall, the application of ZnO NPs enhanced the growth, chlorophyll content (by 53 %), relative water content (by 46 %), shoot biomass, membrane stability (by 54 %) and net photosynthesis significantly in a dose-dependent manner. In addition, the supplement of the ZnO NPs augmented K, Fe, Zn and flavonoid contents as well as overcome the effect of reactive oxygen species by increasing antioxidant capacity in mustard leaves up to 97 %. Conclusions: In conclusion, ZnO NPs can be potentially used as a plant growth stimulant and as a novel soil amendment for enhancing crop yields. Besides, the biofortification of B. juncea plants with ZnO NPs helps to improve the nutritional quality of the crop and perhaps potentiates its pharmaceutical effects.

Inhibition of CBP synergizes with the RNA-dependent mechanisms of Azacitidine by limiting protein synthesis.

The nucleotide analogue azacitidine (AZA) is currently the best treatment option for patients with high-risk myelodysplastic syndromes (MDS). However, only half of treated patients respond and of these almost all eventually relapse. New treatment options are urgently needed to improve the clinical management of these patients. Here, we perform a loss-of-function shRNA screen and identify the histone acetyl transferase and transcriptional co-activator, CREB binding protein (CBP), as a major regulator of AZA sensitivity. Compounds inhibiting the activity of CBP and the closely related p300 synergistically reduce viability of MDS-derived AML cell lines when combined with AZA. Importantly, this effect is specific for the RNA-dependent functions of AZA and not observed with the related compound decitabine that is only incorporated into DNA. The identification of immediate target genes leads us to the unexpected finding that the effect of CBP/p300 inhibition is mediated by globally down regulating protein synthesis.

Targeting the p300/CBP Axis in Lethal Prostate Cancer.

Resistance to androgen receptor (AR) blockade in castration-resistant prostate cancer (CRPC) is associated with sustained AR signaling, including through alternative splicing of AR (AR-SV). Inhibitors of transcriptional coactivators that regulate AR activity, including the paralog histone acetyltransferase proteins p300 and CBP, are attractive therapeutic targets for lethal prostate cancer. Herein, we validate targeting p300/CBP as a therapeutic strategy for lethal prostate cancer and describe CCS1477, a novel small-molecule inhibitor of the p300/CBP conserved bromodomain. We show that CCS1477 inhibits cell proliferation in prostate cancer cell lines and decreases AR- and C-MYC-regulated gene expression. In AR-SV-driven models, CCS1477 has antitumor activity, regulating AR and C-MYC signaling. Early clinical studies suggest that CCS1477 modulates KLK3 blood levels and regulates CRPC biopsy biomarker expression. Overall, CCS1477 shows promise for the treatment of patients with advanced prostate cancer. SIGNIFICANCE: Treating CRPC remains challenging due to persistent AR signaling. Inhibiting transcriptional AR coactivators is an attractive therapeutic strategy. CCS1477, an inhibitor of p300/CBP, inhibits growth and AR activity in CRPC models, and can affect metastatic CRPC target expression in serial clinical biopsies.See related commentary by Rasool et al., p. 1011.This article is highlighted in the In This Issue feature, p. 995.

Unique and Shared Epigenetic Programs of the CREBBP and EP300 Acetyltransferases in Germinal Center B Cells Reveal Targetable Dependencies in Lymphoma.

Inactivating mutations of the CREBBP and EP300 acetyltransferases are among the most common genetic alterations in diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL). Here, we examined the relationship between these two enzymes in germinal center (GC) B cells, the normal counterpart of FL and DLBCL, and in lymphomagenesis by using conditional GC-directed deletion mouse models targeting Crebbp or Ep300. We found that CREBBP and EP300 modulate common as well as distinct transcriptional programs implicated in separate anatomic and functional GC compartments. Consistently, deletion of Ep300 but not Crebbp impaired the fitness of GC B cells in vivo. Combined loss of Crebbp and Ep300 completely abrogated GC formation, suggesting that these proteins partially compensate for each other through common transcriptional targets. This synthetic lethal interaction was retained in CREBBP-mutant DLBCL cells and could be pharmacologically targeted with selective small molecule inhibitors of CREBBP and EP300 function. These data provide proof-of-principle for the clinical development of EP300-specific inhibitors in FL and DLBCL.

A Phase Ib Open-Label Multicenter Study of AZD4547 in Patients with Advanced Squamous Cell Lung Cancers.

Purpose: Squamous cell lung cancers (SQCLC) account for 25% of all NSCLCs, yet the prognosis of these patients is poor and treatment options are limited. Amplified FGFR1 is one of the most common oncogenic events in SQCLCs, occurring in approximately 20% of cases. AZD4547 is a potent and selective FGFR1-3 inhibitor with antitumor activity in FGFR1-amplified SQCLC cell lines and patient-derived xenografts.Experimental Design: On the basis of these data, we performed a phase I study of AZD4547 in patients with previously treated stage IV FGFR1-amplified SQCLCs (NCT00979134). FGFR1 amplification (FGFR1:CEP8 ≥ 2) was determined by FISH. The primary endpoint was safety/tolerability. Secondary endpoints included antitumor activity, pharmacokinetics, pharmacodynamics, and molecular analyses.Results: Fifteen FGFR1-amplified patients were treated. The most common related adverse events (AE) were gastrointestinal and dermatologic. Grade ≥3-related AEs occurred in 3 patients (23%). Thirteen patients were evaluable for radiographic response assessment. The overall response rate was 8% (1 PR). Two of 15 patients (13.3%) were progression-free at 12 weeks, and the median overall survival was 4.9 months. Molecular tests, including next-generation sequencing, gene expression analysis, and FGFR1 immunohistochemistry, showed poor correlation between gene amplification and expression, potential genomic modifiers of efficacy, and heterogeneity in 8p11 amplicon.Conclusions: AZD4547 was tolerable at a dosage of 80 mg oral twice a day, with modest antitumor activity. Detailed molecular studies show that these tumors are heterogeneous, with a range of mutational covariates and stark differences in gene expression of the 8p11 amplicon that likely explain the modest efficacy of FGFR inhibition in this disease. Clin Cancer Res; 23(18); 5366-73. ©2017 AACR.

Small-molecule androgen receptor downregulators as an approach to treatment of advanced prostate cancer.

Chemical starting points were investigated for downregulation of the androgen receptor as an approach to treatment of advanced prostate cancer. Although prototypic steroidal downregulators such as 6a designed for intramuscular administration showed insufficient cellular potency, a medicinal chemistry program derived from a novel androgen receptor ligand 8a led to 6-[4-(4-cyanobenzyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (10b), for which high plasma levels following oral administration in a preclinical model compensate for moderate cellular potency.

Inhibitors of the tyrosine kinase EphB4. Part 4: Discovery and optimization of a benzylic alcohol series.

Optimization of our bis-anilino-pyrimidine series of EphB4 kinase inhibitors led to the discovery of compound 12 which incorporates a key m-hydroxymethylene group on the C4 aniline. 12 displays a good kinase selectivity profile, good physical properties and pharmacokinetic parameters, suggesting it is a suitable candidate to investigate the therapeutic potential of EphB4 kinase inhibitors.

Inhibitors of the tyrosine kinase EphB4. Part 3: identification of non-benzodioxole-based kinase inhibitors.

Starting from the initial bis-anilinopyrimidine 1, good potency against EphB4 was retained when benzodioxole at C-4 was replaced by an indazole. The key interactions of the indazole with the protein were characterised by crystallographic studies. Further optimisation led to compound 20, a potent inhibitor of the EphB4 and Src kinases with good pharmacokinetics in various preclinical species and high fraction unbound in plasma. Compound 20 may be used as a tool for evaluating the potential of EphB4 kinase inhibitors in vivo.

The effects of the phytoestrogen genistein on the postnatal development of the rat.

The present studies report the effects on neonatal rats of oral exposure to genistein during the period from birth to postnatal day (PND) 21 to generate data for use in assessing human risk following oral ingestion of genistein. Failure to demonstrate significant exposure of the newborn pups via the mothers milk led us to subcutaneously inject genistein into the pups over the period PND 1-7, followed by daily gavage dosing to PND 21. The targeted doses throughout were 4 mg/kg/day genistein (equivalent to the average exposure of infants to total isoflavones in soy milk) and a dose 10 times higher than this (40 mg/kg genistein). The dose used during the injection phase of the experiment was based on plasma determinations of genistein and its major metabolites. Diethylstilbestrol (DES) at 10 micro g/kg was used as a positive control agent for assessment of changes in the sexually dimorphic nucleus of the preoptic area (SDN-POA). Administration of 40 mg/kg genistein increased uterus weights at day 22, advanced the mean day of vaginal opening, and induced permanent estrus in the developing female pups. Progesterone concentrations were also decreased in the mature females. There were no effects in females dosed with 4 mg/kg genistein, the predicted exposure level for infants drinking soy-based infant formulas. There were no consistent effects on male offspring at either dose level of genistein. Although genistein is estrogenic at 40 mg/kg/day, as illustrated by the effects described above, this dose does not have the same repercussions as DES in terms of the organizational effects on the SDN-POA.