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Engineered biosynthesis of gilvocarcin analogues with altered deoxyhexopyranose moieties.

A combinatorial biosynthetic approach was used to interrogate the donor substrate flexibility of GilGT, the glycosyltransferase involved in C-glycosylation during gilvocarcin biosynthesis. Complementation of gilvocarcin mutant Streptomyces lividans TK24 (cosG9B3-U(-)), in which the biosynthesis of the natural sugar donor substrate was compromised, with various deoxysugar plasmids led to the generation of six gilvocarcin analogues with altered saccharide moieties. Characterization of the isolated gilvocarcin derivatives revealed five new compounds, including 4-β-C-D-olivosyl-gilvocarcin V (D-ol

Reduced growth of human sarcoma xenografts in hosts homozygous for the lit mutation.

BACKGROUND AND OBJECTIVES: Prior studies have shown that sarcoma growth can be stimulated by insulin-like growth factor-I (IGF-I). To extend this line of research, we carried out in vivo growth studies of primary human sarcoma in immunosuppressed control and IGF-I-deficient mice. METHODS: Human sarcoma specimens (one osteosarcoma and seven soft tissue sarcomas) were harvested in the operating room and implanted in immunosuppressed mice. Second-generation sarcomas were transplanted to control (GH replete lit/+ mice) and to experimental (GH/IGF-I-deficient lit/lit) animals. When tumors reached

MINDEC-An Enhanced Negative Depletion Strategy for Circulating Tumour Cell Enrichment.

Most current methods of circulating tumour cell (CTC) enrichment target the epithelial protein EpCAM, which is commonly expressed in adenocarcinoma cells. However, such methods will not recover the fraction of CTCs that have a non-epithelial phenotype due to epithelial-mesenchymal transition. For phenotype-independent CTC enrichment, we developed a new enhanced negative depletion strategy-termed MINDEC-that is based on multi-marker (CD45, CD16, CD19, CD163, and CD235a/GYPA) depletion of blood cells rather than targeted enrichment of CTCs. Here we validated the performance of MINDEC using epith

Inhibition of IRAK1/4 sensitizes T cell acute lymphoblastic leukemia to chemotherapies.

Signaling via the MyD88/IRAK pathway in T cells is indispensable for cell survival; however, it is not known whether this pathway functions in the progression of T acute lymphoblastic leukemia (T-ALL). Here, we determined that compared with thymic and peripheral T cells, T-ALL cells from patients have elevated levels of IRAK1 and IRAK4 mRNA as well as increased total and phosphorylated protein. Targeted inhibition of IRAK1 and IRAK4, either with shRNA or with a pharmacological IRAK1/4 inhibitor, dramatically impeded proliferation of T-ALL cells isolated from patients and T-ALL cells in a murin

Integrated computational and in vitro investigation to explore the preliminary anti-proliferative and anti-mitotic potential of γ-oryzanol against breast cancer.

This study investigated the preliminary role of γ-oryzanol (γ-O) against breast cancer through computational and in vitro analyses. Reference protein set (RPS) and functional enrichment set (FES) proteins were identified and subjected to network pharmacology. Pharmacogenomics analysis assessed expression profiles and survival associations. Molecular docking of γ-O with PIK3CA, AKT1, AKR1C3, ESR1, and MAPK1 was performed, followed by molecular dynamics (MD) simulation of the γ-O-PIK3CA complex. Brine shrimp lethality assay (BSLA) evaluated the effect of γ-O on nauplii survival and percentage le

Synthesis and computational investigation of novel 2-mercaptoimidazolones as dual antimicrobial and anti-proliferative agents with potential multitargeting kinase inhibitory activity.

Anticancer drug therapy-induced immunosuppression increases the incidence of treatment-resistant infectious diseases in cancer patients. Combining antibacterial and anticancer capabilities into a single medication can potentially enhance the treatment outcomes. In this light, the current study focused on developing innovative 5-arylidene-3-phenyl-2-thioimidazolones 1a-e and evaluated them as antimicrobial candidates against a panel of Gram-positive and Gram-negative bacterial and fungal isolates. Compounds 1e and 2d exhibited the most potent microbial activity, with MIC values ranging from 24 

Microwave-assisted one-pot green synthesis, ADMET profiling, DFT, and molecular docking of novel 3-cyano-2-pyridone derivatives as dual EGFR and cytokine (TNF-α, IL-6) inhibitors.

Epidermal Growth Factor Receptor (EGFR) is crucial for cancer cell growth, survival, and resistance. Inflammatory cytokines like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) also help tumors grow and evade the immune system. Developing multi-targeted inhibitors that hit both cancerous and inflammatory pathways has strong therapeutic potential. This study aims to design, create, and test novel series of pyridone-based derivatives serving as dual inhibitors of EGFR signaling pathways with anti-inflammatory effects by suppressing IL-6 and TNF-α. We synthesized and structurally cha

Drug Encapsulated Lipid-Polymeric Nanohybrid as a Chemo-therapeutic Platform of Cancer.

The focus of this research is to design a bioengineered drug delivery vehicle that is efficient in anti-cancer drug delivery in a controlled manner. The experimental work focuses on constructing a methotrexate-loaded nano lipid polymer system (MTX-NLPHS) that can transport methotrexate (MTX) in MCF-7 cell lines in a controlled manner through endocytosis via phosphatidylcholine. In this experiment, MTX is embedded with polylactic-co-glycolic acid (PLGA) in phosphatidylcholine, which acts as a liposomal framework for regulated drug delivery. Scanning electron microscopy (SEM), Fourier transform

Tumour kinome re-wiring governs resistance to palbociclib in oestrogen receptor positive breast cancers, highlighting new therapeutic modalities.

Combination of CDK4/6 inhibitors and endocrine therapy improves clinical outcome in advanced oestrogen receptor (ER)-positive breast cancer, however relapse is inevitable. Here, we show in model systems that other than loss of RB1 few gene-copy number (CN) alterations are associated with irreversible-resistance to endocrine therapy and subsequent secondary resistance to palbociclib. Resistance to palbociclib occurred as a result of tumour cell re-wiring leading to increased expression of EGFR, MAPK, CDK4, CDK2, CDK7, CCNE1 and CCNE2. Resistance altered the ER genome wide-binding pattern, leadi

Novel theranostic zinc phthalocyanine-phospholipid complex self-assembled nanoparticles for imaging-guided targeted photodynamic treatment with controllable ROS production and shape-assisted enhanced cellular uptake.

The novel drug delivery system based on self-assembly of zinc phthalocyanine-soybean phosphatidylcholine (ZnPc-SPC) complex was developed by … hat ZSPM exhibited stronger cellular uptake efficacy and photodynamic cytotoxicity against HeLa and MCF-7 cells than ZS functionalized with DSPE-mPEG (ZSP) and free ZnPc. More importantly, ZSPM showed the enhanced accumulation effect at the tumor region compared with ZSP by the active-plus-passive targeting via enhanced permeability and retention (EPR) effect …

A novel role for the apoptosis inhibitor ARC in suppressing TNFα-induced regulated necrosis.

TNFα signaling can promote apoptosis or a regulated form of necrosis. ARC (apoptosis repressor with CARD (caspase recruitment domain)) is an endogenous inhibitor of apoptosis that antagonizes both the extrinsic (death receptor) and intrinsic (mitochondrial/ER) apoptosis pathways. We discovered that ARC blocks not only apoptosis but also necrosis. TNFα-induced necrosis was abrogated by overexpression of wild-type ARC but not by a CARD mutant that is also defective for inhibition of apoptosis. Conversely, knockdown of ARC exacerbated TNFα-induced necrosis, an effect that was rescued by reconstit

Приобретение онколитических аденовирусов с последующим лечением от ПД-1 и паклитакселя ведет к повышению эффективности борьбы с раком в модели 3D TNBC.

Трижды отрицательный рак груди (TNBC) считается одним из наиболее неизлечимых магнатов в силу его клинических характеристик, включая высокую инвазивность, высокий метастатический потенциал, подверженность рецидиву и плохое прогнозирование. Поэтому она по-прежнему является одной из важнейших неудовлетворенных медицинских потребностей. С другой стороны, низкая эффективность доставки продолжает снижать эффективность антираковых терапевтических средств, разработанных для борьбы с твердыми опухолями, с использованием различных стратегий, таких, как генетически разработанные онколитические векторы,

Совпадение в аннотации оригинала
Triple-negative breast cancer (TNBC) is considered one of the most incurable malignancies due to its clinical characteristics, including hig … two-dimensional (2D) and three-dimensional (3D) breast cancer models in MDA-MB-231, MDA-MB-468 and MCF-7 cells. Then, to further evaluate the efficacy of combinatorial therapy, including immunological aspects, we established a three-dimensional (3D) co-culture model based on MDA-MB-231 cells with peripheral blood mononuclear cells (PBMCs) to create an integr …

N-acyl-dopamines: novel synthetic CB(1) cannabinoid-receptor ligands and inhibitors of anandamide inactivation with cannabimimetic activity in vitro and in vivo.

We reported previously that synthetic amides of polyunsaturated fatty acids with bioactive amines can result in substances that interact with proteins of the endogenous cannabinoid system (ECS). Here we synthesized a series of N-acyl-dopamines (NADAs) and studied their effects on the anandamide membrane transporter, the anandamide amidohydrolase (fatty acid amide hydrolase, FAAH) and the two cannabinoid receptor subtypes, CB(1) and CB(2). NADAs competitively inhibited FAAH from N18TG2 cells (IC(50)=19-100 microM), as well as the binding of the selective CB(1) receptor ligand, [(3)H]SR141716A,

Development of (p-O-sulfamoyl)-N-alkanoyl-phenylalkyl amines as non-steroidal estrone sulfatase inhibitors.

Estrogen levels in breast tumors of postmenopausal women are as much as 10 times higher than estrogen levels in plasma, presumably due to in situ formation of estrogen. The major source of estrogen in breast cancer cells may be conversion of estrone sulfate to estrone by the enzyme estrone sulfatase. Thus, inhibitors of estrone sulfatase are potential agents for treatment of estrogen-dependent breast cancer. Several steroidal compounds have been developed that are potent estrone sulfatase inhibitors, most notably estrone-3-O-sulfamate. However, these compounds and their metabolites may have un

Anti-oestrogens but not oestrogen deprivation promote cellular invasion in intercellular adhesion-deficient breast cancer cells.

INTRODUCTION: Anti-oestrogens have been the mainstay of therapy in patients with oestrogen-receptor (ER) positive breast cancer and have pro … DS: The effect of oestrogen and 4-hydroxy-tamoxifen on the invasive capacity of endocrine-sensitive MCF-7 cells, in the presence or absence of functional E-cadherin, was determined by Matrigel invasion assays. Studies also monitored the impact of oestrogen withdrawal or treatment with fulvestrant on cell invasion. Western blotting using phospho-specific antib …

Design, synthesis, structural characterization, anticancer evaluation, and computational studies of novel quinoline-1,2,3-triazole glycohybrids.

A novel series of eleven phenyl-substituted quinoline 1,2,3-triazole glycoconjugates 6(a-k) was synthesized via the copper(i)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction between 2-phenyl-substituted quinoline-4-carboxylic acid propargyl ester (4a-4e) and various sugar azides (5a, 5b, and 5c). The obtained compounds were comprehensively characterized by FT-IR, 1H NMR, 13C NMR, and mass spectrometry. The chemical structures of compounds 6a, 6b, and 6e were further established by single-crystal X-ray diffraction analysis. Their crystal packing was stabilized through a network of intermo

Unusual norcucurbitacin glycosides from the roots of Siraitia grosvenorii.

Siraitia grosvenorii Swingle is one of the first approved medicine food homology species in China, and it has been used as a natural sweetener in the food industry and as a traditional medicine to relieve cough and reduce phlegm. However, many S. grosvenorii roots are discarded yearly, which results in a great waste of resources. Twelve undescribed norcucurbitacin-type triterpenoid glycosides, siraitiaosides A-L (1-12), and six known analogs (13-18) were isolated from the roots of S. grosvenorii. The structures of isolated norcucurbitacin glycosides were elucidated by comprehensive data analys

Essential Oils from the Leaves and Stem Barks of Pluchea Indica (L.) Less.: Chemical Analysis, Cytotoxicity, Anti-inflammation, Antimicrobial Activity, Molecular Docking, and ADMET Profiling.

Pluchea indica (L.) Less. is a medicinal plant native to Asia. Traditionally, it is known for numerous traditional uses, such as treatments for fever, cough, and digestive issues. The present investigation aims to determine the chemical compositions of essential oils from its fresh leaves and stem barks. By using hydro-distillation and the GC-FID/MS (gas chromatography-flame ionization detection/mass spectrometry) analysis, the studied samples were dominated by sesquiterpene hydrocarbons (76.8-82.2 %) and their oxygenated derivatives (8.4-19.0 %). β-Selinene (42.0-43.5 %) and silphinene (21.1-

Nanohybrid Based on (Mn, Zn) Ferrite Nanoparticles Functionalized With Chitosan and Sodium Alginate for Loading of Curcumin Against Human Breast Cancer Cells.

This study reports on the synthesis of Mn1 - xZnxFe2O4 (Mn, Zn ferrite) magnetic nanoparticles (MNPs) as drug delivery carriers for effective therapeutic outcomes. The MNPs were prepared using the coprecipitation method, and their magnetic properties were investigated based on their composition. Among the compositions tested, Mn0.8Zn0.2Fe2O4 MNPs exhibited superparamagnetic properties with a saturation magnetization moment of 34.6 emu/g at room temperature (25°C). To enhance the water solubility of curcumin (Cur), known for its hydrophobic nature, it was successfully loaded onto alginate (Alg)

H2S donor GYY4137 ameliorates paclitaxel-induced neuropathic pain in mice.

Paclitaxel-induced neuropathic pain (PINP) is a dose-limiting side effect that largely affects the patient's quality of life and may limit the use of the drug as a chemotherapeutic agent for treating metastatic breast cancer and other solid tumors. Recently, a putative role for the gaseous mediator hydrogen sulfide (H2S) in nociception modulation has been suggested. The aim of the present study was to investigate the potential efficacy of the slow release H2S donor GYY4137 to alleviate and prevent PINP. Female BALB/c mice that were intraperitoneally (i.p.) injected with paclitaxel (2 mg/kg) fo