Lyophilized liposomal formulation of a peptidomimetic-Dox conjugate for HER2 positive breast and lung cancer.

Nanocarrier-mediated administration of chemotherapeutic drugs can increase the therapeutic index of drugs by reducing off-target site toxicity. Ligand-targeted drug delivery can be utilized to deliver chemotherapeutic drugs to cancer cells selectively and specifically. Here we report the evaluation of a lyophilized formulation of a liposome containing a peptidomimetic-doxorubicin conjugate for targeted delivery of doxorubicin to HER2-positive cancer cells.

Towards Developing Novel Prostate Cancer Recurrence Suppressors: Acute Toxicity of Pseurotin A, an Orally Active PCSK9 Axis-Targeting Small-Molecule in Swiss Albino Mice.

The proprotein convertase subtilisin kexin type 9 (PCSK9) emerged as a molecular target of great interest for the management of cardiovascular disorders due to its ability to reduce low density lipoprotein (LDL) cholesterol by binding and targeting at LDLR for lysosomal degradation in cells. Preliminary studies revealed that pseurotin A (PsA), a spiro-heterocyclic γ-lactam alkaloid from several marine and terrestrial and species, has the ability to dually suppress the PCSK9 expression and protein-protein interaction (PPI) with LDLR, resulting in an anti-hypercholesterolemic effect and modulating the oncogenic role of PCSK9 axis in breast and prostate cancers progression and recurrence. Thus, a preliminary assessment of the PsA acute toxicity represents the steppingstone to develop PsA as a novel orally active PCSK9 axis modulating cancer recurrence inhibitor.

A pH-sensitive liposome formulation of a peptidomimetic-Dox conjugate for targeting HER2 + cancer.

Cancer treatment faces the challenge of selective delivery of the cytotoxic drug to the desired site of action to minimize undesired side effects. The liposomal formulation containing targeting ligand conjugated cytotoxic drug can be an effective approach to specifically deliver chemotherapeutic drugs to cancer cells that overexpress a particular cell surface receptor. This research focuses on the in vitro and in vivo studies of a peptidomimetic ligand attached doxorubicin for the HER2 positive lung and breast cancer cells transported by a pH-dependent liposomal formulation system for the enhancement of targeted anticancer treatment.

Olive Oil Lignan (+)-Acetoxypinoresinol Peripheral Motor and Neuronal Protection against the Tremorgenic Mycotoxin Penitrem A Toxicity STAT1 Pathway.

Penitrem A, PA, is an indole diterpene alkaloid produced by several fungal species. PA acts as a selective Ca-dependent K-channels (Maxi-K, BK) antagonist in brain, causing motor system dysfunctions including tremors and seizures. However, its molecular mechanism at the peripheral nervous system (PNS) is still ambiguous.

(-)-Oleocanthal as a Dual c-MET-COX2 Inhibitor for the Control of Lung Cancer.

Lung cancer (LC) represents the topmost mortality-causing cancer in the U.S. LC patients have overall poor survival rate with limited available treatment options.

Safety Evaluations of Single Dose of the Olive Secoiridoid -(-)-Oleocanthal in Swiss Albino Mice.

Epidemiological and clinical studies compellingly showed the ability of Mediterranean diet rich in extra-virgin olive oil (EVOO) to reduce multiple diseases such as cancer, cardiovascular diseases, and aging cognitive functions decline. The -(-)-Oleocanthal (OC) is a minor phenolic secoiridoid exclusively found in extra-virgin olive oil (EVOO). OC recently gained notable research attention due to its excellent in vitro and in vivo biological effects against multiple cancers, inflammations, and Alzheimer's disease.

(-)-Oleocanthal Prevents Breast Cancer Locoregional Recurrence After Primary Tumor Surgical Excision and Neoadjuvant Targeted Therapy in Orthotopic Nude Mouse Models.

Breast cancer (BC) recurrence represents a challenge for survivors who have had their primary tumors surgically excised, and/or have completed radiation, neoadjuvant, or adjuvant therapeutic regimens. Current BC treatments mostly lack the ability to reduce the risk of disease recurrence. About 70% of BC patients will subsequently suffer disease relapse, manifesting as local, regional, or distant tumor recurrence, which clearly underscores the urgent need to discover novel recurrence inhibitors.

(-)-Oleocanthal Combined with Lapatinib Treatment Synergized against HER-2 Positive Breast Cancer In Vitro and In Vivo.

Dysregulation of epidermal growth factor receptor (EGFR)/human epidermal growth factor-2 (HER2) family is a hallmark of aggressive breast cancer. Small-molecule tyrosine kinase inhibitors are among the most effective cancer targeted treatments. (-)-Oleocanthal (OC) is a naturally occurring phenolic secoiridoid lead from extra-virgin olive oil with documented anti-cancer activities via targeting mesenchymal epithelial transition factor (c-Met).

Megakaryocyte expansion and macrophage infiltration in bone marrow of rats subchronically treated with MNX, N-nitroso environmental degradation product of munitions compound RDX (hexahydro-1,3,5-trinitro-1,3,5-triazine).

Hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX), environmental degradation product of munitions hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), causes seizures in rats with acute oral exposure like parent RDX. Our previous studies have additionally reported hematotoxicity with acute MNX exposure manifested as myelosuppression, anemia and splenic hemosiderosis. This study explored whether MNX administered subchronically continued to target bone marrow to elicit peripheral blood cytopenia.

Marine natural products-inspired phenylmethylene hydantoins with potent in vitro and in vivo antitumor activities via suppression of Brk and FAK signaling.

Breast and prostate cancers are among the most common cancers worldwide with devastating statistics for the metastatic, chemotherapy- and radiotherapy-resistant phenotypes. Novel therapies interfering with new and/or multiple pathways involved in the pathology of cancer are urgently needed. Preliminary results showed that the marine natural product Z-4-hydroxyphenylmethylene hydantoin (PMH, ) and its 4-ethylthio-analog (SEth, ) promoted tight junction formation and showed anti-invasive and anti-migratory activities in vitro against metastatic prostate cancer cells and inhibited tumor growth and micrometastases in distant organs in orthotopic and transgenic mice models.

Validation of a genomics-based hypothetical adverse outcome pathway: 2,4-dinitrotoluene perturbs PPAR signaling thus impairing energy metabolism and exercise endurance.

2,4-dinitrotoluene (2,4-DNT) is a nitroaromatic used in industrial dyes and explosives manufacturing processes that is found as a contaminant in the environment. Previous studies have implicated antagonism of PPARα signaling as a principal process affected by 2,4-DNT. Here, we test the hypothesis that 2,4-DNT-induced perturbations in PPARα signaling and resultant downstream deficits in energy metabolism, especially from lipids, cause organism-level impacts on exercise endurance.

The marine-derived sipholenol A-4-O-3',4'-dichlorobenzoate inhibits breast cancer growth and motility in vitro and in vivo through the suppression of Brk and FAK signaling.

Sipholenol A is a natural sipholane triterpenoid isolated from the Red Sea sponge, Callyspongia siphonella. Previous studies showed the antimigratory and antiproliferative activities of the semisynthetic sipholenol A esters against breast cancer cell lines. This study investigated the effects of sipholenol A-4-O-3',4'-dichlorobenzoate (SPA) on the growth, migration and invasion of diverse human breast cancer cells.

Indole diterpene alkaloids as novel inhibitors of the Wnt/β-catenin pathway in breast cancer cells.

Penitrems are indole diterpene alkaloids best known for their BK channel inhibition and tremorgenic effects in mammals. In a previous study, penitrems A-F (1-5), their biosynthetic precursors, paspaline (6) and emindole SB (7), and two brominated penitrem analogs 8 and 9 demonstrated promising in vitro antiproliferative, antimigratory, and anti-invasive effects in the MTT (MCF-7 and MDA-MB-231), wound-healing, and Cultrex BME cell invasion (MDA-MB-231) assays, respectively. The study herein reports the novel ability of penitrem A to suppress total β-catenin levels in MDA-MB-231 mammary cancer cells.

Old dance with a new partner: EGF receptor as the phenobarbital receptor mediating Cyp2B expression.

The decades-long quest for the phenobarbital (PhB) receptor that mediates activation of Cyp2B would appear fulfilled with the discovery by Mutoh et al., who found that PhB binds with pharmacological affinity to the epidermal growth factor receptor (EGFR). This finding provides a molecular basis for the suppression of hepatocyte EGFR signaling observed with PhB treatment, as previously noted in the context of tumor promotion.

Delayed myelosuppression with acute exposure to hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) and environmental degradation product hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX) in rats.

Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), a widely used munitions compound, and hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX), its N-nitroso product of anaerobic microbial nitroreduction, are contaminants of military sites. Previous studies have shown MNX to be the most acutely toxic among the nitroreduced degradation products of RDX and to cause mild anemia at high dose. The present study compares hematotoxicity with acute oral exposure to MNX with parent RDX.

The opposite effects of doxorubicin on bone marrow stem cells versus breast cancer stem cells depend on glucosylceramide synthase.

Myelosuppression and drug resistance are common adverse effects in cancer patients with chemotherapy, and those severely limit the therapeutic efficacy and lead treatment failure. It is unclear by which cellular mechanism anticancer drugs suppress bone marrow, while drug-resistant tumors survive. We report that due to the difference of glucosylceramide synthase (GCS), catalyzing ceramide glycosylation, doxorubicin (Dox) eliminates bone marrow stem cells (BMSCs) and expands breast cancer stem cells (BCSCs).

Effects of chemically characterized fractions from aerial parts of Echinacea purpurea and E. angustifolia on myelopoiesis in rats.

Echinacea species are used for beneficial effects on immune function, and various prevalent phytochemicals have immunomodulatory effects. Using a commercial E. purpurea (L.

Analysis of common and specific mechanisms of liver function affected by nitrotoluene compounds.

Background: Nitrotoluenes are widely used chemical manufacturing and munitions applications. This group of chemicals has been shown to cause a range of effects from anemia and hypercholesterolemia to testicular atrophy. We have examined the molecular and functional effects of five different, but structurally related, nitrotoluenes on using an integrative systems biology approach to gain insight into common and disparate mechanisms underlying effects caused by these chemicals.

A new approach to construct pathway connected networks and its application in dose responsive gene expression profiles of rat liver regulated by 2,4DNT.

Background: Military and industrial activities have lead to reported release of 2,4-dinitrotoluene (2,4DNT) into soil, groundwater or surface water. It has been reported that 2,4DNT can induce toxic effects on humans and other organisms. However the mechanism of 2,4DNT induced toxicity is still unclear.

Design, synthesis, and biological evaluation of dibromotyrosine analogues inspired by marine natural products as inhibitors of human prostate cancer proliferation, invasion, and migration.

Bioactive secondary metabolites originating from dibromotyrosine are common in marine sponges, such as sponges of the Aplysina species. Verongiaquinol (1), 3,5-dibromo-1-hydroxy-4-oxocyclohexa-2,5-diene-1-acetamide, and aeroplysinin-1 are examples of such bioactive metabolites. Previous studies have shown the potent antimicrobial as well as cytotoxic properties of verongiaquinol and the anti-angiogenic activity of aeroplysinin-1.

Comparative cytotoxicity of alachlor, acetochlor, and metolachlor herbicides in isolated rat and cryopreserved human hepatocytes.

Noncancerous adverse effects observed at the lowest dose for chloroacetanilide herbicides alachlor [2-chloro-2',6'-diethyl-N-(methoxymethyl)-acetanilide] and acetochlor [2-chloro-2'-methyl-6'-ethyl-N-(ethoxymethyl)acetanilide], but not metolachlor [2-chloro-2'-ethyl-6'-methyl-N-(1-methyl-2-methoxymethyl)acetanilide], are hepatotoxicity in rats and dogs. Liver microsomal N-dealkylation, a step in the putative activating pathway, of acetochlor exceeds that of alachlor and is negligible for metolachlor. In the present investigation, cytotoxicity of the three chloroacetanilides was ranked using isolated rat and cryopreserved human hepatocytes to correlate this endpoint with CYP3A-dependent metabolism.

Comparison of transcriptional responses in liver tissue and primary hepatocyte cell cultures after exposure to hexahydro-1, 3, 5-trinitro-1, 3, 5-triazine.

Background: Cell culture systems are useful in studying toxicological effects of chemicals such as Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), however little is known as to how accurately isolated cells reflect responses of intact organs. In this work, we compare transcriptional responses in livers of Sprague-Dawley rats and primary hepatocyte cells after exposure to RDX to determine how faithfully the in vitro model system reflects in vivo responses.

Results: Expression patterns were found to be markedly different between liver tissue and primary cell cultures before exposure to RDX.

Cytotoxicity of chloroacetanilide herbicide alachlor in HepG2 cells independent of CYP3A4 and CYP3A7.

Alachlor is cytotoxic to human hepatoblastoma HepG2s, a cell line that expresses constitutive CYP3A7 and dexamethasone (DEX)-inducible CYP3A4 and CYP3A7. CYP3A4 catalyzes alachlor N-dealkylation to 2-chloro-N-(2,6-diethylphenyl)acetamide (CDEPA), precursor of 2,6-diethylbenzoquinoneimine, putative reactive metabolite for rat nasal carcinogenicity. We hypothesized that HepG2 alachlor cytotoxicity would be mediated by CYP3A4/7 and increased with DEX.

Up-and-down procedure (UDP) determinations of acute oral toxicity of nitroso degradation products of hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX).

Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), a widely used military explosive and soil and ground water contaminant of munitions manufacturing and artillery training sites, undergoes microbial nitroreductase metabolism to hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX), hexahydro-1,3-dinitroso-5-nitro-1,3,5-triazine (DNX), and hexahydro-1,3,5-trinitroso-1,3,5-triazine (TNX). Human occupational and accidental exposures to RDX, as well as acute oral exposures in rats, result in seizures, but little is known about the toxicity of the RDX degradation products. The main objective of the present study was to determine the oral LD50 of the most potent RDX N-nitroso product in female Sprague-Dawley rats using the recently validated up-and-down procedure (UDP).

The herbicide metolachlor induces liver cytochrome P450s 2B1/2 and 3A1/2, but not thyroxine-uridine dinucleotide phosphate glucuronosyltransferase and associated thyroid gland activity.

Metolachlor (2-chloro-N-(2-ethyl-6-methylphenyl)-N-(2-methoxy-1-methylethyl) acetamide) is widely used internationally as a corn and cotton herbicide. The metolachlor effects noted in rats during testing for U.S.