Publications by authors named "Danyelle M Townsend"

109 Publications

Recent progress in micro and nano-encapsulation of bioactive derivatives of the Brazilian genus Pterodon.

Biomed Pharmacother 2021 Sep 7;143:112137. Epub 2021 Sep 7.

Department of Clinical and Toxicological Analysis, Faculty of Pharmacy, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, Minas Gerais, Brazil. Electronic address:

In the last few decades, utilization of medicinal plants by the pharmaceutical industry has led to the identification of many new bioactive compounds. The genus Pterodon, native of the Brazilian Flora, is known for the therapeutic properties attributed to its species, which are widely used in popular medicine for their anti-inflammatory, anti-rheumatic, tonic, and depurative properties. The intrinsic low water solubility of the plant derivatives from the genus, including diterpenes with vouacapane skeletons that are partially associated with the pharmacological activities, impairs the bioavailability of these bioactive compounds. Recent studies have aimed to encapsulate Pterodon products to improve their water solubility, achieve stability, increase their efficacy, and allow clinical applications. The purpose of this paper is to review recent research on the use of nanotechnology for the development of new products from plant derivatives of the Pterodon genus in different types of micro- and nanocarriers. Therapeutic properties of their different products are also presented. Finally, an update about the current and future applications of encapsulated formulations is provided.
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http://dx.doi.org/10.1016/j.biopha.2021.112137DOI Listing
September 2021

Cisplatin chemotherapy and renal function.

Adv Cancer Res 2021 28;152:305-327. Epub 2021 Apr 28.

Department of Pharmaceutical and Biomedical Sciences, Medical University of South Carolina, Charleston, SC, United States. Electronic address:

Cisplatin has been a mainstay of cancer chemotherapy since the 1970s. Despite its broad anticancer potential, its clinical use has regularly been constrained by kidney toxicities. This review details those biochemical pathways and metabolic conversions that underlie the kidney toxicities. A wide range of redox events contribute to the eventual physiological consequences of drug activities.
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http://dx.doi.org/10.1016/bs.acr.2021.03.008DOI Listing
April 2021

The role of sacubitril/valsartan in the treatment of chronic heart failure with reduced ejection fraction in hypertensive patients with comorbidities: From clinical trials to real-world settings.

Biomed Pharmacother 2020 Oct 21;130:110596. Epub 2020 Aug 21.

Nuclear Medicine Unit, Santa Maria della Misericordia Hospital, Rovigo, Italy. Electronic address:

Background: Sacubitril/valsartan, the first agent to be approved in a new class of drugs called angiotensin receptor neprilysin inhibitors (ARNIs), has been shown to reduce cardiovascular mortality and morbidity compared to enalapril in outpatient subjects with chronic heart failure (HF) and reduced left ventricular ejection fraction (HFrEF). However, there is little real-world evidence about the efficacy of ARNIs in elderly hypertensive patients with HFrEF and comorbidities.

Methods: In this prospective open-label study, 108 subjects, 54 of them (mean age 78.6 ± 8.2 years, 75.0 % male), with HFrEF (29.8 ± 4.3 %) and New York Heart Association (NYHA) class II-III symptoms were assigned to receive ARNIs twice daily, according to the recommended dosage of 24/26, 49/51, 97/103 mg. Patients were gender- and age-matched with a control arm of patients with HFrEF receiving the optimal standard therapy for HF. The clinic blood pressure (BP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), estimated glomerular filtration rate (eGFR), blood glucose and glycated hemoglobin (HbA1c), uric acid (UA), left ventricular ejection fraction (LVEF) and NYHA class were evaluated at a mean follow-up of 12 months. During the follow-up, the clinical outcomes, including mortality and re-hospitalization for HF, were collected.

Results: NYHA class significantly improved in the ARNI arm compared to the control (24.9 vs. 6.4 %, shifting from class III to II, and 55.4 vs. 25.2 %, from class II to I, p < 0.05 for all). A significant improvement in LVEF and eGFR levels was found in the ARNI arm compared to controls (42.4 vs. 34.2 %, 73.8 vs. 61.2 mL/min, respectively; p < 0.001 for all). NT-proBNP, clinic systolic and diastolic BP, blood glucose, HbA1c and UA values were reduced in both treatment arms, but they were lower in the ARNI arm compared controls (3107 vs. 4552 pg/mL, 112.2 vs. 120.4 and 68.8 vs. 75.6 mmHg, 108.4 vs. 112.6 mg/dL, 5.4 vs. 5.9 % and 5.9 vs. 6.4 mg/dL, respectively, p < 0.05). Mortality and re-hospitalization for HF was lower in the ARNI arm than controls (20.1 vs. 33.6 % and 27.7 vs. 46.3 % respectively; p < 0.05 for all). Gender differences were not found in either arm. No patients refused to continue the study, and no side effects to the ARNI treatment were observed.

Conclusions: In elderly patients with HFrEF and comorbidities, ARNI treatment seems effective and safe. The improvement in LVEF and cardiac remodeling, BP, eGFR, serum glucose, UA and HbA1c could be the mechanisms by which ARNIs play their beneficial role on clinical outcomes. However, these results need to be confirmed in studies involving a greater number of subjects, and with a longer follow-up.
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http://dx.doi.org/10.1016/j.biopha.2020.110596DOI Listing
October 2020

Glutathione -Transferase P Influences Redox Homeostasis and Response to Drugs that Induce the Unfolded Protein Response in Zebrafish.

J Pharmacol Exp Ther 2021 04 29;377(1):121-132. Epub 2021 Jan 29.

Leilei Zhang, Seok-Hyung Kim, Ki-Hoon Park, Zhi-wei Ye, Jie Zhang, Danyelle M. Townsend, Kenneth D. Tew Department of Cell and Molecular Pharmacology and Experimental Therapeutics (L.Z., Z.Y., J.Z., K.D.T.), Division of Nephrology, Department of Medicine (S.-H.K., K.-H.P.), and Department of Pharmaceutical and Biomedical Sciences (D.M.T.), Medical University of South Carolina, Charleston, South Carolina

We have created a novel glutathione -transferase 1 () knockout (KO) zebrafish model and used it for comparative analyses of redox homeostasis and response to drugs that cause endoplasmic reticulum (ER) stress and induce the unfolded protein response (UPR). Under basal conditions, KO larvae had higher expression of antioxidant nuclear factor erythroid 2-related factor 2 (Nrf2) accompanied by a more reduced larval environment and a status consistent with reductive stress. Compared with wild type, various UPR markers were decreased in KO larvae, but treatment with drugs that induce ER stress caused greater toxicities and increased expression of Nrf2 and UPR markers in KO. Tunicamycin and 0-{2,4-dinitro-5-[4-(-methylamino)benzoyloxy]phenyl}1-(,-dimethylamino)diazen-1-ium-1,2-diolate (PABA/nitric oxide) activated inositol-requiring protein-1/X-box binding protein 1 pathways, whereas thapsigargin caused greater activation of protein kinase-like ER kinase/activating transcription factor 4/CHOP pathways. These results suggest that this teleost model is useful for predicting how GSTP regulates organismal management of oxidative/reductive stress and is a determinant of response to drug-induced ER stress and the UPR. SIGNIFICANCE STATEMENT: A new zebrafish model has been created to study the importance of glutathione transferase 1 in development, redox homeostasis, and response to drugs that enact cytotoxicity through endoplasmic reticulum stress and induction of the unfolded protein response.
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http://dx.doi.org/10.1124/jpet.120.000417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047768PMC
April 2021

Selective internal radiation therapy of hepatic tumors: Morphologic and functional imaging for voxel-based computer-aided dosimetry.

Biomed Pharmacother 2020 Dec 3;132:110865. Epub 2020 Nov 3.

Division of Human Health, International Atomic Energy Agency, Wagramer Str. 5, 1220 Vienna, Austria. Electronic address:

Introduction: Selective Internal Radiation Therapy (SIRT) is used for the treatment of hepatic tumors. The aim of this retrospective study was to compare two dosimetric approaches based on Tc-MAA SPECT/CT and Y PET/CT, using SimplicitY™ versus the supplier suggested method of activity calculation.

Material And Methods: A total of 19 patients underwent 21 SIRT after baseline angiography and 99mTc-MAA SPECT/CT, followed by 90Y PET/CT. Overlap between 99mTc-MAA and 90Y-microspheres was quantified with different thresholds isocontours. The perfused volume and tumor absorbed dose were estimated using Simplicit90Y™ based on SPECT/CT and PET/CT, then compared with the supplier suggested method. These data were related to overall survival to evaluate their prognostic impact.

Results: The overlap between PET/CT and SPECT/CT was dependent on thresholds, decreasing with an increasing threshold. The overlap between the 99mTc-MAA and 90Y-microspheres biodistributions versus the tumor distribution on morphological imaging was suboptimal, in particular for small tumor volume. The tumor absorbed dose estimated after 90Y PET/CT was not different from tumor absorbed dose estimated after SPECT/CT. The Perfused lobe absorbed dose was significantly lower while the volume of the perfused lobe was significantly higher when estimated by Simplicit90Y™ compared to the supplier suggested conventional approach. A statistical parameter based on overlap between tumor and 90Y-microspheres distribution as well as tumoral dosimetry was significantly related to the overall survival.

Conclusion: Post-treatment imaging remains paramount to estimate the irradiation dosimetry, due to an imperfect overlap. The perfused volume could be estimated from functional imaging, given its impact on dosimetry. Finally, survival seems related to tumoral overlap and dosimetry.
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http://dx.doi.org/10.1016/j.biopha.2020.110865DOI Listing
December 2020

Enhanced antitumor efficacy of lapachol-loaded nanoemulsion in breast cancer tumor model.

Biomed Pharmacother 2021 Jan 27;133:110936. Epub 2020 Nov 27.

Department of Clinical and Toxicological Analysis, Faculty of Pharmacy, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, Minas Gerais, Brazil. Electronic address:

Lapachol (LAP) is a natural compound with various biological properties, including anticancer activity. However, its clinical application is limited due to the low aqueous solubility and potential adverse side effects. Nanoemulsions are drug delivery systems that can assist in the administration of hydrophobic drugs, increasing their bioavailability and protecting from degradation. Thus, this study aimed to prepare a LAP-loaded nanoemulsion (NE-LAP), and evaluate its antitumor activity. For this purpose, the nanoemulsion was prepared using a hot homogenization method and characterized morphologically by cryogenic transmission electron microscopy (cryo-TEM). Mean diameter, polydispersity index, and zeta potential was evaluated by DLS, encapsulation efficiency was measured by HPLC. Moreover, the short-term storage stability, the drug release and hemolysis in vitro was determined. Additionally, pharmacokinetic, toxicology and toxicity properties ofTc-NE-LAP were evaluated in a breast cancer (4T1) tumor model. The cryo-TEM showed spherical globules, and the physicochemical characterization of NE-LAP showed a homogeneous stable nanoemulsion with a mean diameter of ∼170 nm, zeta potential of around -20 mV, and encapsulation greater than 85 %. In vitro studies validated that encapsulation did not impair the cytotoxicity activity of LAP. The nanoemulsion was successfully radiolabeled and Tc-NE-LAP showed prolonged blood circulation and tumor affinity was confirmed by tumor-to-muscle ratio. Moreover, NE-LAP showed higher antitumor activity than the free drug and the treatment did not result in any signs of toxicity. Therefore, these findings suggest that NE-LAP can be considered an effective strategy for cancer treatment.
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http://dx.doi.org/10.1016/j.biopha.2020.110936DOI Listing
January 2021

Altered redox regulation and S-glutathionylation of BiP contribute to bortezomib resistance in multiple myeloma.

Free Radic Biol Med 2020 11 13;160:755-767. Epub 2020 Sep 13.

Department of Pharmaceutical and Biomedical Sciences, Medical University of South Carolina, 274 Calhoun Street, MSC 141, Charleston, SC, 29425, USA. Electronic address:

Multiple myeloma (MM) cells have high rates of secretion of proteins rich in disulfide bonds and depend upon compartmentalized redox balance for accurate protein folding. The proteasome inhibitor bortezomib (Btz) is a successful frontline treatment for the disease, but its long-term efficacy is restricted by the acquisition of resistance. We found that MM cell lines resistant to Btz maintain high levels of oxidative stress and are cross resistant to endoplasmic reticulum (ER) stress-inducing agents thapsigargin (ThG), and tunicamycin (TuM). Moreover, cells expressing high/wild type levels of glutathione S-transferase P (GSTP) are more resistant than Gstp1/p2 knockout cells. In agreement, basal levels of S-glutathionylated proteins and redox regulation enzymes, including GSTP are elevated at mRNA and protein levels in resistant cells. GSTP mediated S-glutathionylation (SSG) regulates the activities of a number of redox active ER proteins. Here we demonstrated that the post-translational modification determines the balance between foldase and ATPase activities of the binding immunoglobulin protein (BiP), with Cys41-SSG important for ATPase, and Cys420-SSG for foldase. BiP expression and S-glutathionylation are increased in clinical specimens of bone marrow from MM patients compared to non-cancerous samples. Preventing S-glutathionylation in MM cells with a GSTP specific inhibitor restored BiP activities and reversed resistance to Btz. Therefore, S-glutathionylation of BiP confers pro-survival advantages and represents a novel mechanism of drug resistance in MM cells. We conclude that altered GSTP expression leads to S-glutathionylation of BiP, and contributes to acquired resistance to Btz in MM.
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http://dx.doi.org/10.1016/j.freeradbiomed.2020.09.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704679PMC
November 2020

Development of Telintra as an Inhibitor of Glutathione S-Transferase P.

Handb Exp Pharmacol 2021 ;264:71-91

Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, USA.

Glutathione S-transferase P (GSTP) is a component of a complex series of pathways that provide cellular redox homeostasis. It is an abundant protein in certain tumors and is over-expressed in cancer drug resistance. It has diverse cellular functions that include, thiolase activities with small electrophilic agents or susceptible cysteine residues on the protein to mediate S-glutathionylation, and chaperone binding with select protein kinases. Preclinical and clinical testing of a nanomolar inhibitor of GSTP, TLK199 (Telintra; Ezatiostat) has indicated a role for the enzyme in hematopoiesis and utility for the drug in the treatment of patients with myelodysplastic syndrome.
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http://dx.doi.org/10.1007/164_2020_392DOI Listing
February 2021

Author Correction: 3-ketodihydrosphingosine reductase mutation induces steatosis and hepatic injury in zebrafish.

Sci Rep 2020 Jul 15;10(1):11971. Epub 2020 Jul 15.

Department of Medicine, Medical University of South Carolina, Charleston, SC, 29425, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-67912-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360750PMC
July 2020

Mitochondrial Function in Enamel Development.

Front Physiol 2020 29;11:538. Epub 2020 May 29.

College of Dentistry, Department of Molecular Pathobiology, New York University, New York, NY, United States.

Enamel is the most calcified tissue in vertebrates. Enamel formation and mineralization is a two-step process that is mediated by ameloblast cells during their secretory and maturation stages. In these two stages, ameloblasts are characterized by different morphology and function, which is fundamental for proper mineral growth in the extracellular space. Ultrastructural studies have shown that the mitochondria in these cells localize to different subcellular regions in both stages. However, limited knowledge is available on the role/s of mitochondria in enamel formation. To address this issue, we analyzed mitochondrial biogenesis and respiration, as well as the redox status of rat primary enamel cells isolated from the secretory and maturation stages. We show that maturation stage cells have an increased expression of PGC1α, a marker of mitochondrial biogenesis, and of components of the electron transport chain. Oxygen consumption rate (OCR), a proxy for mitochondrial function, showed a significant increase in oxidative phosphorylation during the maturation stage, promoting ATP production. The GSH/GSSG ratio was lower in the maturation stage, indicative of increased oxidation. Because higher oxidative phosphorylation can lead to higher ROS production, we tested if ROS affected the expression of and genes that are essential for enamel formation. The ameloblast cell line LS8 treated with HO to promote ROS elicited significant expression changes in and . Our data highlight important metabolic and physiological differences across the two enamel stages, with higher ATP levels in the maturation stage indicative of a higher energy demand. Besides these metabolic shifts, it is likely that the enhanced ETC function results in ROS-mediated transcriptional changes.
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http://dx.doi.org/10.3389/fphys.2020.00538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274036PMC
May 2020

Voltage-Dependent Anion Channels Influence Cytotoxicity of ME-344, a Therapeutic Isoflavone.

J Pharmacol Exp Ther 2020 08 16;374(2):308-318. Epub 2020 Jun 16.

Department of Cell and Molecular Pharmacology and Experimental Therapeutics (L.Z., M.M., E.N.M., Y.-L.J., A.-M.B., J.R.B., L.E.B., K.D.T.) and Department of Pharmaceutical and Biomedical Sciences (D.M.T.), Medical University of South Carolina, Charleston, South Carolina

ME-344 is a second-generation cytotoxic isoflavone with anticancer activity promulgated through interference with mitochondrial functions. Using a click chemistry version of the drug together with affinity-enriched mass spectrometry, voltage-dependent anion channels (VDACs) 1 and 2 were identified as drug targets. To determine the importance of VDAC1 or 2 to cytotoxicity, we used lung cancer cells that were either sensitive (H460) or intrinsically resistant (H596) to the drug. In H460 cells, depletion of VDAC1 and VDAC2 by small interfering RNA impacted ME-344 effects by diminishing generation of reactive oxygen species (ROS), preventing mitochondrial membrane potential dissipation, and moderating ME-344-induced cytotoxicity and mitochondrial-mediated apoptosis. Mechanistically, VDAC1 and VDAC2 knockdown prevented ME-344-induced apoptosis by inhibiting Bax mitochondrial translocation and cytochrome c release as well as apoptosis in these H460 cells. We conclude that VDAC1 and 2, as mediators of the response to oxidative stress, have roles in modulating ROS generation, Bax translocation, and cytochrome c release during mitochondrial-mediated apoptosis caused by ME-344. SIGNIFICANCE STATEMENT: Dissecting preclinical drug mechanisms are of significance in development of a drug toward eventual Food and Drug Administration approval.
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http://dx.doi.org/10.1124/jpet.120.000009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372917PMC
August 2020

Endoplasmic Reticulum Protein Disulfide Isomerase Shapes T Cell Efficacy for Adoptive Cellular Therapy of Tumors.

Cells 2019 11 26;8(12). Epub 2019 Nov 26.

Department of Orthopedics, Medical University of South Carolina, Charleston, SC 29425, USA.

Effective cancer therapies simultaneously restrict tumor cell growth and improve anti-tumor immune responses. Targeting redox-dependent protein folding enzymes within the endoplasmic reticulum (ER) is an alternative approach to activation of the unfolded protein response (UPR) and a novel therapeutic platform to induce malignant cell death. E64FC26 is a recently identified protein disulfide isomerase (PDI) inhibitor that activates the UPR, oxidative stress, and apoptosis in tumor cells, but not normal cell types. Given that targeting cellular redox homeostasis is a strategy to augment T cell tumor control, we tested the effect of E64FC26 on healthy and oncogenic T cells. In stark contrast to the pro-UPR and pro-death effects we observed in malignant T cells, we found that E64FC26 improved viability and limited the UPR in healthy T cells. E64FC26 treatment also diminished oxidative stress and decreased global PDI expression in normal T cells. Oxidative stress and cell death are limited in memory T cells and we found that PDI inhibition promoted memory traits and reshaped T cell metabolism. Using adoptive transfer of tumor antigen-specific CD8 T cells, we demonstrate that T cells activated and expanded in the presence of E64FC26 control tumor growth better than vehicle-matched controls. Our data indicate that PDI inhibitors are a new class of drug that may dually inhibit tumor cell growth and improve T cell tumor control.
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http://dx.doi.org/10.3390/cells8121514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953024PMC
November 2019

Thermosensitive Nanosystems Associated with Hyperthermia for Cancer Treatment.

Pharmaceuticals (Basel) 2019 Nov 25;12(4). Epub 2019 Nov 25.

Faculdade de Farmácia, Universidade Federal de Minas Gerais, 31279-901 Belo Horizonte, Brazil.

Conventional chemotherapy regimens have limitations due to serious adverse effects. Targeted drug delivery systems to reduce systemic toxicity are a powerful drug development platform. Encapsulation of antitumor drug(s) in thermosensitive nanocarriers is an emerging approach with a promise to improve uptake and increase therapeutic efficacy, as they can be activated by hyperthermia selectively at the tumor site. In this review, we focus on thermosensitive nanosystems associated with hyperthermia for the treatment of cancer, in preclinical and clinical use.
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http://dx.doi.org/10.3390/ph12040171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958340PMC
November 2019

Long-term effect of the perindopril/indapamide/amlodipine single-pill combination on left ventricular hypertrophy in outpatient hypertensive subjects.

Biomed Pharmacother 2019 Dec 15;120:109539. Epub 2019 Oct 15.

Department of Nuclear Medicine, Radiology, Neuroradiology, Medical Physics, Clinical Laboratory, Microbiology, Pathology, Trasfusional Medicine, Santa Maria della Misericordia Hospital, Rovigo, Italy.

Background: Most antihypertensive drugs used in monotherapy or in combination therapy reduce the left ventricular mass index (LVMI). However, little is known about the effects on LVMI of a triple fixed-dose combination (TFC) therapy, containing in a single pill an angiotensin-converting enzyme inhibitor (ACEI), a diuretic and a calcium channel blocker (CCB).

Methods: In this prospective open-label study, 92 patients with essential hypertension were randomized to treatment with a TFC of perindopril/indapamide/amlodipine at different doses or a triple free combination therapy (FCT) including ACEI/diuretic/CCB. Office blood pressure (BP) measurement, 24 h-ambulatory BP monitoring and echocardiography were performed at baseline and during a 14-month follow-up. The BP variability (BPV) over 24 h was calculated as ± standard deviation of the daytime systolic BP. Differences between office and monitored BP and LVMI were evaluated by ANOVA for repeated measures.

Results: A significant BP-lowering effect was observed for both treatments. At follow-up, BPV was reduced in both the treatment groups vs. the baseline (14.0±1.5 vs. 17.0±1.8 and 16.2±2.1 vs. 17.6±2.3, respectively), but it was lower in the TFC vs. the FCT group (14.0±1.5 vs. 16.1±2.2, P < 0.05). LVMI was lower in both the treatment groups, but the change was greater for TFC vs. FCT (-8.3±4.9% vs. -2.0 ±2.1%, P < 0.0001). Left ventricular hypertrophy (LVH) regression was greater in the TFC vs. the FCT group (43.5% vs. 30.4%, P < 0.05).

Conclusions: Independently of BP values achieved, the antihypertensive TFC therapy was more effective than FCT in LVMI reduction and LVH regression, possibly related to drugs' intrinsic properties and to BPV modulation.
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http://dx.doi.org/10.1016/j.biopha.2019.109539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104809PMC
December 2019

S-Glutathionylated Serine Proteinase Inhibitors as Biomarkers for Radiation Exposure in Prostate Cancer Patients.

Sci Rep 2019 09 24;9(1):13792. Epub 2019 Sep 24.

Departments of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, South Carolina, USA.

In biological tissues, radiation causes the formation of reactive oxygen species (ROS), some of which lead to sequential oxidation of certain protein cysteine residues. Resultant cysteinyl radicals are subject to post-translational modification through S-glutathionylation. The present clinical trial was designed to determine if S-glutathionylated serine protease inhibitors (serpins) in blood could be used as biomarkers of exposure to radiation. 56 male prostate cancer patients treated with radiotherapy were enrolled in the trial and levels of S-glutathionylated serpins A1 and A3 were assessed by immunoblotting. Patients were classified into three groups: (1) external beam radiation therapy (EBRT); (2) brachytherapy (BT); (3) both EBRT and BT. Prior to treatment, baseline plasma levels of both unmodified and S-glutathionylated serpins were similar in each group. We identified elevated plasma levels of S-glutathionylated serpin A1 monomer, trimer and serpin A3 monomer in patient blood following radiation. Maximal increased levels of these S-glutathionylated serpins were correlated with increased duration of radiotherapy treatments. We conclude that it is practical to quantify patient plasma S-glutathionylated serpins and that these post-translationally modified proteins are candidate biomarkers for measuring radiation exposure. This provides a platform for use of such biomarkers in trials with the range of drugs that, like radiation, produce ROS.
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http://dx.doi.org/10.1038/s41598-019-50288-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760651PMC
September 2019

Post-translational S-glutathionylation of cofilin increases actin cycling during cocaine seeking.

PLoS One 2019 24;14(9):e0223037. Epub 2019 Sep 24.

Department of Cell and Molecular Pharmacology & Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, United States of America.

Neuronal defense against oxidative damage is mediated primarily by the glutathione redox system. Traditionally considered a mechanism to protect proteins from irreversible oxidation, mounting evidence supports a role for protein S-glutathionylation in cell signaling in response to changes in intracellular redox status. Here we determined the specific sites on the actin binding protein cofilin that undergo S-glutathionylation. In addition, we show that S-glutathionylation of cofilin reduces its capacity to depolymerize F-actin. We further describe an assay to determine the S-glutathionylation of target proteins in brain tissue from behaving rodents. Using this technique, we show that cofilin in the rat nucleus accumbens undergoes S-glutathionylation during 15-minutes of cued cocaine seeking in the absence of cocaine. Our findings demonstrate that cofilin S-glutathionylation is increased in response to cocaine-associated cues and that increased cofilin S-glutathionylation reduces cofilin-dependent depolymerization of F-actin. Thus, S-glutathionylation of cofilin may serve to regulate actin cycling in response to drug-conditioned cues.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0223037PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759170PMC
April 2020

Folate-coated, long-circulating and pH-sensitive liposomes enhance doxorubicin antitumor effect in a breast cancer animal model.

Biomed Pharmacother 2019 Oct 7;118:109323. Epub 2019 Aug 7.

Department of Clinical and Toxicological Analyses, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil. Electronic address:

Long circulating pH-sensitive liposomes have been shown to effectively deliver doxorubicin (DOX) to tumors and reduce its toxic effects. Folic acid receptors are upregulated in a wide variety of solid, epithelial tumors, including breast cancer. In order to improve liposomal endocytosis and antitumor activity, folic acid has been added to nanoparticles surfaces to exploit overexpression of folate receptors in tumor cells. The purpose of this study was to evaluate the antitumor activity in vitro and in vivo of long circulating pH-sensitive folate-coated DOX-loaded liposomes (SpHL-DOX-Fol) in a 4T1 breast cancer model system in vitro and in vivo. Biodistribution studies were performed and in vivo electrocardiographic parameters were evaluated. A higher tumor uptake for radiolabeled SpHL-Fol (Tc-SpHL-Fol) 4 h after intravenous administration was observed in comparision with non-folate-coated liposomes (Tc-SpHL). Antitumor activity showed that SpHL-DOX-Fol treatment led to a 68% growth arrest and drastically reduce pulmonary metastasis foci. Additionally, eletrocardiographic parameters analysis revealed no dispersion in the QT and QTc interval was observed in liposomal treated mice. In summary, this novel multifunctional nanoplatform deomonstrated higher tumor uptake and antitumor activity. SpHL-DOX-Fol represents a drug delivery platform to improve DOX tumor delivery and reduce dose-limiting toxicity.
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http://dx.doi.org/10.1016/j.biopha.2019.109323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104811PMC
October 2019

Racial disparities, cancer and response to oxidative stress.

Adv Cancer Res 2019 23;144:343-383. Epub 2019 Apr 23.

Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, United States.

At the intersection of genetics, biochemistry and behavioral sciences, there is a largely untapped opportunity to consider how ethnic and racial disparities contribute to individual sensitivity to reactive oxygen species and how these might influence susceptibility to various cancers and/or response to classical cancer treatment regimens that pervasively result in the formation of such chemical species. This chapter begins to explore these connections and builds a platform from which to consider how the disciplines can be strengthened further.
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http://dx.doi.org/10.1016/bs.acr.2019.03.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104807PMC
June 2020

The impact of infection and inflammation in oncologic F-FDG PET/CT imaging.

Biomed Pharmacother 2019 Sep 1;117:109168. Epub 2019 Jul 1.

Department of Nuclear Medicine, Radiology, Neuroradiology, Interventional Radiology, Pathology, Santa Maria della Misericordia Hospital, Rovigo, Italy. Electronic address:

Sites of infection and inflammation can be misleading in oncology PET/CT imaging because these areas commonly show F-FDG activity. Caution in the interpretation must be taken to avoid the misdiagnosis of malignancy. Utilization of both CT findings as well as patient history can help differentiate benign infectious and inflammatory processes from malignancy, although occasionally additional work-up may be required. This article discusses the mechanism of F-FDG uptake in infection and inflammation with illustrative examples.
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http://dx.doi.org/10.1016/j.biopha.2019.109168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104808PMC
September 2019

Isoflavone ME-344 Disrupts Redox Homeostasis and Mitochondrial Function by Targeting Heme Oxygenase 1.

Cancer Res 2019 08 21;79(16):4072-4085. Epub 2019 Jun 21.

Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, South Carolina.

ME-344 is a second-generation isoflavone with unusual cytotoxic properties that is in clinical testing in cancer. To identify targets that contribute to its anticancer activity and therapeutic index, we used lung cancer cell lines that are naturally sensitive or resistant to ME-344. Drug-induced apoptosis was linked with enhanced levels of reactive oxygen species and this initiated a nuclear erythroid factor 2-like 2 signaling response, downstream of which, heme oxygenase 1 (HO-1) was also found to be time-dependently inhibited by ME-344. ME-344 specifically bound to, and altered, HO-1 structure and increased HO-1 translocation from the rough endoplasmic reticulum to mitochondria, but only in drug-sensitive cells. These effects did not occur in either drug-resistant or primary lung fibroblasts with lower HO-1 basal levels. HO-1 was confirmed as a drug target by using surface plasmon resonance technology and through interaction with a clickable ME-344 compound (M2F) and subsequent proteomic analyses, showing direct binding of ME-344 with HO-1. Proteomic analysis showed that clusters of mitochondrial proteins, including voltage-dependent anion-selective channels, were also impacted by ME-344. Human lung cancer biopsies expressed higher levels of Nrf2 and HO-1 compared with normal tissues. Overall, our data show that ME-344 inhibits HO-1 and impacts its mitochondrial translocation. Other mitochondrial proteins are also affected, resulting in interference in tumor cell redox homeostasis and mitochondrial function. These factors contribute to a beneficial therapeutic index and support continued clinical development of ME-344. SIGNIFICANCE: A novel cytotoxic isoflavone is shown to inhibit heme oxygenase, a desirable yet elusive target that disrupts redox homeostasis causing cell death.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-3503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697583PMC
August 2019

Diuresis renography in equivocal urinary tract obstruction. A historical perspective.

Biomed Pharmacother 2019 Aug 25;116:108981. Epub 2019 May 25.

Department of Nuclear Medicine, Radiology, Neuroradiology, and Clinical Pathology, Santa Maria della Misericordia Hospital, Rovigo, Italy. Electronic address:

Obstructive nephropathy may be suspected for the incidental detection of dilated renal collecting system at ultrasonography, CT or MRI. A dilated renal collecting dilation (calyco-pelvis or ureteres) might be related 1) to an anatomical variant of the excretory tract without obstruction and, therefore, without consequence on renal function, or 2) to an obstruction/stenosis of the urinary tract that may cause a damage of kidney function. In the present review we annotated the various methods proposed for Diuresis Renography (DR) used with the purpose to make early diagnosis of obstructive nephropathy. First, the F + 20 method (i.e. furosemide 40 mg injected IV 20 min after radiotracer injection) in seated position (sp) (F + 20) was reported to distinguish between an anatomical dilation from an anatomical obstruction of the urinary tract. It was also suggested to perform DR with the patient in supine or prone position in order to minimize possible furosemide-induced hypotension and patient's movements during exam. Other DR methods were proposed administering furosemide EV to the patient in supine position at different times: F-15 (furosemide injected IV 15 min prior to radiotracer), F0 (furosemide injected contemporary to radiotracer), F + 20 (furosemide injected 20 min after the radiotracer), F-20 and Well Tempered (other than F + 20 this modality requires saline infusion for all duration of the test plus bladder catheterization). Unfortunately, in all the above described DR methods with patientin supine position, despite the furosemide administration, a sensitive slowing down of urinary outflow could be related to the supine position itself of the patient during the examination. Lastly, there are reports of a new DR method based on furosemide IV injection 10 min after radiotracer with the patient in seated position, F+10. This method allows a better timing between hydration (400 mL of water) at 5 min, and the injection of relatively low dose of furosemide (20 mg), thus avoiding side effects as diuretic-induced hypotension and favouring bladder filling, therefore ameliorating patient compliance and reducing equivocal responses.
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http://dx.doi.org/10.1016/j.biopha.2019.108981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104806PMC
August 2019

A seleno-hormetine protects bone marrow hematopoietic cells against ionizing radiation-induced toxicities.

PLoS One 2019 29;14(4):e0205626. Epub 2019 Apr 29.

Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy.

2,2'-diselenyldibenzoic acid (DSBA) is a chemical probe produced to explore the pharmacological properties of diphenyldiselenide-derived agents with seleno-hormetic activity undergoing preclinical development. The present study was designed to verify in vivo the drug's properties and to determine mechanistically how these may mediate the protection of tissues against stress conditions, exemplified by ionizing radiation induced damage in mouse bone marrow. In murine bone marrow hematopoietic cells, the drug initiated the activation of the Nrf2 transcription factor resulting in enhanced expression of downstream stress response genes. This type of response was confirmed in human liver cells and included enhanced expression of glutathione S-transferases (GST), important in the metabolism and pharmacological function of seleno-compounds. In C57 BL/6 mice, DSBA prevented the suppression of bone marrow hematopoietic cells caused by ionizing radiation exposure. Such in vivo prevention effects were associated with Nrf2 pathway activation in both bone marrow cells and liver tissue. These findings demonstrated for the first time the pharmacological properties of DSBA in vivo, suggesting a practical application for this type of Se-hormetic molecules as a radioprotective and/or prevention agents in cancer treatments.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0205626PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488049PMC
December 2019

Pharmacology of ME-344, a novel cytotoxic isoflavone.

Adv Cancer Res 2019 6;142:187-207. Epub 2019 Mar 6.

Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, United States. Electronic address:

Isoflavones isolated from members of the Fabaceae (primarily Leguminosae) family have been characterized for their phytoestrogenic properties, but certain derivatives have also shown potential as possible cancer therapeutic agents. ME-344, related to phenoxodiol (Fig. 1), is a second generation isoflavone with a recent history of both preclinical and early clinical testing. The drug has unusual cytotoxicity profiles, where cancer cell lines can be categorized as either intrinsically sensitive or resistant to the drug. Evolving studies show that the cytotoxic properties of the drug are enacted through targeting mitochondrial bioenergetics. While the drug has undergone early Phase I/II trials in solid tumors with confined dose limiting effects and some evidence of disease response, there is a continuing need to define specific cellular targets that determine sensitivity, with the long-term goal of applying such information to individualized therapy. This review article details some of the existing and ongoing studies that are assisting in the continued drug development processes that may lead to new drug application (NDA) status.
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http://dx.doi.org/10.1016/bs.acr.2019.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432957PMC
May 2020

Effects of plasma glucose levels on regional cerebral 18F-fluorodeoxyglucose uptake: Implications for dementia evaluation with brain PET imaging.

Biomed Pharmacother 2019 Apr 20;112:108628. Epub 2019 Feb 20.

Division of Nuclear Medicine, Department of Radiology, University of Michigan, Ann Arbor, MI, USA; Nuclear Medicine Service, Department of Veterans Affairs Healthcare System, Ann Arbor, MI, USA.

Purpose: Hyperglycemia affects FDG uptake in the brain, potentially emulating Alzheimer's disease in normal individuals. This study investigates global and regional cerebral FDG uptake as a function of plasma glucose in a cohort of patients.

Methods: 120 consecutive male patients with FDG PET/CT for initial oncologic staging (July-Dec 2015) were reviewed. Patients with dementia, cerebrovascular accident, structural brain lesion, prior oncology treatment or high metabolic tumor burden (recently shown affecting brain FDG uptake) were excluded. 53 (24 nondiabetic) eligible patients (age 65.7 ± 2.8 mean ± SE) were analyzed with parametric computer software, MIMneuro™. Regional Z-scores were evaluated as a function of plasma glucose and age using multi variable linear mixed effects models with false discovery analysis adjusting for multiple comparisons. If the regression slope was significantly (p < 0.05) different than zero, hyperglycemia effect was present.

Results: There was a negative inverse relationship (p < 0.001) between global brain FDG uptake and hyperglycemia. No regional hyperglycemia effect on uptake were present when subjects were normalized using pons or cerebellum. However, regional hyperglycemia effects were seen (p < 0.047-0.001) when normalizing by the whole brain. No obvious pattern was seen in the regions affected. Age had a significant effect using whole brain normalization (p < 0.04-0.01).

Conclusions: Cortical variation in FDG uptake were identified when subjects were hyperglycemic. However, these variations didn't fit a particular pattern of dementia and the severity of the affect is not likely to alter clinical interpretation.
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http://dx.doi.org/10.1016/j.biopha.2019.108628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714976PMC
April 2019

3-ketodihydrosphingosine reductase mutation induces steatosis and hepatic injury in zebrafish.

Sci Rep 2019 02 4;9(1):1138. Epub 2019 Feb 4.

Department of Medicine, Medical University of South Carolina, Charleston, SC, 29425, USA.

3-ketodihydrosphingosine reductase (KDSR) is the key enzyme in the de novo sphingolipid synthesis. We identified a novel missense kdsr mutation in zebrafish that led to a loss of function, and resulted in progression of hepatomegaly to steatosis, then hepatic injury phenotype. Lipidomics analysis of the kdsr mutant revealed compensatory activation of the sphingolipid salvage pathway, resulting in significant accumulation of sphingolipids including ceramides, sphingosine and sphingosine 1-phosphate (S1P). Ultrastructural analysis revealed swollen mitochondria with cristae damage in the kdsr mutant hepatocytes, which can be a cause of hepatic injury in the mutant. We found elevated sphingosine kinase 2 (sphk2) expression in the kdsr mutant. Genetic interaction analysis with the kdsr and the sphk2 mutants showed that sphk2 depletion suppressed liver defects observed in the kdsr mutant, suggesting that liver defects were mediated by S1P accumulation. Further, both oxidative stress and ER stress were completely suppressed by deletion of sphk2 in kdsr mutants, linking these two processes mechanistically to hepatic injury in the kdsr mutants. Importantly, we found that the heterozygous mutation in kdsr induced predisposed liver injury in adult zebrafish. These data point to kdsr as a novel genetic risk factor for hepatic injury.
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http://dx.doi.org/10.1038/s41598-018-37946-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361991PMC
February 2019

Editorial: Redox and Metabolic Circuits in Cancer.

Front Oncol 2018 26;8:403. Epub 2018 Sep 26.

Redox Signaling and Oxidative Stress Research Group, Cell Stress and Survival Unit, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Copenhagen, Denmark.

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http://dx.doi.org/10.3389/fonc.2018.00403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168671PMC
September 2018

Influence of PEG coating on the biodistribution and tumor accumulation of pH-sensitive liposomes.

Drug Deliv Transl Res 2019 02;9(1):123-130

Faculdade de Farmácia, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, Belo Horizonte, Minas Gerais, 31279-901, Brazil.

Liposomes are lipid vesicles widely used as nanocarriers in targeted drug delivery systems for therapeutic and/or diagnostic purposes. A strategy to prolong the blood circulation time of the liposomes includes the addition of a hydrophilic polymer polyethylene glycol (PEG) moiety onto the surface of the vesicle. Several studies claim that liposome PEGylation by a single chain length or a combination of PEG with different chain lengths may alter the liposomes' pharmacokinetic properties. Therefore, the purpose of this study was to evaluate the influence of PEG on the biodistribution of pH-sensitive liposomes in a tumor-bearing animal model. Three liposomal formulations (PEGylated or not) were prepared and validated to have a similar mean diameter, monodisperse distribution, and neutral zeta potential. The pharmacokinetic properties of each liposome were evaluated in healthy animals, while the biodistribution and scintigraphic images were evaluated in tumor-bearing mice. High tumor-to-muscle ratios were not statistically different between the PEGylated and non-PEGylated liposomes. While PEGylation is a well-established strategy for increasing the blood circulation of nanostructures, in our study, the use of polymer coating did not result in a better in vivo profile. Further studies must be carried out to confirm the feasibility of the non-PEGylated pH-sensitive liposomes for tumor treatment.
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http://dx.doi.org/10.1007/s13346-018-0583-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361166PMC
February 2019

Targeting redox regulation to treat substance use disorder using N‐acetylcysteine

Eur J Neurosci 2019 08 24;50(3):2538-2551. Epub 2018 Sep 24.

Department of Cellular and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, 409 Drug Discovery Building, 70 President Street, Charleston, SC, 29425, USA.

Substance use disorder (SUD) is a chronic relapsing disorder characterized by transitioning from acute drug reward to compulsive drug use. Despite the heavy personal and societal burden of SUDs, current treatments are limited and unsatisfactory. For this reason, a deeper understanding of the mechanisms underlying addiction is required. Altered redox status, primarily due to drug-induced increases in dopamine metabolism, is a unifying feature of abused substances. In recent years, knowledge of the effects of oxidative stress in the nervous system has evolved from strictly neurotoxic to include a more nuanced role in redox-sensitive signaling. More specifically, S-glutathionylation, a redox-sensitive post-translational modification, has been suggested to influence the response to drugs of abuse. In this review we will examine the evidence for redox-mediating drugs as therapeutic tools focusing on N-acetylcysteine as a treatment for cocaine addiction. We will conclude by suggesting future research directions that may further advance this field.
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http://dx.doi.org/10.1111/ejn.14130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387857PMC
August 2019

Effect of Monacolin K and COQ10 supplementation in hypertensive and hypercholesterolemic subjects with metabolic syndrome.

Biomed Pharmacother 2018 09 19;105:992-996. Epub 2018 Jun 19.

Department of Nuclear Medicine, Radiology, Neuroradiology, Medical Physics, Clinical Laboratory, Microbiology, Pathology, Trasfusional Medicine, Santa Maria della Misericordia Hospital, Viale Tre Martiri 140, Rovigo, Italy. Electronic address:

Introduction: Metabolic syndrome (MetS) is a world-wide epidemic disease with an increased risk of morbidity and mortality. Treatment strategies of MetS include pharmacologic and non-pharmacologic interventions and in this respect a relevant role has been shown for nutraceutical compounds (NCs). The aim of this study was to investigate the efficacy and safety of NCs incorporated with diet and lifestyle management versus diet alone, in lowering blood pressure (BP) values and improving lipid and glucose profile, in a group of hypertensives and hyper-cholesterolemic patients with MetS.

Methods: 104 subjects with MetS (mean age 57.4 ± 8.8 years, 51% males) without history of cardio-vascular (CV) diseases were enrolled in the study. 52 subjects were treated with a once-daily oral formulation of a NCs containing red yeast rice and coenzyme Q10 added to their diet for 2 months and were compared with the 52 patients following a diet program. Differences in BP, serum total cholesterol (TC), low- and high-density-lipoprotein cholesterol (LDLC and HDLC), triglycerides (TG) and glucose values were compared by analysis of variance.

Results: A significant reduction of BP, TC, TG, LDLC and glucose levels was observed in both treatment groups. However, a greater reduction of systolic BP (-5.2 vs. -3.0 mmHg), diastolic BP (-4.9 vs. 2.9 mmHg), total cholesterol (-17.2%), LDLC (-21.8%), TG (-16.0%) and serum glucose (-3.4%) was observed in the treatment group relative to the control (p < 0.001 for all); HDLC remained unchanged (p = N.S.). Gender difference was not found in either group (p = N.S.).

Conclusions: In patients with MetS, NC supplementation was safe, well tolerated and effective in improving clinic BP, lipid and glucose profile.
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http://dx.doi.org/10.1016/j.biopha.2018.06.076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361161PMC
September 2018

α- Tocopherol succinate loaded nano-structed lipid carriers improves antitumor activity of doxorubicin in breast cancer models in vivo.

Biomed Pharmacother 2018 Jul 7;103:1348-1354. Epub 2018 May 7.

Faculty of Pharmacy, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, 31270-901, Belo Horizonte, Minas Gerais, Brazil. Electronic address:

Combination-based chemotherapies have been the standard treatment for multiple solid tumors since the 1960s. Combined therapies where both agents have toxicity results in dose-limiting effects. α- tocopherol succinate (TS) is an analogue of vitamin E that exhibits antitumor properties in the absence of toxicity. Hence, its combination with a frontline chemotherapy, doxorubicin (DOX) is an alternative to increase antitumor efficacy. Therefore, the aim of this work was to evaluate the antitumor activity of nanostructed lipid carriers (NLC) loaded with TS and DOX. The NLC-TS-DOX were prepared, characterized and radiolabeled with technetium-99m. Cytotoxicity studies were performed in vitro, using two breast cancer cell lines, MDA-MB-231 and 4T1. Biodistribution and antitumor activity were evaluated in 4T1 tumor-bearing mice. The results showed that NLC-TS-DOX had a small diameter (85 nm) and a long blood clearance (Tβ = 1107.71 min) that consequently resulted in a higher tumor uptake compared to contralateral muscle for up to 48 h. Drug combination studies in MDA-MB-231 and 4T1 cells showed a combination index below 0.8 at ED for both cell lines. Interestingly, a high synergism was found at ED Antitumor activity showed a better control of tumor growth for animals treated with NLC-ST-DOX. The small particle size, along with the EPR effect and the controlled release of DOX from the particle, associated with the synergic combination between TS and DOX led to an increase of the antitumor efficacy. Therefore, NLC-TS-DOX can be considered a plausible alternative to improve antitumor efficacy in DOX therapeutic regimens.
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http://dx.doi.org/10.1016/j.biopha.2018.04.139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361145PMC
July 2018
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