Publications by authors named "Anindita Das"

152 Publications

Investigation of dual plasmonic core-shell Ag@CuS nanoparticles for potential surface-enhanced Raman spectroscopy-guided photothermal therapy.

Nanomedicine (Lond) 2021 Apr 30. Epub 2021 Apr 30.

Department of Physics, Nanophotonics Lab, Indian Institute of Technology (Indian School of Mines), Dhanbad 826004, Jharkhand, India.

To prepare efficient metal-semiconductor nanoparticles as noninvasive, real-time imaging probes for photothermal therapy (PTT) applications. A bottom-up approach was used to fabricate core-shell Ag@CuS nanoparticles (NPs). PTT and Raman mapping were done using HeLa cells. Theoretical simulation of electric field enhancement and heat dissipation density of Ag@CuS NPs was performed. PTT-induced hyperthermia was achieved under 940 nm near-infrared light irradiation. Surface-enhanced Raman spectroscopy (SERS) signals of dye molecules were observed when conjugated with Ag@CuS NPs. Ag@CuS NPs are found to be efficient for SERS imaging and localized heating under laser irradiation, making a promising candidate for SERS-guided PTT.
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http://dx.doi.org/10.2217/nnm-2020-0385DOI Listing
April 2021

Role of phosphodiesterase 1 in the pathophysiology of diseases and potential therapeutic opportunities.

Pharmacol Ther 2021 Apr 22;226:107858. Epub 2021 Apr 22.

Division of Cardiology, Pauley Heart Center, Virginia Commonwealth University, Richmond, VA 23298-0204, USA. Electronic address:

Cyclic nucleotide phosphodiesterases (PDEs) are superfamily of enzymes that regulate the spatial and temporal relationship of second messenger signaling in the cellular system. Among the 11 different families of PDEs, phosphodiesterase 1 (PDE1) sub-family of enzymes hydrolyze both 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP) in a mutually competitive manner. The catalytic activity of PDE1 is stimulated by their binding to Ca/calmodulin (CaM), resulting in the integration of Ca and cyclic nucleotide-mediated signaling in various diseases. The PDE1 family includes three subtypes, PDE1A, PDE1B and PDE1C, which differ for their relative affinities for cAMP and cGMP. These isoforms are differentially expressed throughout the body, including the cardiovascular, central nervous system and other organs. Thus, PDE1 enzymes play a critical role in the pathophysiology of diseases through the fundamental regulation of cAMP and cGMP signaling. This comprehensive review provides the current research on PDE1 and its potential utility as a therapeutic target in diseases including the cardiovascular, pulmonary, metabolic, neurocognitive, renal, cancers and possibly others.
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http://dx.doi.org/10.1016/j.pharmthera.2021.107858DOI Listing
April 2021

A mortal prosody.

Authors:
Anindita Das

Indian J Cancer 2021 Mar 21. Epub 2021 Mar 21.

Department of Radiation Oncology, Christian Medical College, Vellore, Tamil Nadu, India.

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http://dx.doi.org/10.4103/ijc.IJC_1102_20DOI Listing
March 2021

Conformational heterogeneity of the voltage sensor loop of KvAP in micelles and membranes: A fluorescence approach.

Biochim Biophys Acta Biomembr 2021 May 30;1863(5):183568. Epub 2021 Jan 30.

Crystallography and Molecular Biology Division, Saha Institute of Nuclear Physics, Homi Bhabha National Institute, 1/AF Bidhannagar, Kolkata, India. Electronic address:

KvAP is a tetrameric voltage-gated potassium channel that is composed of a pore domain and a voltage-sensing domain (VSD). The VSD is crucial for sensing transmembrane potential and gating. At 0 mV, the VSD adopts an activated conformation in both n-octylglucoside (OG) micelles and phospholipid membranes. Importantly, gating-modifier toxins that bind at S3b-S4 loop of KvAP-VSD exhibit pronounced differences in binding affinity in these membrane-mimetic systems. However, the conformational heterogeneity of this functionally-important sensor loop in membrane mimetics is poorly understood, and is the focus of this work. In this paper, we establish, using intrinsic fluorescence of the uniquely positioned W70 in KvAP-VSD and environment-sensitive NBD (7-nitrobenz-2-oxa-1,3-diazol-4-yl-ethylenediamine) fluorescence of the labelled S3b-S4 loop, that the surface charge of the membrane does not significantly affect the topology and structural dynamics of the sensor loop in membranes. Importantly, the dynamic variability of the sensor loop is preserved in both zwitterionic (POPC) and anionic (POPC/POPG) membranes. Further, the lifetime distribution analysis for the NBD-labelled residues by maximum entropy method (MEM) demonstrates that, in contrast to micelles, the membrane environment not only reduces the relative discrete population of sensor loop conformations, but also broadens the lifetime distribution peaks. Overall, our results strongly suggest that the conformational heterogeneity of the sensor loop is significantly altered in membranes and this correlates well with its environmental heterogeneity. This constitutes the first report demonstrating that MEM-lifetime distribution could be a powerful tool to distinguish changes in conformational heterogeneity in potassium channels with similar architecture and topology.
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http://dx.doi.org/10.1016/j.bbamem.2021.183568DOI Listing
May 2021

An almanac of pandemonium.

Authors:
Anindita Das

Lancet Respir Med 2021 01;9(1):15-17

Department of Radiation Oncology, Christian Medical College & Hospital, Vellore 632004, India. Electronic address:

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http://dx.doi.org/10.1016/S2213-2600(20)30572-5DOI Listing
January 2021

Reversal of Endothelial Extracellular Vesicle-Induced Smooth Muscle Phenotype Transition by Hypercholesterolemia Stimulation: Role of NLRP3 Inflammasome Activation.

Front Cell Dev Biol 2020 21;8:597423. Epub 2020 Dec 21.

Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, United States.

Recent studies reported that vascular endothelial cells (ECs) secrete NLR family pyrin domain-containing 3 (NLRP3) inflammasome products such as interleukin-1β (IL-1β) via extracellular vesicles (EVs) under various pathological conditions. EVs represent one of the critical mechanisms mediating the cell-to-cell communication between ECs and vascular smooth muscle cells (VSMCs). However, whether or not the inflammasome-dependent EVs directly participate in the regulation of VSMC function remains unknown. In the present study, we found that in cultured carotid ECs, atherogenic stimulation by oxysterol 7-ketocholesterol (7-Ket) induced NLRP3 inflammasome formation and activation, reduced lysosome-multivesicular bodies (MVBs) fusion, and increased secretion of EVs that contain inflammasome product IL-1β. These EC-derived IL-1β-containing EVs promoted synthetic phenotype transition of co-cultured VSMCs, whereas EVs from unstimulated ECs have the opposite effects. Moreover, acid ceramidase deficiency or lysosome inhibition further exaggerated the 7-Ket-induced release of IL-1β-containing EVs in ECs. Using a Western diet (WD)-induced hypercholesterolemia mouse model, we found that endothelial-specific gene knockout mice (Asah1/EC) exhibited augmented WD-induced EV secretion with IL-1β and more significantly decreased the interaction of MVBs with lysosomes in the carotid arterial wall compared to their wild-type littermates (WT/WT). The endothelial deficiency in Asah1/EC mice also resulted in enhanced VSMC phenotype transition and accelerated neointima formation. Together, these results suggest that NLRP3 inflammasome-dependent IL-1β production during hypercholesterolemia promotes VSMC phenotype transition to synthetic status EV machinery, which is controlled by lysosomal activity. Our findings provide novel mechanistic insights into understanding the pathogenic role of endothelial NLRP3 inflammasome in vascular injury through EV-mediated EC-to-VSMC regulation.
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http://dx.doi.org/10.3389/fcell.2020.597423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779768PMC
December 2020

Differential Regulation of mTOR Complexes with miR-302a Attenuates Myocardial Reperfusion Injury in Diabetes.

iScience 2020 Dec 26;23(12):101863. Epub 2020 Nov 26.

Division of Cardiology, Pauley Heart Center, Box 980204, Virginia Commonwealth University Medical Center, 1101 East Marshall Street, Sanger Hall, Room 7020d & 7020b, Richmond, VA 23298-0204, USA.

Persistent activation of mTOR (mammalian target of rapamycin) in diabetes increases the vulnerability of the heart to ischemia/reperfusion (I/R) injury. We show here that infusion of rapamycin (mTOR inhibitor) at reperfusion following ischemia reduced myocardial infarct size and apoptosis with restoration of cardiac function in type 1 diabetic rabbits. Likewise, treatment with rapamycin protected hyperglycemic human-pluripotent-stem-cells-derived cardiomyocytes (HG-hiPSC-CMs) following simulated ischemia (SI) and reoxygenation (RO). Phosphorylation of S6 (mTORC1 marker) was increased, whereas AKT phosphorylation (mTORC2 marker) and microRNA-302a were reduced with concomitant increase of its target, PTEN, following I/R injury in diabetic heart and HG-hiPSC-CMs. Rapamycin inhibited mTORC1 and PTEN, but augmented mTORC2 with restoration of miRNA-302a under diabetic conditions. Inhibition of miRNA-302a blocked mTORC2 and abolished rapamycin-induced protection against SI/RO injury in HG-hiPSC-CMs. We conclude that rapamycin attenuates reperfusion injury in diabetic heart through inhibition of PTEN and mTORC1 with restoration of miR-302a-mTORC2 signaling.
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http://dx.doi.org/10.1016/j.isci.2020.101863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725936PMC
December 2020

Cardiovascular Complications Associated with COVID-19 and Potential Therapeutic~Strategies.

Int J Mol Sci 2020 Sep 16;21(18). Epub 2020 Sep 16.

Division of Cardiology, Pauley Heart Center, Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA.

The outbreak of coronavirus disease 2019 (COVID-19), an infectious disease with severe acute respiratory syndrome, has now become a worldwide pandemic. Despite the respiratory complication, COVID-19 is also associated with significant multiple organ dysfunction, including severe cardiac impairment. Emerging evidence reveals a direct interplay between COVID-19 and dire cardiovascular complications, including myocardial injury, heart failure, heart attack, myocarditis, arrhythmias as well as blood clots, which are accompanied with elevated risk and adverse outcome among infected patients, even sudden death. The proposed pathophysiological mechanisms of myocardial impairment include invasion of SARS-CoV-2 virus via angiotensin-converting enzyme 2 to cardiovascular cells/tissue, which leads to endothelial inflammation and dysfunction, de-stabilization of vulnerable atherosclerotic plaques, stent thrombosis, cardiac stress due to diminish oxygen supply and cardiac muscle damage, and myocardial infarction. Several promising therapeutics are under investigation to the overall prognosis of COVID-19 patients with high risk of cardiovascular impairment, nevertheless to date, none have shown proven clinical efficacy. In this comprehensive review, we aimed to highlight the current integrated therapeutic approaches for COVID-19 and we summarized the potential therapeutic options, currently under clinical trials, with their mechanisms of action and associated adverse cardiac events in highly infectious COVID-19 patients.
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http://dx.doi.org/10.3390/ijms21186790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554795PMC
September 2020

Sildenafil Potentiates the Therapeutic Efficacy of Docetaxel in Advanced Prostate Cancer by Stimulating NO-cGMP Signaling.

Clin Cancer Res 2020 Nov 26;26(21):5720-5734. Epub 2020 Aug 26.

Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.

Purpose: Docetaxel plays an indispensable role in the management of advanced prostate cancer. However, more than half of patients do not respond to docetaxel, and those good responders frequently experience significant cumulative toxicity, which limits its dose duration and intensity. Hence, a second agent that could increase the initial efficacy of docetaxel and maintain tolerability at biologically effective doses may improve outcomes for patients.

Experimental Design: We determined phosphodiesterase 5 (PDE5) expression levels in human and genetically engineered mouse (GEM) prostate tissues and tumor-derived cell lines. Furthermore, we investigated the therapeutic benefits and underlying mechanism of PDE5 inhibitor sildenafil in combination with docetaxel using , Pten conditional knockout (cKO), derived tumoroid and xenograft prostate cancer models.

Results: PDE5 expression was higher in both human and mouse prostate tumors and cancer cell lines compared with normal tissues/cells. In GEM prostate-derived cell lines, PDE5 expression increased from normal prostate (wild-type) epithelial cells to androgen-dependent and castrated prostate-derived cell lines. The addition of physiologically achievable concentrations of sildenafil enhanced docetaxel-induced prostate cancer cell growth inhibition and apoptosis , reduced murine 3D tumoroid growth, and tumorigenicity as compared with docetaxel alone. Furthermore, sildenafil enhanced docetaxel-induced NO and cGMP levels thereby augmenting antitumor activity.

Conclusions: Our results demonstrate that sildenafil's addition could sensitize docetaxel chemotherapy in prostate cancer cells at much lesser concentration than needed for inducing cell death. Thus, the combinatorial treatment of sildenafil and docetaxel may improve anticancer efficacy and reduce chemotherapy-induced side-effects among patients with advanced prostate cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642013PMC
November 2020

Tailoring the Design of a Lanthanide Complex/Magnetic Ferrite Nanocomposite for Efficient Photoluminescence and Magnetic Hyperthermia Performance.

ACS Appl Mater Interfaces 2020 Sep 3;12(37):42016-42029. Epub 2020 Sep 3.

Special Centre for Nanoscience, Jawaharlal Nehru University, New Delhi 110067, India.

In this work, we have designed a magnetoluminescent nanocomposite as a single platform for optical imaging and safe magnetic hyperthermia therapy by optimizing the composition of magnetic nanoparticles and controlling the conjugation strategy of the luminescent lanthanide complex. We have synthesized CoMnFeO nanoferrites, with = 0 to 1 in 0.25 steps, from soft (MnFeO) to hard (CoFeO) ferrites of size (∼20 nm) following a one-pot oxidative hydrolysis method. We have performed the induction heating study with an aqueous dispersion of nanoferrites using an alternating magnetic field (AMF) of 12 kAm, 335 kHz. This shows an enhancement of heating efficiency with the increment of manganese content and attains the highest intrinsic loss power (ILP) of 6.47 nHm kg for MnFeO nanoparticles. We have then fabricated a magnetoluminescent nanocomposite employing MnFeO nanoparticles as it shows outstanding heating performance within the threshold limit of AMF (≤5 × 10 Am s). A layer-by-layer coating strategy is followed, where a pure silica coating of thickness ∼10 nm on MnFeO nanoparticles is achieved before encapsulation of the luminescent complex of europium(III), 2-thenoyltrifluoroacetone, and 1,10-phenanthroline in the second layer of silica. This is to ensure the optimal distance between the magnetic core and Eu(III)-complex to pertain significant luminescence in the composite (Eu-MnFeO). The photoluminescence spectra of an aqueous dispersion of Eu-MnFeO by excitation in the UV region show a narrow and strong emission at 612 nm, which is stable even after 72 h. The induction heating study of an aqueous dispersion of Eu-MnFeO in 12 kAm, 335 kHz AMF shows an ILP as 4.02 nHm kg, which is remarkably higher than the hyperthermia efficiency of reported magnetoluminescent nanoparticles.
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http://dx.doi.org/10.1021/acsami.0c13690DOI Listing
September 2020

Patterns of Recurrence in Locally Advanced Resectable Oesophageal Carcinoma: Retrospective Review from a Tertiary Cancer Centre in South India.

J Gastrointest Cancer 2020 Jul 28. Epub 2020 Jul 28.

Department of Radiation Oncology, Ida B. Scudder Cancer Centre, Christian Medical College, Vellore, Tamil Nadu, 632004, India.

Purpose: The study aims to analyse patterns of recurrence following neoadjuvant treatment and surgery in carcinoma oesophagus with an intent to postulate optimal nodal radiation.

Methodology: A retrospective review of patients who presented to our centre within a 5-year period (2014-2018), with recurrence following sequential neoadjuvant treatment and radical surgery, was conducted in this single-institution study. The patterns of recurrence and duration of disease-free survival were analysed.

Results: Twenty-one patients (14 men, 7 women) presented with recurrence, of which 13, 7, and 1 patient(s) had received NACT, NACTRT, or both, respectively. Six patients who did not receive neoadjuvant radiotherapy received adjuvant RT. Among the 10 patients who had nodal recurrence after RT (either neoadjuvant or adjuvant), 6 and 4 patients had in-field and out-of-field nodal recurrences, respectively-the latter were equally distributed within 5 cm and outside 5 cm of the PTV margin.

Conclusion: Among the patients who presented with recurrence, more than half had not received neoadjuvant RT (treated in the 'pre-CROSS era' or due to long-segment disease), reasserting the therapeutic superiority of NACTRT. Increased regularity of recurrences in the draining nodal region was not noted in this study, but large-scale, prospective, randomised head-to-head comparative trials to determine optimal nodal irradiation in carcinoma oesophagus are required.
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http://dx.doi.org/10.1007/s12029-020-00464-2DOI Listing
July 2020

Remote Ischemic Pre-Conditioning Attenuates Adverse Cardiac Remodeling and Mortality Following Doxorubicin Administration in Mice.

JACC CardioOncol 2019 Dec 17;1(2):221-234. Epub 2019 Dec 17.

Pauley Heart Center, Department of Internal Medicine, Division of Cardiology, Virginia Commonwealth University, Richmond, Virginia.

Objectives: Because of its multifaceted cardioprotective effects, remote ischemic pre-conditioning (RIPC) was examined as a strategy to attenuate doxorubicin (DOX) cardiotoxicity.

Background: The use of DOX is limited by dose-dependent cardiotoxicity and heart failure. Oxidative stress, mitochondrial dysfunction, inflammation, and autophagy modulation have been proposed as mediators of DOX cardiotoxicity.

Methods: After baseline echocardiography, adult male CD1 mice were randomized to either sham or RIPC protocol (3 cycles of 5 min femoral artery occlusion followed by 5 min reperfusion) 1 h before receiving DOX (20 mg/kg, intraperitoneal). The mice were observed primarily for survival over 85 days (86 mice). An additional cohort of 50 mice was randomized to either sham or RIPC 1 h before DOX treatment and was followed for 25 days, at which time cardiac fibrosis, apoptosis, and mitochondrial oxidative phosphorylation were assessed, as well as the expression profiles of apoptosis and autophagy markers.

Results: Survival was significantly improved in the RIPC cohort compared with the sham cohort (p = 0.007). DOX-induced cardiac fibrosis and apoptosis were significantly attenuated with RIPC compared with sham (p < 0.05 and p < 0.001, respectively). Although no mitochondrial dysfunction was detected at 25 days, there was a significant increase in autophagy markers with DOX that was attenuated with RIPC. Moreover, DOX caused a 49% decline in cardiac BCL2/BAX expression, which was restored with RIPC (p < 0.05 vs. DOX). DOX also resulted in a 17% reduction in left ventricular mass at 25 days, which was prevented with RIPC (p < 0.01), despite the lack of significant changes in left ventricular ejection fraction.

Conclusions: Our preclinical results suggested that RIPC before DOX administration might be a promising approach for attenuating DOX cardiotoxicity.
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http://dx.doi.org/10.1016/j.jaccao.2019.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375406PMC
December 2019

Endoplasmic reticulum stress-mediated mitochondrial dysfunction in aged hearts.

Biochim Biophys Acta Mol Basis Dis 2020 11 19;1866(11):165899. Epub 2020 Jul 19.

Department of Medicine, Division of Cardiology, Virginia Commonwealth University, Richmond, VA 23298, United States of America; Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, 23298, United States of America; Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, VA 23298, United States of America; McGuire Department of Veterans Affairs Medical Center, Richmond, VA 23249, United States of America. Electronic address:

Aging impairs the mitochondrial electron transport chain (ETC), especially in interfibrillar mitochondria (IFM). Mitochondria are in close contact with the endoplasmic reticulum (ER). Induction of ER stress leads to ETC injury in adult heart mitochondria. We asked if ER stress contributes to the mitochondrial dysfunction during aging. Subsarcolemmal mitochondria (SSM) and IFM were isolated from 3, 18, and 24 mo. C57Bl/6 mouse hearts. ER stress progressively increased with age, especially in 24 mo. mice that manifest mitochondrial dysfunction. OXPHOS was decreased in 24 mo. IFM oxidizing complex I and complex IV substrates. Proteomic analysis showed that the content of multiple complex I subunits was decreased in IFM from 24 mo. hearts, but remained unchanged in in 18 mo. IFM without a decrease in OXPHOS. Feeding 24 mo. old mice with 4-phenylbutyrate (4-PBA) for two weeks attenuated the ER stress and improved mitochondrial function. These results indicate that ER stress contributes to the mitochondrial dysfunction in aged hearts. Attenuation of ER stress is a potential approach to improve mitochondrial function in aged hearts.
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http://dx.doi.org/10.1016/j.bbadis.2020.165899DOI Listing
November 2020

PDE5 inhibitor sildenafil attenuates cardiac microRNA 214 upregulation and pro-apoptotic signaling after chronic alcohol ingestion in mice.

Mol Cell Biochem 2020 Aug 13;471(1-2):189-201. Epub 2020 Jun 13.

Division of Cardiology, Department of Internal Medicine, Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, 23298-0204, USA.

Abusive chronic alcohol consumption can cause metabolic and functional derangements in the heart and is a risk factor for development of non-ischemic cardiomyopathy. microRNA 214 (miR-214) is a molecular sensor of stress signals that negatively impacts cell survival. Considering cardioprotective and microRNA modulatory effects of sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, we investigated the impact of chronic alcohol consumption on cardiac expression of miR-214 and its anti-apoptotic protein target, Bcl-2 and whether sildenafil attenuates such changes. Adult male FVB mice received unlimited access to either normal liquid diet (control), alcohol diet (35% daily calories intake), or alcohol + sildenafil (1 mg/kg/day, p.o.) for 14 weeks (n = 6-7/group). The alcohol-fed groups with or without sildenafil had increased total diet consumption and lower body weight as compared with controls. Echocardiography-assessed left ventricular function was unaltered by 14-week alcohol intake. Alcohol-fed group had 2.6-fold increase in miR-214 and significant decrease in Bcl-2 expression, along with enhanced phosphorylation of ERK1/2 and cleavage of PARP (marker of apoptotic DNA damage) in the heart. Co-ingestion with sildenafil blunted the alcohol-induced increase in miR-214, ERK1/2 phosphorylation, and maintained Bcl-2 and decreased PARP cleavage levels. In conclusion, chronic alcohol consumption triggers miR-214-mediated pro-apoptotic signaling in the heart, which was prevented by co-treatment with sildenafil. Thus, PDE5 inhibition may serve as a novel protective strategy against cardiac apoptosis due to chronic alcohol abuse.
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http://dx.doi.org/10.1007/s11010-020-03779-7DOI Listing
August 2020

Cardiovascular risks and toxicity - The Achilles heel of androgen deprivation therapy in prostate cancer patients.

Biochim Biophys Acta Rev Cancer 2020 08 11;1874(1):188383. Epub 2020 Jun 11.

Pauley Heart Center, Department of Internal Medicine, Virginia Commonwealth University Richmond, VA 23298-0204, USA. Electronic address:

Androgen deprivation therapy (ADT) is the primary systemic therapy for treating locally advanced or metastatic prostate cancer (PCa). Despite its positive effect on PCa patient survival, ADT causes various adverse effects, including increased cardiovascular risk factors and cardiotoxicity. Lifespans extension, early use of ADT, and second-line treatment with next-generation androgen receptor pathway inhibitors would further extend the duration of ADT and possibly increase the risk of ADT-induced cardiotoxicity. Meanwhile, information on the molecular mechanisms underlying ADT-induced cardiotoxicity and measures to prevent it is limited, mainly due to the lack of specifically designed preclinical studies and clinical trials. This review article compiles up-to-date evidence obtained from observational studies and clinical trials, in order to gain new insights for deciphering the association between ADT use and cardiotoxicity. In addition, potential cardioprotective strategies involving GnRH receptors and second messenger cGMP are discussed.
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http://dx.doi.org/10.1016/j.bbcan.2020.188383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473503PMC
August 2020

Hydrogen Sulfide Therapy Suppresses Cofilin-2 and Attenuates Ischemic Heart Failure in a Mouse Model of Myocardial Infarction.

J Cardiovasc Pharmacol Ther 2020 09 11;25(5):472-483. Epub 2020 May 11.

Division of Cardiology, Department of Internal Medicine, VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA.

Aims: Hydrogen sulfide (HS) protects against ischemic and inflammatory injury following myocardial ischemia via induction of microRNA (miR)-21. We sought to determine whether HS attenuates ischemic heart failure with reduced ejection fraction (HFrEF) and interrogate the role of cofilin-2, a target of miR-21, in this protective process.

Methods And Results: Adult male mice underwent myocardial infarction (MI) by coronary artery ligation after baseline echocardiography. Following MI, mice were treated with NaS (100 μg/kg/day; intraperitoneal [IP]) or saline up to 28 days. End-diastolic pressure, measured by Millar catheter, was significantly increased ( < .05 vs sham) at 3 days post-MI in the saline group, which was attenuated with NaS. Left ventricular (LV) fractional shortening decreased significantly at 28 days post-MI in the saline group but was preserved with NaS and LV infarct scar size was smaller in NaS group as compared to control. Apoptotic signaling, measured by Bcl-2/Bax ratio, was significantly increased in the saline group but was mitigated with NaS. Survival rate was 2-fold higher in NaS group compared to saline control ( < .05). Proteomic analysis and Matrix-Assisted Laser Desorption/Ionization-Time of Flight (TOF)/TOF tandem mass spectrometry identified significant changes in proapoptotic cofilin-2 expression, a specific target of miR-21, between saline- and sodium sulfide -treated mice at 28 days post-MI. Western blot analysis confirmed a significant increase in cofilin-2 after MI, which was suppressed with NaS treatment. Chronic NaS treatment also attenuated inflammasome formation and activation leading to reduction of maladaptive signaling.

Conclusion: NaS treatment after MI preserves LV function and improves survival through attenuation of inflammasome-mediated adverse remodeling. We propose HS donors as promising therapeutic tools for ischemic HFrEF.
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http://dx.doi.org/10.1177/1074248420923542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365756PMC
September 2020

B7-33, a Functionally Selective Relaxin Receptor 1 Agonist, Attenuates Myocardial Infarction-Related Adverse Cardiac Remodeling in Mice.

J Am Heart Assoc 2020 04 16;9(8):e015748. Epub 2020 Apr 16.

Division of Cardiology Pauley Heart Center Virginia Commonwealth University Richmond VA.

Background Human relaxin-2 is a peptide hormone capable of pleiotropic effects in several organ systems. Its recombinant formulation (serelaxin) has been demonstrated to reduce infarct size and prevent excessive scar formation in animal models of cardiac ischemia-reperfusion injury. B7-33, a synthetically designed peptide analogous to B-chain of relaxin-2, invokes signaling at relaxin family peptide receptor 1 (cognate receptor for relaxin-2) by preferentially phosphorylating the mitogen-activated protein kinase extracellular signal-regulated kinase 1/2. We sought to investigate the effects of B7-33 treatment post ischemia-reperfusion injury in mice. Methods and Results Adult male CD1 mice were subjected to ischemia-reperfusion via ligation of left anterior descending artery for 30 minutes, followed by 24 hours or 7 days of reperfusion. Echocardiography was performed to assess cardiac function, and cardiac tissue was stained to determine infarct size at 24 hours. B7-33 significantly reduced infarct size (21.99% versus 45.32%; =0.02) and preserved fractional shortening (29% versus 23%; =0.02) compared with vehicle. The difference in fractional shortening further increased at 7 days post myocardial infarction (29% versus 20% for B7-33 and vehicle groups, respectively). In vitro primary cardiomyocytes were isolated from adult hearts and subjected to simulated ischemia-reperfusion injury (simulated ischemia reoxygenation). B7-33 (50 and 100 nmol/L) improved cell survival and reduced the expression of GRP78 (glucose regulated protein), an endoplasmic reticulum stress marker. Subsequently, B7-33 (100 nmol/L) reduced tunicamycin (2.5 μg/mL) induced upregulation of GRP78 in an extracellular signal-regulated kinase 1/2-dependent manner. Conclusions B7-33 confers acute cardioprotection and limits myocardial infarction-related adverse remodeling in mice by attenuating cardiomyocyte death and endoplasmic reticulum stress as well as preserving cardiac function.
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http://dx.doi.org/10.1161/JAHA.119.015748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428518PMC
April 2020

Structurally Tunable pH-Responsive Luminescent Assemblies from Halogen Bonded Supra-π-amphiphiles.

Langmuir 2020 Mar 20;36(12):3089-3095. Epub 2020 Mar 20.

School of Applied and Interdisciplinary Sciences, Indian Association for the Cultivation of Science, 2A & 2B Raja S. C. Mullick Road, Jadavpur, Kolkata-700032, India.

Supra-amphiphiles constituted of noncovalent bonds have emerged as attractive systems for fabrication of stimuli-responsive self-assembled nanostructures. A unique supramolecular strategy utilizing halogen (X)-bonding interaction has been demonstrated for constructing emissive supra-π-amphiphiles in water from a hydrophobic pyridyl functionalized naphthalene monoimide () based X-bond acceptor and hydrophilic iodotetrafluorophenyl functionalized polyethylene glycol () or triethylene glycol () based X-bond donors, while their luminescent higher ordered assemblies were governed by orthogonal dipole-dipole interaction and π-stacking of the fluorophore as probed by SCXRD and DFT calculations. Control molecules lacking iodotetrafluorophenyl moiety at the polyethylene glycol chain end failed to create any defined morphology from the , suggesting X-bonding is prerequisite for the nanostructure formation. Variation in the chain length of the X-bond donors leads to different morphologies (fiber vs vesicle) for and . Acid triggered denaturing of the X-bonds caused pH responsive disassembly of the thermally robust nanostructures. This strategy paves the way for facile fabrication of structurally diverse smart and adaptive luminescent functional materials with tunable morphology.
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http://dx.doi.org/10.1021/acs.langmuir.0c00443DOI Listing
March 2020

A dual PI3 kinase/mTOR inhibitor BEZ235 reverses doxorubicin resistance in ABCB1 overexpressing ovarian and pancreatic cancer cell lines.

Biochim Biophys Acta Gen Subj 2020 06 14;1864(6):129556. Epub 2020 Feb 14.

VCU Pauley Heart Center, Division of Cardiology, Virginia Commonwealth University, Richmond, VA 23298, United States. Electronic address:

Background: Multi-drug resistance (MDR) develops because cancer cells evade toxicity of several structurally unrelated drugs. Besides other mechanisms, MDR is linked to the overexpression of ATP Binding Cassette (ABC), transporters, among which ABCB1 is the best characterized one. Since overactivation of PI3K/Akt/mTOR plays a pivotal role in the growth of human cancers, we hypothesized whether dual PI3K and mTOR inhibitor, BEZ235 (BEZ, dactolisib) reverses resistance to doxorubicin (DOX).

Methods: Ovarian (A2780) and pancreatic (MiaPaca2) cancer cells were used to generate DOX-resistant clones by overexpressing ABCB1 or stepwise treatment of DOX. Intracellular accumulation of DOX was measured by flow cytometry after treatment with BEZ.

Results: BEZ treatment caused an increase in intracellular levels of DOX which was almost identical to the naïve parental cell lines. BEZ was found to be a weak substrate for ABCB1 as demonstrated by minimal increase in ATPase activity. BEZ treatment caused a dose-dependent decrease in cell viability in combination with DOX, which was associated with an increase in cleaved PARP expression in the drug resistant clones.

Conclusions: These results suggest that BEZ is a non-substrate inhibitor of ABCB1 and is able to effectively re-sensitize cells overexpressing ABCB1 to the effects of DOX.

General Significance: Dual PI3 Kinase/mTOR inhibitor, BEZ, has the potential to reverse MDR in cancer patients.
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http://dx.doi.org/10.1016/j.bbagen.2020.129556DOI Listing
June 2020

Persistent Proarrhythmic Neural Remodeling Despite Recovery From Premature Ventricular Contraction-Induced Cardiomyopathy.

J Am Coll Cardiol 2020 01;75(1):1-13

Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia; Electrophysiology Section, Division of Cardiology, Hunter Holmes McGuire VA Medical Center, Richmond, Virginia.

Background: The presence and significance of neural remodeling in premature ventricular contraction-induced cardiomyopathy (PVC-CM) remain unknown.

Objectives: This study aimed to characterize cardiac sympathovagal balance and proarrhythmia in a canine model of PVC-CM.

Methods: In 12 canines, the investigators implanted epicardial pacemakers and radiotelemetry units to record cardiac rhythm and nerve activity (NA) from the left stellate ganglion (SNA), left cardiac vagus (VNA), and arterial blood pressure. Bigeminal PVCs (200 ms coupling) were applied for 12 weeks to induce PVC-CM in 7 animals then disabled for 4 weeks to allow complete recovery of left ventricular ejection fraction (LVEF), versus 5 sham controls.

Results: After 12 weeks of PVCs, LVEF (p = 0.006) and dP/dT (p = 0.007) decreased. Resting SNA (p = 0.002) and VNA (p = 0.04), exercise SNA (p = 0.01), SNA response to evoked PVCs (p = 0.005), heart rate (HR) at rest (p = 0.003), and exercise (p < 0.04) increased, whereas HR variability (HRV) decreased (p = 0.009). There was increased spontaneous atrial (p = 0.02) and ventricular arrhythmias (p = 0.03) in PVC-CM. Increased SNA preceded both atrial (p = 0.0003) and ventricular (p = 0.009) arrhythmia onset. Clonidine suppressed SNA and abolished all arrhythmias. After disabling PVC for 4 weeks, LVEF (p = 0.01), dP/dT (p = 0.047), and resting VNA (p = 0.03) recovered to baseline levels. However, SNA, resting HR, HRV, and atrial (p = 0.03) and ventricular (p = 0.03) proarrhythmia persisted. There was sympathetic hyperinnervation in stellate ganglia (p = 0.02) but not ventricles (p = 0.2) of PVC-CM and recovered animals versus sham controls.

Conclusions: Neural remodeling in PVC-CM is characterized by extracardiac sympathetic hyperinnervation and sympathetic neural hyperactivity that persists despite normalization of LVEF. The altered cardiac sympathovagal balance is an important trigger and substrate for atrial and ventricular proarrhythmia.
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http://dx.doi.org/10.1016/j.jacc.2019.10.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7006705PMC
January 2020

STAT3-miR-17/20 signalling axis plays a critical role in attenuating myocardial infarction following rapamycin treatment in diabetic mice.

Cardiovasc Res 2020 Nov;116(13):2103-2115

Division of Cardiology, Pauley Heart Center, Department of Internal Medicine, Virginia Commonwealth University, 1101 East Marshall Street, Room 7020B, Richmond, VA 23298-0204, USA.

Aims: Deregulation of mTOR (mammalian target of rapamycin) signalling occurs in diabetes, which exacerbates injury following myocardial infarction (MI). We therefore investigated the infarct-limiting effect of chronic treatment with rapamycin (RAPA, mTOR inhibitor) in diabetic mice following myocardial ischaemia/reperfusion (I/R) injury and delineated the potential protective mechanism.

Methods And Results: Adult male diabetic (db/db) or wild-type (WT) (C57) mice were treated with RAPA (0.25 mg/kg/day, intraperitoneal) or vehicle (5% DMSO) for 28 days. The hearts from treated mice were subjected to global I/R in Langendorff mode. Cardiomyocytes, isolated from treated mice, were subjected to simulated ischaemia/reoxygenation (SI/RO) to assess necrosis and apoptosis. Myocardial infarct size was increased in diabetic heart following I/R as compared to WT. Likewise, enhanced necrosis and apoptosis were observed in isolated cardiomyocytes of diabetic mice following SI/RO. Treatment with RAPA reduced infarct size as well as cardiomyocyte necrosis and apoptosis of diabetes and WT mice. RAPA increased STAT3 phosphorylation and miRNA-17/20a expression in diabetic hearts. In addition, RAPA restored AKT phosphorylation (target of mTORC2) but suppressed S6 phosphorylation (target of mTORC1) following I/R injury. RAPA-induced cardioprotection against I/R injury as well as the induction of miR-17/20a and AKT phosphorylation were abolished in cardiac-specific STAT3-deficient diabetic mice, without alteration of S6 phosphorylation. The infarct-limiting effect of RAPA was obliterated in cardiac-specific miRNA-17-92-deficient diabetic mice. The post-I/R restoration of phosphorylation of STAT3 and AKT with RAPA were also abolished in miRNA-17-92-deficient diabetic mice. Additionally, RAPA suppressed the pro-apoptotic prolyl hydroxylase (Egln3/PHD3), a target of miRNA-17/20a in diabetic hearts, which was abrogated in miRNA-17-92-deficient diabetic mice.

Conclusion: Induction of STAT3-miRNA-17-92 signalling axis plays a critical role in attenuating MI in RAPA-treated diabetic mice. Our study indicates that chronic treatment with RAPA might be a promising pharmacological intervention for attenuating MI and improving prognosis in diabetic patients.
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http://dx.doi.org/10.1093/cvr/cvz315DOI Listing
November 2020

Site-Directed Fluorescence Approaches for Dynamic Structural Biology of Membrane Peptides and Proteins.

Front Mol Biosci 2019 25;6:96. Epub 2019 Sep 25.

Crystallography and Molecular Biology Division, Saha Institute of Nuclear Physics, Homi Bhabha National Institute, Kolkata, India.

Membrane proteins mediate a number of cellular functions and are associated with several diseases and also play a crucial role in pathogenicity. Due to their importance in cellular structure and function, they are important drug targets for ~60% of drugs available in the market. Despite the technological advancement and recent successful outcomes in determining the high-resolution structural snapshot of membrane proteins, the mechanistic details underlining the complex functionalities of membrane proteins is least understood. This is largely due to lack of structural dynamics information pertaining to different functional states of membrane proteins in a membrane environment. Fluorescence spectroscopy is a widely used technique in the analysis of functionally-relevant structure and dynamics of membrane protein. This review is focused on various site-directed fluorescence (SDFL) approaches and their applications to explore structural information, conformational changes, hydration dynamics, and lipid-protein interactions of important classes of membrane proteins that include the pore-forming peptides/proteins, ion channels/transporters and G-protein coupled receptors.
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http://dx.doi.org/10.3389/fmolb.2019.00096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774292PMC
September 2019

Structural Dynamics of the Paddle Motif Loop in the Activated Conformation of KvAP Voltage Sensor.

Biophys J 2020 02 22;118(4):873-884. Epub 2019 Aug 22.

Crystallography and Molecular Biology Division, Saha Institute of Nuclear Physics, Homi Bhabha National Institute, 1/AF Bidhannagar, Kolkata, India. Electronic address:

Voltage-dependent potassium (K) channels play a fundamental role in neuronal and cardiac excitability and are potential therapeutic targets. They assemble as tetramers with a centrally located pore domain surrounded by a voltage-sensing domain (VSD), which is critical for sensing transmembrane potential and subsequent gating. Although the sensor is supposed to be in "Up" conformation in both n-octylglucoside (OG) micelles and phospholipid membranes in the absence of membrane potential, toxins that bind VSD and modulate the gating behavior of K channels exhibit dramatic affinity differences in these membrane-mimetic systems. In this study, we have monitored the structural dynamics of the S3b-S4 loop of the paddle motif in activated conformation of KvAP-VSD by site-directed fluorescence approaches, using the environment-sensitive fluorescent probe 7-nitrobenz-2-oxa-1,3-diazol-4-yl-ethylenediamine (NBD). Emission maximum of NBD-labeled loop region of KvAP-VSD (residues 110-117) suggests a significant change in the polarity of local environment in 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine/1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1'-rac-glycerol) membranes compared to OG micelles. This indicates that S3b-S4 loop residues might be partitioning to membrane interface, which is supported by an overall increased mean fluorescence lifetimes and significantly reduced water accessibility in membranes. Further, the magnitude of red edge excitation shift (REES) supports the presence of restricted/bound water molecules in the loop region of the VSD in micelles and membranes. Quantitative analysis of REES data using Gaussian probability distribution function clearly indicates that the sensor loop has fewer discrete equilibrium conformational states when reconstituted in membranes. Interestingly, this reduced molecular heterogeneity is consistent with the site-specific NBD polarization results, which suggest that the membrane environment offers a relaxed/dynamic organization for most of the S3b-S4 loop residues of the sensor. Overall, our results are relevant for understanding toxin-VSD interaction and gating mechanisms of K channels in membranes.
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http://dx.doi.org/10.1016/j.bpj.2019.08.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036696PMC
February 2020

Label-free gold nanorod-based plasmonic sensing of arsenic(iii) in contaminated water.

Analyst 2019 Aug 5;144(15):4708-4718. Epub 2019 Jul 5.

Special Centre for Nanoscience, Jawaharlal Nehru University, New Delhi-110067, India.

In this paper, we report a strategy based on unmodified gold nanorods for sensitive and selective detection of arsenic(iii) in contaminated water for the first time. The strategy relies on the inhibitory effect of arsenic(iii) on iron(iii)-mediated oxidative shortening of gold nanorods (Au-NRs) in acidic pH and at increased temperature. The arsenic(iii)-mediated inhibition of Au-NR oxidation is demonstrated by the red-shift of the longitudinal surface plasmon resonance (LSPR) band of Au-NRs. The novelty of our sensing strategy is the fact that it is label-free as it doesn't include any arsenic(iii) selective functionalization of Au-NRs. Moreover, this strategy can detect the arsenic(iii) content in water down to 10 ppb, which is the maximum permissible limit of the arsenic trace in drinking water according to the World Health Organization (WHO) guidelines. The effect of HO in controlling the selectivity of our sensing strategy is investigated. It is found that in the absence of HO, the strategy is selective for arsenic(iii) with a broad dynamic response range (10-500 ppb), except for the interference from copper(ii). However, the interference of copper(ii) is efficiently eliminated by selective removal of copper(ii) from water via magnetic separation using polyethyleneimine-functionalized cobalt ferrite nanoparticles. The morphology of Au-NRs and the shift of the LSPR band during the sensing of arsenic(iii) are established by electron microscopy images and Vis-NIR absorption spectroscopy. This strategy is successfully applied for the estimation of arsenic(iii) in the real water sample and this paves the way for the implementation of our strategy for the real-time estimation of arsenic(iii) contamination levels found across prevalent drinking water sources, which are otherwise difficult to achieve with traditional sensors.
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http://dx.doi.org/10.1039/c9an00668kDOI Listing
August 2019

Particle analogs of electrons in colloidal crystals.

Science 2019 06;364(6446):1174-1178

Department of Materials Science and Engineering, Northwestern University, Evanston, IL 60208, USA.

A versatile method for the design of colloidal crystals involves the use of DNA as a particle-directing ligand. With such systems, DNA-nanoparticle conjugates are considered programmable atom equivalents (PAEs), and design rules have been devised to engineer crystallization outcomes. This work shows that when reduced in size and DNA grafting density, PAEs behave as electron equivalents (EEs), roaming through and stabilizing the lattices defined by larger PAEs, as electrons do in metals in the classical picture. This discovery defines a new property of colloidal crystals-metallicity-that is characterized by the extent of EE delocalization and diffusion. As the number of strands increases or the temperature decreases, the EEs localize, which is structurally reminiscent of a metal-insulator transition. Colloidal crystal metallicity, therefore, provides new routes to metallic, intermetallic, and compound phases.
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http://dx.doi.org/10.1126/science.aaw8237DOI Listing
June 2019

Biochemical and biophysical characterization of a prokaryotic Mg ion channel: Implications for cost-effective purification of membrane proteins.

Protein Expr Purif 2019 09 24;161:8-16. Epub 2019 Apr 24.

Crystallography and Molecular Biology Division, Saha Institute of Nuclear Physics, Homi Bhabha National Institute, 1/AF Bidhannagar, Kolkata, 700 064, India. Electronic address:

Although magnesium is the second most abundant cation present in the cell, the transport mechanism of Mg across membranes is poorly understood. Importantly, the prokaryotic MgtE Mg channel is related to mammalian SLC41A1 transporters and, therefore, biochemical and biophysical characterization of MgtE and its orthologs assumes significance. To date, the purification and structure determination of MgtE from Thermus thermophilus has been carried out using the widely used nonionic detergent, n-dodecyl-β-d-maltopyranoside (DDM). However, DDM is an expensive detergent and alternative methods to produce high-quality proteins in stable and functional form will be practically advantageous to carry out structural studies in a cost-effective manner. In this work, we have utilized 'dual-detergent strategy' to successfully purify MgtE channel in a stable and functional form by employing relatively inexpensive detergents (Triton X-100 and Anzergent 3-14) for membrane solubilization and subsequently changed to DDM during purification. Our results show that Triton X-100 and Anzergent 3-14 extract MgtE well and the quality of purified protein is comparable to DDM-extracted MgtE. Interestingly, addition of high concentration of salt and glycerol during solubilization does not significantly affect the quantity and quality of MgtE. Importantly, limited proteolysis assay, circular dichroism spectroscopy and ensemble tryptophan fluorescence strongly support the use of Triton X-100, in particular, as an inexpensive, alternative detergent for the purification of MgtE without compromising the structural integrity of the channel and Mg-induced gating-related conformational dynamics. Overall, these results are relevant for the cost-effective purification of stable and functional membrane proteins in general, and magnesium channels, in particular.
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http://dx.doi.org/10.1016/j.pep.2019.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116351PMC
September 2019

mTOR Signaling in Cardiometabolic Disease, Cancer, and Aging 2018.

Oxid Med Cell Longev 2019;2019:9692528. Epub 2019 Feb 4.

Department of Cellular & Integrative Physiology, and Department of Anesthesiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.

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http://dx.doi.org/10.1155/2019/9692528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378800PMC
August 2019

Cardiac Specific Knockout of p53 Decreases ER Stress-Induced Mitochondrial Damage.

Front Cardiovasc Med 2019 19;6:10. Epub 2019 Feb 19.

Division of Cardiology, Departments of Medicine, Virginia Commonwealth University, Richmond, VA, United States.

Endoplasmic reticulum (ER) stress contributes to cardiovascular disease including heart failure. Interactions between the ER and mitochondria during ER stress can impair the mitochondrial respiratory chain and increase cell injury. p53 is a tumor suppressor protein that regulates apoptosis. p53 contributes to the regulation of mitochondrial and ER interactions, especially during the progression of ER stress. The knockout (KO) of p53 leads to decreased injury in hearts following ischemia-reperfusion. We asked if KO of p53 can protect mitochondria during the induction of ER stress and decrease cell injury. Floxed p53 mice were crossed with mice carrying an α-myosin heavy chain to generate cardiac specific p53 KO mice. Thapsigargin (THAP) was used to induce ER stress in wild type (WT) and p53 KO mice. Mice were euthanized after 48 h THAP treatment. Cardiac mitochondria were isolated for functional measurement. TUNEL staining was used to assess myocyte death. In WT mice, THAP treatment decreased the rate of oxidative phosphorylation using pyruvate + malate as complex I substrates compared to vehicle-treated control. Complex I activity was also decreased in the THAP-treated WT mice. The rate of oxidative phosphorylation and complex I activity were not altered in THAP-treated p53 KO mice. The content of pyruvate dehydrogenase (PDH) α1 subunit was decreased in THAP-treated WT mice but not in p53 KO mice. ER stress led to a release of cytochrome and apoptosis inducing factor from mitochondria into cytosol in WT but not in KO mice. Knockout of p53 also preserved mitochondrial bcl-2 content in THAP-treated mice. In WT mice, THAP treatment markedly increased cell death compared to vehicle treated hearts. In contrast, cell injury was decreased in THAP-treated p53 KO mice compared to corresponding wild type. Thus, KO of p53 decreased cell injury by protecting mitochondria during the ER stress.
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http://dx.doi.org/10.3389/fcvm.2019.00010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389610PMC
February 2019

Incidence of single-drug resistant, multidrug-resistant and extensively drug-resistant Escherichia coli urinary tract infections: An Australian laboratory-based retrospective study.

J Glob Antimicrob Resist 2019 03 6;16:254-259. Epub 2018 Nov 6.

Faculty of Health Sciences, Australian Catholic University, Australian Capital Territory, Australia; School of Public Health and Social Work, Queensland University of Technology, Queensland, Australia.

Objectives: The aim of this study was to evaluate the incidence of single-drug resistant, multidrug-resistant (MDR), extensively drug-resistant (XDR) and pandrug-resistant (PDR) Escherichia coli urinary tract infections (UTIs) in a sample of Australian Capital Territory (ACT) residents.

Methods: Laboratory-based retrospective data from all ACT residents whose urine samples were processed from January 2009 to December 2013 at ACT Pathology were utilised. Multivariate logistic regression models were constructed to determine the associations of age, sex, urine sample source and socioeconomic status with risk of resistant infections.

Results: A total of 146 915 urine samples from 57 837 ACT residents were identified over 5 years. The mean±standard deviation age of residents at first sample submitted was 48±26years, and 64.4% were female. The 5-year incidence of single-drug resistant E. coli UTI was high for ampicillin, trimethoprim and cefazolin (6.8%, 3.5% and 1.9%, respectively). No PDR E. coli UTI was detected. Five-year incidences of MDR and XDR E. coli UTIs were 1.9% and 0.2%, respectively, which is low in comparison with international rates. Female sex and age ≥38 years were significantly associated with single-drug and multidrug resistance. The risk of single-drug resistance was significantly higher in samples from after-hours general practice (GP) clinics compared with hospitals, office-hours GP clinics, and community and specialist health services (adjusted odds ratio=2.6, 95% confidence interval 2.2-3.1).

Conclusions: These findings have significant implications for antimicrobial prescribing given the identified risk factors for the detection of resistance, especially in patients attending after-hours GP clinics.
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http://dx.doi.org/10.1016/j.jgar.2018.10.026DOI Listing
March 2019

Sacubitril/Valsartan Averts Adverse Post-Infarction Ventricular Remodeling and Preserves Systolic Function in Rabbits.

J Am Coll Cardiol 2018 11;72(19):2342-2356

Pauley Heart Center, Department of Internal Medicine, Division of Cardiology, Virginia Commonwealth University, Richmond, Virginia. Electronic address:

Background: Sacubitril/valsartan (SAC/VAL) is approved by the U.S. Food and Drug Administration for heart failure with reduced ejection fraction (HFrEF).

Objectives: This study investigated the effects of SAC/VAL on acute myocardial infarction (MI) and cardiac remodeling in a translational rabbit model of MI.

Methods: New Zealand White rabbits were sedated and underwent conscious MI (45-min ischemia) by balloon inflation (previously implanted surgically) followed by 72 h (acute protocol) or 10 weeks (chronic protocols) of reperfusion. "Infarct-sparing" protocol: SAC/VAL, VAL, or placebo were randomly allocated and administered at reperfusion. "HFrEF-treatment" protocol: rabbits were randomized, and treatment commenced after echocardiography-confirmed left ventricular ejection fraction (LVEF) ≤40%. "HFrEF-prevention" protocol: treatment started at reperfusion and continued daily throughout the study.

Results: Compared with placebo, SAC/VAL and VAL significantly reduced infarct size (TTC staining) and plasma troponin levels; however, only SAC/VAL preserved LVEF at 72 h post-MI. In the HFrEF-treatment protocol, LVEF improvement was observed with SAC/VAL compared with both placebo and VAL starting 2 weeks post-treatment, a benefit that persisted throughout study duration. In the HFrEF-prevention protocol, SAC/VAL and VAL attenuated the decline in LVEF post-MI, although SAC/VAL offered better functional protection. The functional improvement observed in both treatment protocols was paralleled by significant reduction in left ventricular (LV) scar size (Picrosirius red staining) in the SAC/VAL groups.

Conclusions: Reperfusion therapy with SAC/VAL or VAL offers robust acute infarct-sparing benefits; however, SAC/VAL treatment offered superior short-term and long-term benefits in preventing MI-induced LV dysfunction compared with VAL. SAC/VAL also significantly attenuated LV scar size following MI compared with placebo, whereas VAL did not reach statistical significance in scar reduction.
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http://dx.doi.org/10.1016/j.jacc.2018.07.102DOI Listing
November 2018