Digital Commons Network^™

Toward Systems-Informed Models For Biologics Disposition: Covariates Of The Abundance Of The Neonatal Fc Receptor (Fcrn) In Human Tissues And Implications For Pharmacokinetic Modelling, Jill Barber, Zubida M. Al-Majdoub, Narciso Couto, Martyn Howard, Yasmine Elmorsi, Daniel Scotcher, Naved Alizai, Saskia De Wildt, Felix Stader, Armin Sepp, Amin Rostami-Hodjegan, Brahim Achour

Biomedical and Pharmaceutical Sciences Faculty Publications

Biologics are a fast-growing therapeutic class, with intertwined pharmacokinetics and pharmacodynamics, affected by the abundance and function of the FcRn receptor. While many investigators assume adequacy of classical models, such as allometry, for pharmacokinetic characterization of biologics, advocates of physiologically-based pharmacokinetics (PBPK) propose consideration of known systems parameters that affect the fate of biologics to enable a priori predictions, which go beyond allometry. The aim of this study was to deploy a systems-informed modelling approach to predict the disposition of Fc-containing biologics. We used global proteomics to quantify the FcRn receptor [p51 and β₂-microglobulin (B2M) subunits] in 167 …

Proteomic Quantification Of Receptor Tyrosine Kinases Involved In The Development And Progression Of Colorectal Cancer Liver Metastasis, Areti-Maria Vasilogianni, Zubida M. Al-Majdoub, Brahim Achour, Sheila Annie Peters, Amin Rostami-Hodjegan, Jill Barber

Biomedical and Pharmaceutical Sciences Faculty Publications

Introduction: Alterations in expression and activity of human receptor tyrosine kinases (RTKs) are associated with cancer progression and in response to therapeutic intervention.

Methods: Thus, protein abundance of 21 RTKs was assessed in 15 healthy and 18 cancerous liver samples [2 primary and 16 colorectal cancer liver metastasis (CRLM)] matched with non-tumorous (histologically normal) tissue, by a validated QconCAT-based targeted proteomic approach.

Results: It was demonstrated, for the first time, that the abundance of EGFR, INSR, VGFR3 and AXL, is lower in tumours relative to livers from healthy individuals whilst the opposite is true for IGF1R. EPHA2 was upregulated in …

Synergistic Inhibiting Effect Of Phytochemicals In Rheum Palmatum On Tyrosinase Based On Metabolomics And Isobologram Analyses, Yin Xiong, Hye Kyong Kim, Övgü Çelikler Özer, Bert Van Duijn, Henrie A. A. J. Korthout, Lihong Zi, Ang Cai

Biomedical and Pharmaceutical Sciences Faculty Publications

Tyrosinase (TYR) plays a key role in the enzymatic reaction that is responsible for a range of unwanted discoloration effects, such as food browning and skin hyperpigmentation. TYR inhibitors could, therefore, be candidates for skin care products that aim to repair pigmentation problems. In this study, we used a metabolomics approach combined with the isobologram analysis to identify anti-TYR compounds within natural resources, and evaluate their possible synergism with each other. Rheum palmatum was determined to be a model plant for observing the effect, of which seven extracts with diverse phytochemicals were prepared by way of pressurized solvent extraction. Each …

Developing Virtual And Augmented Reality Applications For Science, Technology, Engineering And Math Education, Christopher L. Hemme, Rachel Carley, Arielle Norton, Moez Ghumman, Hannah Nguyen, Ryan Ivone, Jyothi Menon, Jie Shen, Matthew Bertin, Roberta King, Elizabeth Leibovitz, Roy Bergstrom, Bongsup P. Cho

Biomedical and Pharmaceutical Sciences Faculty Publications

The Rhode Island IDeA Network of Biomedical Research Excellence Molecular Informatics Core at the University of Rhode Island Information Technology Services Innovative Learning Technologies developed virtual and augmented reality applications to teach concepts in biomedical science, including pharmacology, medicinal chemistry, cell culture and nanotechnology. The apps were developed as full virtual reality/augmented reality and 3D gaming versions, which do not require virtual reality headsets. Development challenges included creating intuitive user interfaces, text-to-voice functionality, visualization of molecules and implementing complex science concepts. In-app quizzes are used to assess the user's understanding of topics, and user feedback was collected for several apps …

Inhibitory Effects Of Cannabinoids On Acetylcholinesterase And Butyrylcholinesterase Enzyme Activities, Tess Puopolo, Chang Liu, Hang Ma, Navindra P. Seeram

Biomedical and Pharmaceutical Sciences Faculty Publications

Introduction: Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are two cholinergic enzymes catalyzing the reaction of cleaving acetylcholine into acetate and choline at the neuromuscular junction. Abnormal hyperactivity of AChE and BChE can lead to cholinergic deficiency, which is associated with several neurological disorders including cognitive decline and memory impairments. Preclinical studies support that some cannabinoids including cannabidiol (CBD) and tetrahydrocannabinol (THC) may exert pharmacological effects on the cholinergic system, but it remains unclear whether cannabinoids can inhibit AChE and BChE activities. Herein, we aimed to evaluate the inhibitory effects of a panel of cannabinoids including CBD, Δ8-THC, cannabigerol (CBG), cannabigerolic …

Mechanisms Of Cannabidiol (Cbd) In Cancer Treatment: A Review, Camren G. Heider, Sasha A. Itenberg, Jiajia Rao, Hang Ma, Xian Wu

Biomedical and Pharmaceutical Sciences Faculty Publications

Cannabis sativa L. (Cannabis) and its bioactive compounds, including cannabinoids and non-cannabinoids, have been extensively studied for their biological effects in recent decades. Cannabidiol (CBD), a major non-intoxicating cannabinoid in Cannabis, has emerged as a promising intervention for cancer research. The purpose of this review is to provide insights into the relationship between CBD and cancer based on recent research findings. The anticancer effects of CBD are mainly mediated via its interaction with the endocannabinoid system, resulting in the alleviation of pain and the promotion of immune regulation. Published reviews have focused on the applications of CBD in cancer pain …

Analysis Of Botanicals And Botanical Supplements By Lc-Ms/Ms-Based Molecular Networking: Approaches For Annotating Plant Metabolites And Authentication, Terra Marie M. Jouaneh, Neil Motta, Christine Wu, Cole Coffey, Christopher W. Via, Riley D. Kirk, Matthew Bertin

Biomedical and Pharmaceutical Sciences Faculty Publications

Prior to the advent of modern medicine, humans have used botanicals extensively for their therapeutic potential. With the majority of newly approved drugs having their origins in natural products, plants remain at the forefront of drug discovery. Continued research and discovery necessitate the use of high-throughput analytical methods to screen and identify bioactive components and potential therapeutic molecules from plants. Utilizing a pre-generated plant extract library, we subjected botanicals to LC-MS/MS-based molecular networking to determine their chemical composition and relatively quantify already known metabolites. The LC-MS/MS-based molecular networking approach was also used to authenticate the composition of dietary supplements against …

Screening The Prism Library Against Staphylococcus Aureus Reveals A Sesquiterpene Lactone From Liriodendron Tulipifera With Inhibitory Activity, Riley D. Kirk, Margaret E. Rosario, Nana Oblie, Terra Marie M. Jouaneh, Marina A. Carro, Christine Wu, Andrew M. Kim, Elizabeth Leibovitz, Elizabeth Sage Hunter, Robert Literman, Sara M. Handy, David C. Rowley, Matthew J. Bertin

Biomedical and Pharmaceutical Sciences Faculty Publications

Infections caused by the bacterium Staphylococcus aureus continue to pose threats to human health and put a financial burden on the healthcare system. The overuse of antibiotics has contributed to mutations leading to the emergence of methicillin-resistant S. aureus, and there is a critical need for the discovery and development of new antibiotics to evade drug-resistant bacteria. Medicinal plants have shown promise as sources of new small-molecule therapeutics with potential uses against pathogenic infections. The principal Rhode Island secondary metabolite (PRISM) library is a botanical extract library generated from specimens in the URI Youngken Medicinal Garden by upper-division undergraduate …

Quantitative Assessment Of The Impact Of Crohn's Disease On Protein Abundance Of Human Intestinal Drug-Metabolising Enzymes And Transporters, Sarah Alrubia, Zubida M. Al-Majdoub, Brahim Achour, Amin Rostami-Hodjegan, Jill Barber

Biomedical and Pharmaceutical Sciences Faculty Publications

Crohn's disease affects the mucosal layer of the intestine, predominantly ileum and colon segments, with the potential to affect the expression of intestinal enzymes and transporters, and consequently, oral drug bioavailability. We carried out a quantitative proteomic analysis of inflamed and non-inflamed ileum and colon tissues from Crohn's disease patients and healthy donors. Homogenates from samples in each group were pooled and protein abundance determined by liquid chromatography–mass spectrometry (LC-MS). In inflamed Crohn's ileum, CYP3A4, CYP20A1, CYP51A1, ADH1B, ALPI, FOM1, SULT1A2, SULT1B1 and ABCB7 showed ≥10-fold reduction in abundance compared with healthy baseline. By contrast, only MGST1 showed ≥10 fold …

Quantitative Proteomics Of Hepatic Drug-Metabolizing Enzymes And Transporters In Patients With Colorectal Cancer Metastasis, Areti-Maria Vasilogianni, Zubida M. Al-Majdoub, Brahim Achour, Sheila Annie Peters, Jill Barber, Amin Rostami-Hodjegan

Biomedical and Pharmaceutical Sciences Faculty Publications

The impact of liver cancer metastasis on protein abundance of 22 drug-metabolizing enzymes (DMEs) and 25 transporters was investigated using liquid chromatography-tandem accurate mass spectrometry targeted proteomics. Microsomes were prepared from liver tissue taken from 15 healthy individuals and 18 patients with cancer (2 primary and 16 metastatic). Patient samples included tumors and matching histologically normal tissue. The levels of cytochrome P450 (CYPs 2B6, 2D6, 2E1, 3A4, and 3A5) and uridine 5′-diphospho-glucuronosyltransferases (UGTs 1A1, 1A6, 1A9, 2B15, 2B4, and 2B7) were lower in histologically normal tissue from patients relative to healthy controls (up to 6.6-fold) and decreased further in tumors …

Proteomic Quantification Of Perturbation To Pharmacokinetic Target Proteins In Liver Disease, Areti-Maria Vasilogianni, Eman El-Khateeb, Zubida M. Al-Majdoub, Sarah Alrubia, Amin Rostami-Hodjegan, Jill Barber, Brahim Achour

Biomedical and Pharmaceutical Sciences Faculty Publications

Model-based assessment of drug pharmacokinetics in liver disease requires quantification of abundance and disease-related changes in hepatic enzymes and transporters. This study aimed to assess performance of three label-free methods [high N (HiN), intensity-based absolute quantification (iBAQ) and total protein approach (TPA)] against QconCAT-based targeted data in healthy and diseased (cancer and cirrhosis) liver tissue. Measurements were compared across methods and disease-to-control ratios provided a ‘disease perturbation factor’ (DPF) for each protein. Mean label-free measurements of targets correlated well (Pearson's coefficient, r = 0.91–0.98 p < 0.001) and with targeted data (r = 0.65–0.95, p < 0.001). Concordance with targeted data was generally moderate (Lin's concordance coefficient, ρ_c = 0.46–0.92), depending on methodology. Moderate precision and accuracy …

Identification Of Sars-Cov-2 Main Protease Inhibitors From A Library Of Minor Cannabinoids By Biochemical Inhibition Assay And Surface Plasmon Resonance Characterized Binding Affinity, Chang Liu, Tess Puopolo, Huifang Li, Ang Cai, Navindra P. Seeram, Hang Ma

Biomedical and Pharmaceutical Sciences Faculty Publications

The replication of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is mediated by its main protease (M^pro), which is a plausible therapeutic target for coronavirus disease 2019 (COVID-19). Although numerous in silico studies reported the potential inhibitory effects of natural products including cannabis and cannabinoids on SARS-CoV-2 M^pro, their anti-M^pro activities are not well validated by biological experimental data. Herein, a library of minor cannabinoids belonging to several chemotypes including tetrahydrocannabinols, cannabidiols, cannabigerols, cannabichromenes, cannabinodiols, cannabicyclols, cannabinols, and cannabitriols was evaluated for their anti-M^pro activity using a biochemical assay. Additionally, the binding affinities …

Leucine Carboxyl Methyltransferase 1 Overexpression Protects Against Cognitive And Electrophysiological Impairments In Tg2576 App Transgenic Mice, Madhumathi Gnanaprakash, Agnieszka Staniszewski, Hong Zhang, Rose Pitstick, Michael P. Kavanaugh, Ottavio Arancio, Russell E. Nicholls

Biomedical and Pharmaceutical Sciences Faculty Publications

Background: The serine/threonine protein phosphatase, PP2A, is thought to play a central role in the molecular pathogenesis of Alzheimer’s disease (AD), and the activity and substrate specificity of PP2A is regulated, in part, through methylation and demethylation of its catalytic subunit. Previously, we found that transgenic overexpression of the PP2A methyltransferase, LCMT-1, or the PP2A methylesterase, PME-1, altered the sensitivity of mice to impairments caused by acute exposure to synthetic oligomeric amyloid-β (Aβ).

Objective: Here we sought to test the possibility that these molecules also controlled sensitivity to impairments caused by chronically elevated levels of Aβ produced in vivo. …

Supplemental Ascorbate Diminishes Dna Damage Yet Depletes Glutathione And Increases Acute Liver Failure In A Mouse Model Of Hepatic Antioxidant System Disruption, Colin G. Miller, Jean A. Kundert, Justin R. Prigge, Julie A. Amato, Allison E. Perez, Lucia Coppo, Gabrielle N. Rizzo, Michael P. Kavanaugh, David J. Orlicky, Colin T. Shearn, Edward E. Schmidt

Biomedical and Pharmaceutical Sciences Faculty Publications

Cellular oxidants are primarily managed by the thioredoxin reductase-1 (TrxR1)- and glutathione reductase (Gsr)-driven antioxidant systems. In mice having hepatocyte-specific codisruption of TrxR1 and Gsr (TrxR1/Gsr-null livers), methionine catabolism sustains hepatic levels of reduced glutathione (GSH). Although most mice with TrxR1/Gsr-null livers exhibit long-term survival, ~25% die from spontaneous liver failure between 4- and 7-weeks of age. Here we tested whether liver failure was ameliorated by ascorbate supplementation. Following ascorbate, dehydroascorbate, or mock treatment, we assessed survival, liver histology, or hepatic redox markers including GSH and GSSG, redox enzyme activities, and oxidative damage markers. Unexpectedly, rather than providing protection, ascorbate …

Adjuvantation Of Influenza Vaccines To Induce Cross-Protective Immunity, Zhoufan Li, Yiwen Zhao, Yibo Li, Xinyuan Chen

Biomedical and Pharmaceutical Sciences Faculty Publications

Influenza poses a huge threat to global public health. Influenza vaccines are the most effective and cost-effective means to control influenza. Current influenza vaccines mainly induce neutralizing antibodies against highly variable globular head of hemagglutinin and lack cross-protection. Vaccine adjuvants have been approved to enhance seasonal influenza vaccine efficacy in the elderly and spare influenza vaccine doses. Clinical studies found that MF59 and AS03-adjuvanted influenza vaccines could induce cross-protective immunity against non-vaccine viral strains. In addition to MF59 and AS03 adjuvants, experimental adjuvants, such as Toll-like receptor agonists, saponin-based adjuvants, cholera toxin and heat-labile enterotoxin-based mucosal adjuvants, and physical adjuvants, …

Anti-Parallel Β-Hairpin Structure In Soluble Aβ Oligomers Of Aβ40-Dutch And Aβ40-Iowa, Ziao Fu, William Van Nostrand, Steven O. Smith

Biomedical and Pharmaceutical Sciences Faculty Publications

The amyloid-β (Aβ) peptides are associated with two prominent diseases in the brain, Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). Aβ42 is the dominant component of cored parenchymal plaques associated with AD, while Aβ40 is the predominant component of vascular amyloid associated with CAA. There are familial CAA mutations at positions Glu22 and Asp23 that lead to aggressive Aβ aggregation, drive vascular amyloid deposition and result in degradation of vascular membranes. In this study, we compared the transition of the monomeric Aβ40-WT peptide into soluble oligomers and fibrils with the corresponding transitions of the Aβ40-Dutch (E22Q), Aβ40-Iowa (D23N) and …

Fenamates As Potential Therapeutics For Neurodegenerative Disorders, Jaunetta Hill, Nasser H. Zawia

Biomedical and Pharmaceutical Sciences Faculty Publications

Neurodegenerative disorders are desperately lacking treatment options. It is imperative that drug repurposing be considered in the fight against neurodegenerative diseases. Fenamates have been studied for efficacy in treating several neurodegenerative diseases. The purpose of this review is to comprehensively present the past and current research on fenamates in the context of neurodegenerative diseases with a special emphasis on tolfenamic acid and Alzheimer’s disease. Furthermore, this review discusses the major molecular pathways modulated by fenamates.

Current State Of Breast Cancer Diagnosis, Treatment, And Theranostics, Arya Bhushan, Andrea Gonsalves, Jyothi Menon

Biomedical and Pharmaceutical Sciences Faculty Publications

Breast cancer is one of the leading causes of cancer-related morbidity and mortality in women worldwide. Early diagnosis and effective treatment of all types of cancers are crucial for a positive prognosis. Patients with small tumor sizes at the time of their diagnosis have a significantly higher survival rate and a significantly reduced probability of the cancer being fatal. Therefore, many novel technologies are being developed for early detection of primary tumors, as well as distant metastases and recurrent disease, for effective breast cancer management. Theranostics has emerged as a new paradigm for the simultaneous diagnosis, imaging, and treatment of …

Advances In Lipid-Based Nanoparticles For Cancer Chemoimmunotherapy, Tianqi Wang, Yusuke Suite, Saradha Miriyala, Jordan Dean, Nikos Tapinos, Jie Shen

Biomedical and Pharmaceutical Sciences Faculty Publications

Nanomedicines have shown great potential in cancer therapy; in particular, the combination of chemotherapy and immunotherapy (namely chemoimmunotherapy) that is revolutionizing cancer treatment. Currently, most nanomedicines for chemoimmunotherapy are still in preclinical and clinical trials. Lipid-based nanoparticles, the most widely used nanomedicine platform in cancer therapy, is a promising delivery platform for chemoimmunotherapy. In this review, we introduce the commonly used immunotherapy agents and discuss the opportunities for chemoimmunotherapy mediated by lipid-based nanoparticles. We summarize the clinical trials involving lipid-based nanoparticles for chemoimmunotherapy. We also highlight different chemoimmunotherapy strategies based on lipid-based nanoparticles such as liposomes, nanodiscs, and lipid-based hybrid …

Sequence Dependent Repair Of 1,N6-Ethenoadenine By Dna Repair Enzymes Alkbh2, Alkbh3, And Alkb, Rui Qi, Ke Bian, Fangyi Chen, Qi Tang, Xianhao Zhou, Deyu Li

Biomedical and Pharmaceutical Sciences Faculty Publications

Mutation patterns of DNA adducts, such as mutational spectra and signatures, are useful tools for diagnostic and prognostic purposes. Mutational spectra of carcinogens derive from three sources: adduct formation, replication bypass, and repair. Here, we consider the repair aspect of 1,N⁶-ethenoadenine (εA) by the 2-oxoglutarate/Fe(II)-dependent AlkB family enzymes. Specifically, we investigated εA repair across 16 possible sequence contexts (5′/3′ flanking base to εA varied as G/A/T/C). The results revealed that repair efficiency is altered according to sequence, enzyme, and strand context (ss- versus ds-DNA). The methods can be used to study other aspects of mutational spectra or …

Isoform-Specific Effects Of Apolipoprotein E On Markers Of Inflammation And Toxicity In Brain Glia And Neuronal Cells In Vitro, Jaclyn Iannucci, Abhik Sen, Paula Grammas

Biomedical and Pharmaceutical Sciences Faculty Publications

Mutations to the cholesterol transport protein apolipoprotein E (ApoE) have been identified as a major risk factor for the development of sporadic or late-onset Alzheimer’s disease (AD), with the e4 allele representing an increased risk and the rare e2 allele having a reduced risk compared to the primary e3 form. The reasons behind the change in risk are not entirely understood, though ApoE4 has been connected to inflammation and toxicity in both the brain and the periphery. The goal of this study was to better understand how the ApoE isoforms (ApoE2/3/4) confer differential AD-related risk by assessing cell-specific ApoE-related neuroinflammatory …

Potentiation Of Recombinant Np And M1-Induced Cellular Immune Responses And Protection By Physical Radiofrequency Adjuvant, Yibo Li, Zhoufan Li, Yiwen Zhao, Xinyuan Chen

Biomedical and Pharmaceutical Sciences Faculty Publications

Nucleoprotein (NP) and matrix protein 1 (M1) are highly conserved among influenza A viruses and have been attractive targets to develop vaccines to elicit cross-reactive cytotoxic T lymphocytes (CTLs). Yet, external antigens are often presented on major histocompatibility complex class II molecules and elicit humoral immune responses. In this study, we present a physical radiofrequency adjuvant (RFA) to assist recombinant NP and M1 to elicit potent CTL responses. We found recombinant NP/M1 immunization in the presence of RFA could elicit potent anti-NP CTLs and confer significant protection against homologous viral challenges, while NP/M1 immunization alone failed to elicit significant CTL …

New Micropeptins With Anti-Neuroinflammatory Activity Isolated From A Cyanobacterial Bloom, Riley D. Kirk, Haiyin He, Paul G. Wahome, Shibiao Wu, Guy T. Carter, Matthew Bertin

Biomedical and Pharmaceutical Sciences Faculty Publications

Metabolite mining of environmentally collected aquatic and marine microbiomes offers a platform for the discovery of new therapeutic lead molecules. Combining a prefractionated chromatography library with liquid chromatography tandem mass spectrometry (LC-MS/MS)-based molecular networking and biological assays, we isolated and characterized two new micropeptins (1 and 2) along with the previously characterized micropeptin 996. These metabolites showed potency in anti-neuroinflammatory assays using BV-2 mouse microglial cells, showing a 50% reduction in inflammation in a range from 1 to 10 μM. These results show promise for cyanobacterial peptides in the therapeutic realm apart from their impact on environmental health and provide …

Feasibility Study For Detection Of Retinal Amyloid In Clinical Trials: The Anti-Amyloid Treatment In Asymptomatic Alzheimer's Disease (A4) Trial, Jennifer Ngolab, Michael Donohue, Alison Belsha, Jennifer Salazar, Paula Cohen, Sandhya Jaiswal, Veasna Tan, Devon Gessert, Shaina Korouri, Neelum T. Aggarwal, Jessica Alber, Ken Johnson, Gregory Jicha, Christopher Van Dyck, James Lah, Stephen Salloway, Reisa A. Sperling, Paul S. Aisen, Michael S. Rafii, Robert A. Rissman

Biomedical and Pharmaceutical Sciences Faculty Publications

Introduction: The retina and brain exhibit similar pathologies in patients diagnosed with neurodegenerative diseases. The ability to access the retina through imaging techniques opens the possibility for non-invasive evaluation of Alzheimer's disease (AD) pathology. While retinal amyloid deposits are detected in individuals clinically diagnosed with AD, studies including preclinical individuals are lacking, limiting assessment of the feasibility of retinal imaging as a biomarker for early-stage AD risk detection.

Methods:

In this small cross-sectional study we compare retinal and cerebral amyloid in clinically normal individuals who screened positive for high amyloid levels through positron emission tomography (PET) from the Anti-Amyloid Treatment …

Treprostinil Reduces Mitochondrial Injury During Rat Renal Ischemia-Reperfusion Injury, Meiwen Ding, Evelyn Tolbert, Mark Birkenbach, Reginald Gohh, Fatemeh Akhlaghi, Nisanne S. Ghonem

Biomedical and Pharmaceutical Sciences Faculty Publications

Background: Renal ischemia-reperfusion injury (IRI) is a major factor contributing to acute kidney injury and it is associated with a high morbidity and mortality if untreated. Renal IRI depletes cellular and tissue adenosine triphosphate (ATP), which compromises mitochondrial function, further exacerbating renal tubular injury. Currently, no treatment for IRI is available. This study investigates the protective role of treprostinil in improving mitochondria biogenesis and recovery during rat renal IRI.

Methods: Male Sprague Dawley rats were randomly assigned to groups: control, sham, IRI-placebo or IRI-treprostinil and subjected to 45 min of bilateral renal ischemia followed by 1–72 h reperfusion. Placebo or …

Octa Reveals Remodeling Of The Peripheral Capillary Free Zones In Normal Aging, Edmund Arthur, Jessica Alber, Louisa I. Thompson, Stuart Sinoff, Peter J. Snyder

Biomedical and Pharmaceutical Sciences Faculty Publications

The retinal neurovascular unit consists of blood vessel endothelial cells, pericytes, neurons, astrocytes, and Müller cells that form the inner retinal blood barrier. A peripheral capillary free zone (pCFZ) represents the distance that oxygen and nutrients must diffuse to reach the neural retina, and serves as a metric of retinal tissue oxygenation. The pCFZs are formed based on oxygen saturation in the retinal arterioles and venules. Because retinal arterioles contain a larger concentration of oxygenated blood than venules, there is a reduced need for capillaries to exist closely to arterioles compared to venules. Therefore, in a healthy individual, larger periarteriole …

Neuroendocrine Response To Exogenous Ghrelin Administration, Combined With Alcohol, In Heavy-Drinking Individuals: Findings From A Randomized, Double-Blind, Placebo-Controlled Human Laboratory Study, Mehdi Farokhnia, Kelly M. Abshire, Aaron Hammer, Sara L. Deschaine, Anitha Saravanakumar, Enoch Cobbina, Zhi-Bing You, Carolina L. Haass-Koffler, Mary R. Lee, Fatemeh Akhlaghi, Lorenzo Leggio

Biomedical and Pharmaceutical Sciences Faculty Publications

Background: Accumulating evidence has established a role for the orexigenic hormone ghrelin in alcohol-seeking behaviors. Accordingly, the ghrelin system may represent a potential pharmacotherapeutic target for alcohol use disorder. Ghrelin modulates several neuroendocrine pathways, such as appetitive, metabolic, and stress-related hormones, which are particularly relevant in the context of alcohol use. The goal of the present study was to provide a comprehensive assessment of neuroendocrine response to exogenous ghrelin administration, combined with alcohol, in heavy-drinking individuals.

Methods: This was a randomized, crossover, double-blind, placebo-controlled human laboratory study, which included 2 experimental alcohol administration paradigms: i.v. alcohol self-administration and i.v. alcohol …

Vaccine Delivery Alerts Innate Immune Systems For More Immunogenic Vaccination, Zhoufan Li, Yan Cao, Yibo Li, Yiwen Zhao, Xinyuan Chen

Biomedical and Pharmaceutical Sciences Faculty Publications

Vaccine delivery technologies are mainly designed to minimally invasively deliver vaccines to target tissues with little or no adjuvant effects. This study presents a prototype laser-based powder delivery (LPD) with inherent adjuvant effects for more immunogenic vaccination without incorporation of external adjuvants. LPD takes advantage of aesthetic ablative fractional laser to generate skin microchannels to support high-efficient vaccine delivery and at the same time creates photothermal stress in microchannel-surrounding tissues to boost vaccination. LPD could significantly enhance pandemic influenza 2009 H1N1 vaccine immunogenicity and protective efficacy as compared with needle-based intradermal delivery in murine models. The ablative fractional laser was …

Small Molecule Inhibitors Against Pd-1/Pd-L1 Immune Checkpoints And Current Methodologies For Their Development: A Review, Chang Liu, Navindra P. Seeram, Hang Ma

Biomedical and Pharmaceutical Sciences Faculty Publications

Programmed death-1/programmed death ligand-1 (PD-1/PD-L1) based immunotherapy is a revolutionary cancer therapy with great clinical success. The majority of clinically used PD-1/PD-L1 inhibitors are monoclonal antibodies but their applications are limited due to their poor oral bioavailability and immune-related adverse effects (irAEs). In contrast, several small molecule inhibitors against PD-1/PD-L1 immune checkpoints show promising blockage effects on PD-1/PD-L1 interactions without irAEs. However, proper analytical methods and bioassays are required to effectively screen small molecule derived PD-1/PD-L1 inhibitors. Herein, we summarize the biophysical and biochemical assays currently employed for the measurements of binding capacities, molecular interactions, and blocking effects of small …

Synthesis And Biological Evaluations Of Oleanolic Acid Indole Derivatives As Hyaluronidase Inhibitors With Enhanced Skin Permeability, Hao He, Huifang Li, Toyosi Akanji, Shengli Niu, Zhujun Luo, Dongli Li, Navindra P. Seeram, Panpan Wu, Hang Ma

Biomedical and Pharmaceutical Sciences Faculty Publications

Oleanolic acid (OA) is a natural cosmeceutical compound with various skin beneficial activities including inhibitory effect on hyaluronidase but the anti-hyaluronidase activity and mechanisms of action of its synthetic analogues remain unclear. Herein, a series of OA derivatives were synthesised and evaluated for their inhibitory effects on hyaluronidase. Compared to OA, an induction of fluorinated (6c) and chlorinated (6g) indole moieties led to enhanced anti-hyaluronidase activity (IC50 = 80.3 vs. 9.97 and 9.57 µg/mL, respectively). Furthermore, spectroscopic and computational studies revealed that 6c and 6g can bind to hyaluronidase protein and alter its secondary structure leading …