Life Sciences Commons^™

Host-Level Susceptibility And Irf1 Expression Influence The Ability Of Ifn-Γ To Inhibit Kshv Infection In B Lymphocytes, Nedaa Alomari, Jennifer Totonchy

Pharmacy Faculty Articles and Research

Kaposi’s sarcoma-associated herpesvirus (KSHV) is associated with vascular endothelial cell tumor, Kaposi’s sarcoma (KS) and lymphoproliferative disorder, multicentric Castleman’s disease (MCD), primary effusion lymphoma (PEL) and KSHV inflammatory cytokine syndrome (KICS). Dysregulation of proinflammatory cytokines is found in most KSHV associated diseases. However, little is known about the role of host microenvironment in the regulation of KSHV establishment in B cells. In the present study, we demonstrated that IFN-γ has a strong inhibitory effect on KSHV infection but only in a subset of tonsil-derived lymphocyte samples that are intrinsically more susceptible to infection, contain higher proportions of naïve B cells, …

Chemical Relaxers And Hair-Straightening Products: Potential Targets For Hormone-Related Cancer Prevention And Control, Adana A. M. Llanos, Jasmine A. Mcdonald, Dede K. Teteh, Traci N. Bethea

Health Sciences and Kinesiology Faculty Articles

"Emerging data show that use of permanent hair dyes, chemical relaxers, and straightening products might contribute to increased risk of hormone-related cancers (1-5) and potentially breast tumors with features indicative of more aggressive phenotypes (6). Given the wide use of these products globally, they are an important source of exposure to potentially harmful chemicals, including endocrine-disrupting chemicals—to which we are ubiquitously exposed (7)—and mutagenic and/or genotoxic compounds. The unequal burden of exposure across populations plausibly contributes to cancer inequities as the groups with the greatest exposure also experience poorer cancer outcomes (8). …

Subtype-Selective Positive Modulation Of KCa2.3 Channels Increases Cilia Length, Young-Woo Nam, Rajasekharreddy Pala, Naglaa Salem El-Sayed, Denisse Laren-Henriquez, Farideh Amirrad, Grace Yang, Mohammad Asikur Rahman, Razan Orfali, Myles Downey, Keykavous Parang, Surya M. Nauli, Miao Zhang

Pharmacy Faculty Articles and Research

Small-conductance Ca²⁺-activated potassium (K_Ca2.x) channels are gated exclusively by intracellular Ca²⁺. The activation of K_Ca2.3 channels induces hyperpolarization, which augments Ca²⁺ signaling in endothelial cells. Cilia are specialized Ca²⁺ signaling compartments. Here, we identified compound 4 that potentiates human K_Ca2.3 channels selectively. The subtype selectivity of compound 4 for human K_Ca2.3 over rat K_Ca2.2a channels relies on an isoleucine residue in the HA/HB helices. Positive modulation of K_Ca2.3 channels by compound 4 increased flow-induced Ca²⁺ signaling and cilia length, while negative …

Gaps In Patient Education On Safe Handling And Disposal Of Oral Chemotherapy Drugs: A Pilot Prospective Cohort Survey Study, Sun Yang, Priya Patel, Alexandra Corcoran, Eric Dobberpuhl, Samantha Isidro, Dustin Le, Analise Klassen, Jay Rho, David Tran, Richard Beuttler, Neda Noori Nassr, Katherine Gruenberg, Siu-Fun Wong

Pharmacy Faculty Articles and Research

Background

Oral anticancer chemotherapy (OC) has been misperceived as being safer than intravenous chemotherapy, leading to its increased risk of improper handling and disposal. This survey study assessed the knowledge, practices and attitudes of pharmacists and patients regarding OC handling and disposal, gaps in knowledge and barriers to patient education. Methods

Surveys were developed based on literature review and pilot study validation results. Patients completed a 33-item paper or electronic survey whereas pharmacists completed a 38-item electronic survey. Descriptive statistics and Fisher’s exact test computed using the R Project were used for analyses. Results

Pharmacist group (16/25, 62.5%) and patient …

Identifying A Glucocorticoid-Activated Gpcr That Rapidly And Non-Genomically Increases Camp Levels In Mammalian Cells, Francisco Nunez

Pharmaceutical Sciences (PhD) Dissertations

Glucocorticoids (GCs) are steroid hormones that regulate diverse physiological processes. Synthetic versions of GCs are commonly used to treat inflammatory diseases such as asthma by modulating gene expression to suppressing several inflammatory activities. However, it is estimated that 5-10% of asthmatics are unresponsive to GCs, which may be explained by receptor desensitization and/or the presence of a neutrophilic endotype. One understudied phenomenon of GCs is their ability to induce rapid, non-genomic actions. For example, GCs can acutely modulate calcium concentrations levels, induce smooth muscle relaxation and modulate nitric oxide synthase activity, within minutes and sometimes seconds, which is too rapid …

Ciliogenesis Mechanisms Mediated By Pak2-Arl13b Signaling In Brain Endothelial Cells Is Responsible For Vascular Stability, Karthikeyan Thirugnanam, Shubhangi Prabhudesai, Emma Van Why, Amy Pan, Ankan Gupta, Koji Foreman, Rahima Zennadi, Kevin R. Rarick, Surya M. Nauli, Sean P. Palacek, Ramani Ramchandran

Pharmacy Faculty Articles and Research

In the developing vasculature, cilia, microtubule-based organelles that project from the apical surface of endothelial cells (ECs), have been identified to function cell autonomously to promote vascular integrity and prevent hemorrhage. To date, the underlying mechanisms of endothelial cilia formation (ciliogenesis) are not fully understood. Understanding these mechanisms is likely to open new avenues for targeting EC-cilia to promote vascular stability. Here, we hypothesized that brain ECs ciliogenesis and the underlying mechanisms that control this process are critical for brain vascular stability. To investigate this hypothesis, we utilized multiple approaches including developmental zebrafish model system and primary cell culture systems. …

Comparative Studies Between The Murine Immortalized Brain Endothelial Cell Line (Bend.3) And Induced Pluripotent Stem Cell-Derived Human Brain Endothelial Cells For Paracellular Transport, Jiahong Sun, Weijun Ou, Derick Han, Annlia Paganini-Hill, Mark J. Fisher, Rachita K. Sumbria

Pharmacy Faculty Articles and Research

Brain microvascular endothelial cells, forming the anatomical site of the blood-brain barrier (BBB), are widely used as in vitro complements to in vivo BBB studies. Among the immortalized cells used as in vitro BBB models, the murine-derived bEnd.3 cells offer culturing consistency and low cost and are well characterized for functional and transport assays, but result in low transendothelial electrical resistance (TEER). Human-induced pluripotent stem cells differentiated into brain microvascular endothelial cells (ihBMECs) have superior barrier properties, but the process of differentiation is time-consuming and can result in mixed endothelial-epithelial gene expression. Here we performed a side-by-side comparison of the …

Cytotoxic Activity Of Non-Specific Lipid Transfer Protein (Nsltp1) From Ajwain (Trachyspermum Ammi) Seeds, Saud O. Alshammari, Taibah Aldakhil, Qamar A. Alshammari, David Salehi, Aftab Ahmed

Pharmacy Faculty Articles and Research

Background

Trachyspermum ammi, commonly known as Ajwain, is a member of the Apiaceae family. It is a therapeutic herbal spice with diverse pharmacological properties, used in traditional medicine for various ailments. However, all previous studies were conducted using small molecule extracts, leaving the protein’s bioactivity undiscovered.

Aim

The current study aimed to demonstrate the cytotoxic activity of Ajwain non-specific lipid transfer protein (nsLTP1) in normal breast (MCF10A), breast cancer (MCF-7), and pancreatic cancer (AsPC-1) cell lines. Also, to evaluate its structural stability in human serum as well as at high temperature conditions.

Methods

The cytotoxic activity of Ajwain nsLTP1 was …

A Small Peptide Increases Drug Delivery In Human Melanoma Cells, Shirley Tong, Shaban Darwish, Hanieh Hossein Nejad Ariani, Kate Alison Lozada, David Salehi, Maris A. Cinelli, Richard B. Silverman, Kamaljit Kaur, Sun Yang

Pharmacy Faculty Articles and Research

Melanoma is the most fatal type of skin cancer and is notoriously resistant to chemotherapies. The response of melanoma to current treatments is difficult to predict. To combat these challenges, in this study, we utilize a small peptide to increase drug delivery to melanoma cells. A peptide library array was designed and screened using a peptide array-whole cell binding assay, which identified KK-11 as a novel human melanoma-targeting peptide. The peptide and its D-amino acid substituted analogue (VPWxEPAYQrFL or D-aa KK-11) were synthesized via a solid-phase strategy. Further studies using FITC-labeled KK-11 demonstrated dose-dependent uptake in human melanoma cells. D-aa …

Characterization Of Gangliosides And Fatty Acids In Extracellular Vesicles From Human Milk, Aliya Amin

Food Science (MS) Theses

Extracellular vesicles (EVs) are bioactive components of human milk that may impact functionality to regulate growth, cognitive development, metabolism, and immunity in newborns. The biogenesis of EVs and the mechanism by which EVs elicit biologic effects in vivo have not been characterized entirely. Gangliosides and fatty acids are integral in the formation, release, stability, and functionalities of EVs. Presumably, EV function is related to EV composition and lipids in EVs influence the bioavailability of EV cargo and downstream functions of EVs. The objective of this research was to characterize the fatty acid and ganglioside composition of EVs in human milk. …

Bis-Cinnamamide Derivatives As Ape/Ref-1 Inhibitors For The Treatment Of Human Melanoma, Razan Alhazmi, Shirley Tong, Shaban Darwish, Elina Khanjani, Bharti Khungar, Swati Chawla, Zhonghui Zheng, Richard Chamberlain, Keykavous Parang, Sun Yang

Pharmacy Faculty Articles and Research

Human malignant melanoma exhibits imbalances in redox status, leading to activation of many redox-sensitive signaling pathways. APE/Ref-1 is a multifunctional protein that serves as a redox chaperone that regulates many nuclear transcription factors and is an important mechanism in cancer cell survival of oxidative stress. Previous studies showed that APE/Ref-1 is a potential druggable target for melanoma therapy. In this study, we synthesized a novel APE/Ref-1 inhibitor, bis-cinnamoyl-1,12-dodecamethylenediamine (2). In a xenograft mouse model, compound 2 treatment (5 mg/kg) significantly inhibited tumor growth compared to the control group, with no significant systemic toxicity observed. We further synthesized compound …

Amphiphilic Cell-Penetrating Peptides Containing Natural And Unnatural Amino Acids As Drug Delivery Agents, David Salehi, Saghar Mozaffari, Khalid Zoghebi, Sandeep Lohan, Dindyal Mandal, Rakesh Tiwari, Keykavous Parang

Pharmacy Faculty Articles and Research

A series of cyclic peptides, [(DipR)(WR)₄], [(DipR)₂(WR)₃], [(DipR)₃(WR)₂], [(DipR)₄(WR)], and [DipR]₅, and their linear counterparts containing arginine (R) as positively charged residues and tryptophan (W) or diphenylalanine (Dip) as hydrophobic residues, were synthesized and evaluated for their molecular transporter efficiency. The in vitro cytotoxicity of the synthesized peptides was determined in human epithelial ovary adenocarcinoma cells (SK-OV-3), human lymphoblast peripheral blood cells (CCRF-CEM), human embryonic epithelial kidney healthy cells (HEK-293), human epithelial mammary gland adenocarcinoma cells (MDA-MB-468), pig epithelial kidney normal cells (LLC-PK1), and human epithelial …

Endocrine-Disrupting Chemicals And Breast Cancer: Disparities In Exposure And Importance Of Research Inclusivity, Ashlie Santaliz Casiano, Annah Lee, Dede Teteh, Zeynep Madak Erdogan, Lindsey Trevino

Health Sciences and Kinesiology Faculty Articles

Endocrine-disrupting chemicals (EDCs) are known contributors to breast cancer development. EDC exposures commonly occur through food packaging, cookware, fabrics, and personal care products as well as through the environment. Increasing evidence highlights disparities in EDC exposure across racial/ethnic groups, yet breast cancer research continues to lack the inclusion necessary to positively impact treatment response and overall survival in these socially disadvantaged populations. Additionally, the inequity in environmental exposures has yet to be remedied. Exposure to EDCs due to structural racism poses an unequivocal risk to marginalized communities. In this review, we summarize recent epidemiological and molecular studies on two lesser-studied …

Escherichia Coli Alanyl-Trna Synthetase Maintains Proofreading Activity And Translational Accuracy Under Oxidative Stress, Arundhati Kavoor, Paul Kelly, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Aminoacyl-tRNA synthetases (aaRSs) are enzymes that synthesize aminoacyl-tRNAs to facilitate translation of the genetic code. Quality control by aaRS proofreading and other mechanisms maintains translational accuracy, which promotes cellular viability. Systematic disruption of proofreading, as recently demonstrated for alanyl-tRNA synthetase (AlaRS), leads to dysregulation of the proteome and reduced viability. Recent studies showed that environmental challenges such as exposure to reactive oxygen species can also alter aaRS synthetic and proofreading functions, prompting us to investigate if oxidation might positively or negatively affect AlaRS activity. We found that while oxidation leads to modification of several residues in Escherichia coli AlaRS, unlike …

Cilia Proteins Are Biomarkers Of Altered Flow In The Vasculature, Ankan Gupta, Karthikeyan Thirugnanam, Madhan Thamilarasan, Ashraf M. Mohieldin, Hadeel T. Zedan, Shubhangi Prabhudesai, Meghan R. Griffin, Andrew D. Spearman, Amy Pan, Sean P. Palecek, Huseyin C. Yalcin, Surya M. Nauli, Kevin R. Rarick, Rahima Zennadi, Ramani Ramchandran

Pharmacy Faculty Articles and Research

Cilia, microtubule-based organelles that project from the apical luminal surface of endothelial cells (ECs), are widely regarded as low-flow sensors. Previous reports suggest that upon high shear stress, cilia on the EC surface are lost, and more recent evidence suggests that deciliation—the physical removal of cilia from the cell surface—is a predominant mechanism for cilia loss in mammalian cells. Thus, we hypothesized that EC deciliation facilitated by changes in shear stress would manifest in increased abundance of cilia-related proteins in circulation. To test this hypothesis, we performed shear stress experiments that mimicked flow conditions from low to high shear stress …

Inhibition Of Interferon-Gamma-Stimulated Melanoma Progression By Targeting Neuronal Nitric Oxide Synthase (Nnos), Shirley Tong, Maris A. Cinelli, Naglaa Salem El-Sayed, He Huang, Anika Patel, Richard B. Silverman, Sun Yang

Pharmacy Faculty Articles and Research

Interferon-gamma (IFN-γ) is shown to stimulate melanoma development and progression. However, the underlying mechanism has not been completely defined. Our study aimed to determine the role of neuronal nitric oxide synthase (nNOS)-mediated signaling in IFN-γ-stimulated melanoma progression and the anti-melanoma effects of novel nNOS inhibitors. Our study shows that IFN-γ markedly induced the expression levels of nNOS in melanoma cells associated with increased intracellular nitric oxide (NO) levels. Co-treatment with novel nNOS inhibitors effectively alleviated IFN-γ-activated STAT1/3. Further, reverse phase protein array (RPPA) analysis demonstrated that IFN-γ induced the expression of HIF1α, c-Myc, and programmed death-ligand 1 (PD-L1), in contrast …

Conformational Flexibility And Local Frustration In The Functional States Of The Sars-Cov-2 Spike B.1.1.7 And B.1.351 Variants: Mutation-Induced Allosteric Modulation Mechanism Of Functional Dynamics And Protein Stability, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

Structural and functional studies of the SARS-CoV-2 spike proteins have recently determined distinct functional states of the B.1.1.7 and B.1.351 spike variants, providing a molecular framework for understanding the mechanisms that link the effect of mutations with the enhanced virus infectivity and transmissibility. A detailed dynamic and energetic analysis of these variants was undertaken in the present work to quantify the effects of different mutations on functional conformational changes and stability of the SARS-CoV-2 spike protein. We employed the efficient and accurate coarse-grained (CG) simulations of multiple functional states of the D614G mutant, B.1.1.7 and B.1.351 spike variants to characterize …