Pharmacology Commons^™

Particulate Hexavalent Chromium Inhibits Homologous Recombination Repair By Targeting Rad51 Paralogs In Human Lung Fibroblasts., Aggie R. Williams

Electronic Theses and Dissertations

Hexavalent Chromium [Cr(VI)] is a known human lung carcinogen and general health hazard. The mechanism of carcinogenesis remains poorly understood, but chromosome instability (CIN) is the major theory in its carcinogenic mechanism. Homologous recombination (HR) repair is a DNA repair pathway that prevents CIN by repairing DNA double-strand breaks. RAD51, a key mediator protein of HR repair, along with the RAD51 paralogs (RAD51B, C, D, XRCC2, and 3) are required for HR repair. During HR, RAD51 loads and forms a helical nucleoprotein filament structure to promote DNA strand exchange and stimulate pairing activity of DNA. Cr(VI) exposures have been shown …

Targeting Neuronal Nitric Oxide Synthase (Nnos) For Melanoma Treatment, Shirley Tong

Pharmaceutical Sciences (PhD) Dissertations

Human cutaneous melanoma is the most aggressive form of skin cancer and the incidence rates have continued to increase over the years. Neuronal nitric oxide synthase (nNOS) produces nitric oxide (NO) has been found to be overexpressed in human melanoma and the expression of nNOS is induced by interferon-gamma (IFN-γ). In our studies, nNOS has been implicated in IFN-γ-stimulated melanoma progression and the inhibition of nNOS using novel inhibitors effectively inhibited IFN-γ-stimulated tumor growth in a xenograft mouse model. Programmed death-ligand 1 (PD-L1) is overexpressed in melanoma and plays an important role in suppressing the immune system ^12-14. Our …

Evaluation Of Biochemical And Pathological Parameters At Different Doses Of Cisplatin In Experimental Animal Model: Toxicological Study On An Antineoplastic Drug, Farhana Sultana, Muhammed Mohibul Islam, Mohammad Nurul Amin, Nusrat Jahan, Asma Kabir, Talha Bin Emran, Bibek Chandra Sutradhar, Sujan Banik

Makara Journal of Health Research

Background: This study aimed to assess the effect of cisplatin-induced toxicities on biochemical and pathological parameters such as body, liver, and kidney weights, blood urea nitrogen (BUN), creatinine, alanine aminotransferase (ALT), and blood cells (RBCs and WBCs) in white Swiss albino mice.

Methods: Cisplatin’s potential toxic effects on body, liver, and kidney weights were evaluated using standard laboratory methods. Blood biochemical levels such as BUN, creatinine, and ALT levels were determined by an auto-hemolyzer using commercial diagnostic kits. Blood cells (RBCs and WBCs) were counted under a microscope by a hemocytometer.

Results: Cisplatin’s potential toxic effects on …

Exchange Protein Directly Activated By Camp (Epac1) Protects Human Endothelial Cells From Tumor Necrosis Factor-⍺ (Tnf-⍺) Induced Cell Death, Anh Luu, Abigail Carpenter, Rosetta Tolley

ONU Student Research Colloquium

Millions of people are affected by diseases involving inflammatory states such as sepsis. Sepsis is associated with elevated tumor necrosis factor alpha (TNF-⍺) which mediates inflammation. Excessive TNF-⍺ contributes to death of endothelial cells (EC) with subsequent disruption of vascular endothelial function. Exchange Factor Directly Activated by cAMP (EPAC1) is a cyclic-AMP (cAMP) sensor that regulates multiple EC functions. We hypothesized that EPAC1 activation affects the response of EC to TNF-a. Microvascular EC were pretreated for 45 minutes with 100 mM 8-pCPT-2′-O-Me-cAMP (8-CPT, specific EPAC1 activator) or 10 mM forskolin (adenylyl cyclase activator that increases cAMP), then exposed to 5 …

Study Proposal For Additional Investigation Of Epac1 In Endothelial Apoptosis, Anh Luu

ONU Student Research Colloquium

Inflammatory states such as sepsis are associated with elevated tumor necrosis factor alpha (TNF-⍺), which facilitates inflammation, increases the production of reactive oxygen species (ROS) and oxidative stress, and contributes to death of endothelial cells (EC). Exchange Factor Directly Activated by cAMP (EPAC1) is an intracellular cyclic-AMP (cAMP) sensor involved in EC responses such as barrier function, angiogenesis and proliferation. Previous studies in our lab demonstrated activation of EPAC1 protected EC from TNF⍺-induced cell death. Specifically, microvascular EC were pretreated for 45 minutes with 100 mM 8-pCPT-2′-O-Me-cAMP (8CPT, specific EPAC1 activator) or 10 mM forskolin (adenylyl cyclase activator that increases …

The Efficacy And Safety Of Roxadustat For The Treatment Of Anemia In Non-Dialysis Dependent Chronic Kidney Disease Patients: An Updated Systematic Review And Meta-Analysis Of Randomized Clinical Trials, Basel Abdelazeem, Joseph Shehata, Kirellos Said Abbas, Nahla Ahmed El-Shahat, Bilal Malik, Pramod Savarapu, Mostafa Eltobgy, Arvind Kunadi

School of Medicine Faculty Publications

Background Roxadustat (ROX) is a new medication for anemia as a complication of chronic kidney disease (CKD). Our meta-analysis aims to evaluate the efficacy and safety of ROX, especially on the cardiovascular risks, for anemia in NDD-CKD patients. Methods Electronic databases were searched systematically from inception to July 2021 to look for randomized control trials (RCTs) that evaluated ROX NDD-CKD patients. Hemoglobin level and iron utilization parameters, including ferritin, serum iron, transferrin saturation (TSAT), total iron-binding capacity (TIBC), transferrin, and hepcidin were analyzed for efficacy. Pooled risk ratios (RRs) and standardized mean differences (SMDs) were calculated and presented with their …

Targeting Delivery Of Bcl-2 Family Protein Inhibitor Has The Potential To Treat Cancer And Fibrosis, Mohammad Nurul Huda

Open Access Theses & Dissertations

Apoptosis is a naturally occurring cell death mechanism to remove the selective cell population. B-cell leukemia/lymphoma-2 (BCL-2) family protein plays a critical role in activating the upstream apoptosis signaling pathway, primarily the intrinsic apoptosis pathway. The BCL-2 family consists of both pro-and anti-apoptotic proteins, which are structurally and functionally similar, containing up to four BCL-2 homologies (BH) motifs (BH1-4). Defecting apoptosis along this signaling pathway can lead to various events, including malignant cell transformation, tumor metastasis, tissue fibrosis, and drug resistance. In fibrosis, the aberrant apoptosis signaling also activates multiple effector proteins and growth factors, such as TGF-β, CTGF, and …

Antibacterial, Hemagglutination, And Insecticidal Activity Studies On The Solvent Extracts Of The Roots Of Olea Ferruginea, Muhammad Yaseen, Muhammad Kamran, Arshad Farid, Salmah Ismail, Muhammad Muzammal, Kamal Abdul Amir, Muhammad Hashim Khan, Sohail Ahmad, Sheikh Abdur Rashid

Makara Journal of Science

Olea ferruginea has been used to treat skin ailments, as well as kidney and ocular problems for a long time. The current study was designed with the aim of investigating and scientifically validating its widespread use. Chloroform, n-hexane, and ethyl acetate were used to assess the antibacterial, hemagglutination, and insecticidal properties of O. ferruginea roots. Escherichia coli, Micrococcus luteus, Klebsiella pneumoniae, and Pseudomonas aeruginosa were among the bacterial strains selected for assessing antibacterial activity. The results showed that ethyl-acetate (EtOAc) extract (56%) and chloroform (CHCl₃) extract (56%) showed the widest zone of inhibition against …

Efforts To Increase The Ketamine-Like Activity Of The Rapid-Acting Antidepressant Ro-25-6981 (Mi-4) By Increasing Ampa Potentiation, Nathan Heger

Annual Research Symposium

The small molecule ketamine has generated much interest due to its rapid antidepressant effects. Despite having a rapid onset, ketamine has poor bioavailability, short duration of action, toxicities with long-term use, and a high potential for abuse. The molecule MI-4 (RO 25-6981) has also been shown to have both a rapid and sustained antidepressant effect. Most of the research into the mechanism of the rapid onset of MI-4 and ketamine has focused on their interaction with the NMDA receptor in addition to some monoamine transporters. Some recent publications have shown a significant role of AMPA receptors in the ketamine antidepressant …

The Use Of Atmospheric-Pressure Chemical Ionization For Pesticide Analysis Using Liquid Chromatography Mass Spectrometry, Pei-Ting Jiang, Kuan-Lu Wu, Hsueh-Ting Wang, Sung-Fang Chen

Journal of Food and Drug Analysis

Based on the regulations of the Ministry of Health and Welfare (MOHW) of Taiwan in 2017, an analysis of 373 pesticides in food was conducted using the MOHW official method. The analyses involved the use of either liquid chromatography mass spectrometry (LC-MS) with electrospray ionization (ESI) or gas chromatography mass spectrometry (GC-MS) with electron ionization (EI). In this study, the applicability of detecting pesticides using atmospheric pressure chemical ionization (APCI) was investigated and evaluated. The pesticides were separated using an aqueous solution of ammonium formate with methanol as the mobile phase, and ionization efficiency was compared between APCI, ESI, and …

A Substructure-Based Screening Approach To Uncover N-Nitrosamines In Drug Substances, Yu-Ting Kao, Shu-Fen Wang, Meng-Hsiu Wu, Shwu-Huey Her, Yi-Hsuan Yang, Chung-Hsien Lee, Hsiao-Feng Lee, An-Rong Lee, Li-Chien Chang, Li-Heng Pao

Journal of Food and Drug Analysis

Drug substances are at risk of contamination with N-nitrosamines (NAs), well-known carcinogenic agents, during synthesis processes and/or long-term storage. Therefore, in this study, we developed an efficient data-based screening approach to systemically assess marketed products and investigated its scalability for benefiting both regulatory agencies and pharmaceutical industries. A substructure-based screening method employing DataWarrior, an open-source software, was established to evaluate the risks of NA impurities in drug substances. Eight NA substructures containing susceptible amino sources for N-nitrosation have been identified as screening targets: dimethylamine (DMA), diethylamine, isopropylethylamine, diisopropylamine, N-methyl-2-pyrrolidone, dibutylamine, methylphenylamine, and tetrazoles. Our method detected 192 drug …

Repurposing Lansoprazole And Posaconazole To Treat Leishmaniasis: Integration Of In Vitro Testing, Pharmacological Corroboration, And Mechanisms Of Action, Yash Gupta, Steven Goicoechea, Jesus G. Romero, Raman Mathur, Thomas R. Caulfield, Daniel P. Becker, Ravi Durvasula, Prakasha Kempaiah

Journal of Food and Drug Analysis

Leishmaniasis remains a serious public health problem in many tropical regions of the world. Among neglected tropical diseases, the mortality rate of leishmaniasis is second only to malaria. All currently approved therapeutics have toxic side effects and face rapidly increasing resistance. To identify existing drugs with antileishmanial activity and predict the mechanism of action, we designed a drug-discovery pipeline utilizing both in-silico and in-vitro methods. First, we screened compounds from the Selleckchem Bio-Active Compound Library containing ~1,622 FDA-approved drugs and narrowed these down to 96 candidates based on data mining for possible anti-parasitic properties. Next, we completed preliminary in-vitro testing …

Effect Of Repeated Shengmai-San Administration On Nifedipine Pharmacokinetics And The Risk/Benefit Under Co-Treatment, Hong-Jaan Wang, Elise Chia-Hui Tan, Tzu-Yi Chiang, Wei-Ching Chen, Chien-Chang Shen, Yune-Fang Ueng

Journal of Food and Drug Analysis

Herbal interactions with nifedipine/felodipine through cytochrome P450 (CYP) 3A inhibition is significant in humans. Shengmai-San (SMS), a three-herbal formula of Chinese medicine, is commonly prescribed in Asia populations for cardiovascular disorders. This study aimed to elucidate the impact of SMS on nifedipine/felodipine treatment by the findings from rat pharmacokinetic study of nifedipine to the retrospective cohort study of patients with hypertension. The 3-week SMS treatment increased the systemic exposure to nifedipine by nearly two-fold and decreased nifedipine clearance by 39% in rats. Among the ingredients of SMS component herbs, schisandrin B, schisantherin A, and methylophiopogonanone A, inhibited the nifedipine oxidation …

Evaluation Of Opioid Consumption Trends For Pain In Taiwan And Comparison With Neighboring Asian Countries, Jhi-Joung Wang, Shu-Fang Teng, Yu-Roo Chu, Chin-Chen Chu, Chung-Han Ho, Li-Ling Chu

Journal of Food and Drug Analysis

Opioids are effective analgesics for pain relief, however, inappropriate use may cause risks. The aims of the study were to evaluate trends of opioid consumption for pain management in Taiwan and compare them among neighboring Asian countries. Opioid consumption data, including fentanyl, morphine, oxycodone, hydromorphone, codeine, and pethidine, were collected from the Controlled Drugs Management Information System of Taiwan Food and Drug Administration from 2008 to 2018. Data of different continents and neighboring Asian countries were retrieved from the WHO website. The major findings include: (1) In Taiwan, the total annual opioid consumption has gradually increased from 2008 to 2018, …

A Three-Step Stacking Capillary Electrophoresis Of Field-Amplified Sample Injection, Sweeping, And Micellar Collapse For Determination Of Dabigatran And Its Active Metabolite In Human Plasma, Cheng-Wei Cheng, Wen-Han Feng, Wei-Hua Tang, Hwang-Shang Kou, Chun-Chi Wang, Shou-Mei Wu

Journal of Food and Drug Analysis

A three-step stacking capillary electrophoresis (CE) composed of field-amplified sample injection, sweeping, and analyte focusing by micellar collapse (FASI-sweeping-AFMC) was developed to determine dabigatran (D) and its major active metabolite, dabigatran acyl-beta-d-glucuronide (DAG), in human plasma. After optimization and validation, this novel approach was further applied to monitor 5 real samples, and the 25.2 to 186.8 ng mL^-1 D could be observed among those. Based on these results, the novel CE stacking strategy was successfully applied for the analysis of D and DAG in human plasma and could be served as a tool for clinical assays.

The Antihyperlipidemic Equivalent Combinatorial Components From Peel Of Citrus Reticulata ‘Chachi’, Ping-Ting Xiao, Yu-Jia Kuang, Shi-Yu Liu, Zhi-Shen Xie, Jin-Hua Hao, E-Hu Liu

Journal of Food and Drug Analysis

Since the combinatorial components responsible for the antihyperlipidemic activity of Citrus reticulata‘Chachi’ (CRC) peels remains unclear, we herein developed a bioactive equivalence oriented feedback screening method to discover the bioactive equivalent combinatorial components (BECCs) from CRC peels. Using palmitic acid (PA)- stimulated hepatocyte model, a combination of five polymethoxyflavones (PMFs) including tangeretin, sinensetin, nobiletin, 5,7,8,4′-tetramethoxyflavone and 3,5,6,7,8,3',4'-heptamethoxyflavone was identified to be responsible for the antihyperlipidemic effect of CRC peels. Via evaluation of combination effect by combination index (CI), these 5 PMFs were found to take effect via a synergistic mode. Our data indicated that the antihyperlipidemic mechanism of PMF …

Food Glycomics: Dealing With Unexpected Degradation Of Oligosaccharides During Sample Preparation And Analysis, Yu-Ping Huang, Randall C. Robinson, Daniela Barile

Journal of Food and Drug Analysis

This study reveals that unexpected degradation of food oligosaccharides can occur during conventional glycomics workflows, including sample preparation and analysis by liquid chromatography-mass spectrometry (LC-MS). With the present investigation, we aim to alert the scientific community of the susceptibility of specific glycosidic linkages to degradation induced by heat and acid. Key standard oligosaccharides representing the major types found in foods (3’-sialyllactose and 6’-sialyl-N-acetyllactosamine for milk, raffinose and stachyose for legumes) were selected as model systems and underwent each of the following treatments independently: (1) labeled with the derivatizing agent 1-aminopyrene-3,6,8-trisulfonic (APTS) (followed by analysis with a capillary electrophoresis system coupled …

Ulva Prolifera Polysaccharide Exerts Anti-Obesity Effects Via Upregulation Of Adiponectin Expression And Gut Microbiota Modulation In High-Fat Diet-Fed C57bl/6 Mice, Hai-Ching Pung, Wei-Sheng Lin, Yi-Chen Lo, Cheng-Chih Hsu, Chi-Tang Ho, Min-Hsiung Pan

Journal of Food and Drug Analysis

Obesity is characterized by metabolic disorder and accompanying an altered and less diverse gut microbiota composition during a fat-enriched diet. Recent studies indicated that sulphated polysaccharide prevents high-fat diet (HFD) induced obesity, reduces metabolic disorder, and restores the gut microbiota. However, there are few studies about Ulva prolifera polysaccharide (UPP) may induce anti-obesogenic effects. Therefore, the present study investigates the enzymatic extracted UPP effects in HFD-fed mice. The results showed that UPP considerably slowed down the HFD-induced weight gain and improved metabolic disorders in HFD-fed mice. Notably, the effects were associated with lower body weight gain, reduced adipose tissue hypertrophy, …

Stable Carbon Isotopic Characterization Of Rice Vinegar Protein As An Intrinsic Reference For Discriminating The Authenticity Of Brewed Rice Vinegar, Chun-Jen Fang, Hsin-Cheng You, Zih-Ling Huang, Che-Lun Hsu, Chia-Fen Tsai, Ya-Tze Lin, Ya-Min Kao, Su-Hsiang Tseng, Der-Yuan Wang, Nan-Wei Su

Journal of Food and Drug Analysis

Rice vinegar plays an important role in daily life. However, some unscrupulous manufacturers may deliberately add synthetic acetic acid in vinegar products to reduce fermentation time and save production costs. To protect the rights and health of consumers, vinegar authenticity must be controlled. The rice vinegar protein was used as an intrinsic reference and its stable carbon isotope ratio (δ¹³C_protein) was analyzed by elemental analyzer-isotope ratio mass spectrometry. The stable carbon isotope ratio difference between the acetic acid and the rice vinegar protein (Δδ¹³C_{acetic acid-protein}) was calculated to evaluate vinegar authenticity. Sixteen …

Direct Immersion Solid-Phase Microextraction Combined With Ambient Ionization Tandem Mass Spectrometry To Rapidly Distinguish Pesticides In Serum For Emergency Diagnostics, Hung Su, Hsin-Hua Lin, Lin-Jhen Su, Chia-Chen Lin, Zong-Han Jiang, Shiang-Jin Chen, Jentaie Shiea, Chi-Wei Lee

Journal of Food and Drug Analysis

Despite the fact that carbamates and organophosphates cause acute poisoning via different mechanisms and require disparate management, they are indistinguishable by current clinical assays. Herein, direct immersion solid-phase microextraction (DI-SPME) plus thermal desorption-electrospray ionization tandem mass spectrometry (TD-ESI/MS/MS) was developed to discern them. Both pesticides spiked in human serum were extracted by SPME and analyzed by TD-ESI/MS/MS. This is a promising emergency care platform as rapid analyses could be done in tiny sample volumes with satisfactory recovery (89.46%–116.32%), precision (covariance < 20%), sensitivity (LOD < 0.1 µg/mL), turnaround time (< 5 minutes), and linearity (R² = 0.9827–0.9992) within 0.1–100 µg/mL.