Department of Pharmacology and Toxicology

Permanent URI for this community

https://hdl.handle.net/1805/6757

Browse

Now showing 1 - 10 of 408

14-3-3σ Contributes to Radioresistance by Regulating DNA Repair and Cell Cycle via PARP1 and CHK2
(AACR, 2017) Chen, Yifan; Li, Zhaomin; Dong, Zizheng; Beebe, Jenny; Yang, Ke; Fu, Liwu; Zhang, Jian-Ting; Department of Pharmacology and Toxicology, IU School of Medicine
14-3-3σ has been implicated in the development of chemo and radiation resistance and in poor prognosis of multiple human cancers. While it has been postulated that 14-3-3σ contributes to these resistances via inhibiting apoptosis and arresting cells in G2–M phase of the cell cycle, the molecular basis of this regulation is currently unknown. In this study, we tested the hypothesis that 14-3-3σ causes resistance to DNA-damaging treatments by enhancing DNA repair in cells arrested in G2–M phase following DNA-damaging treatments. We showed that 14-3-3σ contributed to ionizing radiation (IR) resistance by arresting cancer cells in G2–M phase following IR and by increasing non-homologous end joining (NHEJ) repair of the IR-induced DNA double strand breaks (DSB). The increased NHEJ repair activity was due to 14-3-3σ–mediated upregulation of PARP1 expression that promoted the recruitment of DNA-PKcs to the DNA damage sites for repair of DSBs. On the other hand, the increased G2–M arrest following IR was due to 14-3-3σ–induced Chk2 expression. Implications: These findings reveal an important molecular basis of 14-3-3σ function in cancer cell resistance to chemo/radiation therapy and in poor prognosis of human cancers.
14-3-3σ regulation of and interaction with YAP1 in acquired gemcitabine resistance via promoting ribonucleotide reductase expression
(Impact Journals, LLC, 2016-04-05) Qin, Li; Dong, Zizheng; Zhang, Jian-Ting; Department of Pharmacology and Toxicology, IU School of Medicine
Gemcitabine is an important anticancer therapeutics approved for treatment of several human cancers including locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). Its clinical effectiveness, however, is hindered by existence of intrinsic and development of acquired resistances. Previously, it was found that 14-3-3σ expression associates with poor clinical outcome of PDAC patients. It was also found that 14-3-3σ expression is up-regulated in gemcitabine resistant PDAC cells and contributes to the acquired gemcitabine resistance. In this study, we investigated the molecular mechanism of 14-3-3σ function in gemcitabine resistance and found that 14-3-3σ up-regulates YAP1 expression and then binds to YAP1 to inhibit gemcitabine-induced caspase 8 activation and apoptosis. 14-3-3σ association with YAP1 up-regulates the expression of ribonucleotide reductase M1 and M2, which may mediate 14-3-3σ/YAP1 function in the acquired gemcitabine resistance. These findings suggest a possible role of YAP1 signaling in gemcitabine resistance.
2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation
(Elsevier, 2024) Joglar, José A.; Chung, Mina K.; Armbruster, Anastasia L.; Benjamin, Emelia J.; Chyou, Janice Y.; Cronin, Edmond M.; Deswal, Anita; Eckhardt, Lee L.; Goldberger, Zachary D.; Gopinathannair, Rakesh; Gorenek, Bulent; Hess, Paul L.; Hlatky, Mark; Hogan, Gail; Ibeh, Chinwe; Indik, Julia H.; Kido, Kazuhiko; Kusumoto, Fred; Link, Mark S.; Linta, Kathleen T.; Marcus, Gregory M.; McCarthy, Patrick M.; Patel, Nimesh; Patton, Kristen K.; Perez, Marco V.; Piccini, Jonathan P.; Russo, Andrea M.; Sanders, Prashanthan; Streur, Megan M.; Thomas, Kevin L.; Times, Sabrina; Tisdale, James E.; Valente, Anne Marie; Van Wagoner, David R.; Pharmacology and Toxicology, School of Medicine
Aim: The "2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Patients With Atrial Fibrillation" provides recommendations to guide clinicians in the treatment of patients with atrial fibrillation. Methods: A comprehensive literature search was conducted from May 12, 2022, to November 3, 2022, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. Additional relevant studies, published through November 2022, during the guideline writing process, were also considered by the writing committee and added to the evidence tables, where appropriate. Structure: Atrial fibrillation is the most sustained common arrhythmia, and its incidence and prevalence are increasing in the United States and globally. Recommendations from the "2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation" and the "2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation" have been updated with new evidence to guide clinicians. In addition, new recommendations addressing atrial fibrillation and thromboembolic risk assessment, anticoagulation, left atrial appendage occlusion, atrial fibrillation catheter or surgical ablation, and risk factor modification and atrial fibrillation prevention have been developed.
318. Beta-lactam Therapeutic Drug Monitoring Improves Attainment of Target Drug Levels in Critically Ill Patients
(Oxford University Press, 2023-11-27) Ausman, Sara; Braga, Shienna; Hagy, Natalie T.; Rivera, Christina G.; Moreland-Head, Lindsay; Wessel, Rebecca; Abu Saleh, Omar M.; Rule, Andrew D.; Gajic, Ognjen; Barreto, Erin F.; Pharmacology and Toxicology, School of Medicine
Background: Critically ill patients, particularly those treated with extracorporeal devices or at extremes of weight, experience pharmacokinetic variability which can compromise beta-lactam (BL) antibiotic target attainment and treatment response. Therapeutic drug monitoring (TDM) for BL antibiotics can improve precision pharmacotherapy but has had limited implementation. The objective of this study was to evaluate the frequency of BL target attainment among adult intensive care unit (ICU) patients who underwent TDM. Methods: This observational study evaluated adults treated with cefepime, piperacillin/tazobactam or meropenem in ICUs at the Mayo Clinic in Rochester, Minnesota who underwent TDM from June-September 2022. During the study timeframe, multidisciplinary teams were encouraged to perform BL TDM on patients requiring extracorporeal membrane oxygenation, continuous kidney replacement therapy, or at an extreme of body weight (weight < 40 kg or >120 kg or BMI < 18 kg/m2 or > 40 kg/m2). Percentage of patients with initial serum trough concentrations within the therapeutic range was calculated. Results: During the study timeframe, 59 trough concentrations were performed on critically ill patients, of which 5 were excluded due to uninterpretable results. Of the remaining 54 BL trough concentrations analyzed, 49 (91%) were initial troughs during the antibiotic course, and 5 (9%) were repeat troughs. Thirty-six (73%) of the initial trough concentrations were within the therapeutic range. Among the trough concentrations outside the therapeutic range, 10 (77%) were too high, and 3 (23%) were too low (Table 2). Dose adjustment occurred in 19 (39%) of initial trough evaluations, including 6 which were adjusted despite a level within the therapeutic range. All of the repeat trough concentrations drawn during the same antibiotic course were within the therapeutic range (n = 5/5; 100%). Conclusion: One-fourth of initial BL trough concentrations were outside of the therapeutic range. BL levels outside the therapeutic range prompted dose adjustment to improve the potential for effectiveness or limit the potential for toxicity. BL TDM appears to be a promising strategy to enhance precision pharmacotherapy in the critically ill.
4-(4-Chloro-2-methylphenoxy)-N-hydroxybutanamide (CMH) targets mRNA of the c-FLIP variants and induces apoptosis in MCF-7 human breast cancer cells
(Springer US, 2010-09) Bijangi-Vishehsaraei, Khadijeh; Huang, Su; Safa, Ahmad R.; Saadatzadeh, Mohammad Reza; Murphy, Michael P.; Department of Pharmacology & Toxicology, School of Medicine
Cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (c-FLIP) is a major resistance factor for the tumor necrosis factor-related apoptosis-inducing ligand TRAIL and in drug resistance in human malignancies. c-FLIP is an antagonist of caspases-8 and -10, which inhibits apoptosis and is expressed as long (c-FLIPL) and short (c-FLIPS) splice forms. c-FLIP is often overexpressed in various human cancers, including breast cancer. Several studies have shown that silencing c-FLIP by specific siRNAs sensitizes cancer cells to TRAIL and anticancer agents. However, systemic use of siRNA as a therapeutic agent is not practical at present. In order to reduce or inhibit c-FLIP expression, small molecules are needed to allow targeting c-FLIP without inhibiting caspases-8 and -10. We used a small molecule inhibitor of c-FLIP, 4-(4-chloro-2-methylphenoxy)-N-hydroxybutanamide (CMH), and show that CMH, but not its inactive analog, downregulated c-FLIPL and c-FLIPS mRNA and protein levels, caused poly(ADP-ribose) polymerase (PARP) degradation, reduced cell survival, and induced apoptosis in MCF-7 breast cancer cells. These results revealed that c-FLIP is a critical apoptosis regulator that can serve as a target for small molecule inhibitors that downregulate its expression and serve as effective targeted therapeutics against breast cancer cells.
8-aminoquinolines effective against Pneumocystis carinii in vitro and in vivo
(American Society for Microbiology, 1999-10) Queener, Sherry F.; Bartlett, Marilyn S.; Nasr, Mohamed; Smith, James W.; Pharmacology and Toxicology, School of Medicine
The activities of 25 8-aminoquinolines were compared in tests assessing the ability of the compounds to inhibit the growth of Pneumocystis carinii in culture. Six compounds were effective at or below 0.03 microM: CDRI 80/53, NSC19894, NSC305805, NSC305812, WR182234, and primaquine. Four others were effective at between 0.2 and 0.03 microM: NSC305835, WR225448, WR238605, and WR242511. Fourteen drugs were also tested in a standard model of P. carinii pneumonia in rats at daily doses of 2 mg/kg of body weight in drinking water. CDRI 80/53, NSC305805, NSC305835, and WR225448 were extremely effective in the animal model. The effectiveness of WR238605, WR242511, and primaquine in the rat model has been reported elsewhere (M. S. Bartlett, S. F. Queener, R. R. Tidwell, W. K. Milhouse, J. D. Berman, W. Y. Ellis, and J. W. Smith, Antimicrob. Agents Chemother. 35:277-282, 1991). The length of the alkyl chain separating the nitrogens in the substituent at position 8 of the quinoline ring was a strong determinant of anti-P. carinii activity.
A common language for Gulf War Illness (GWI) research studies: GWI common data elements
(Elsevier, 2022) Cohen, Devra E.; Sullivan, Kimberly A.; McNeil, Rebecca B.; Gulf War Illness Common Data Elements Working Group; Symptoms Assessment Working Group; McNeil, Rebecca B.; Ashford, Wes; Bested, Alison; Bunker, James; Cheema, Amanpreet; Cohen, Devra E.; Cook, Dane; Cournoyer, Jeffrey; Craddock, Travis; Golier, Julia; Hardie, Anthony; Helmer, Drew; Lindheimer, Jacob B.; Janulewicz Lloyd, Patricia; Kerr, Kathleen; Krengel, Maxine; Nadkarni, Shree; Nugent, Shannon; Paris, Bonnie; Reinhard, Matthew; Rumm, Peter; Schneiderman, Aaron; Sims, Kellie J.; Steele, Lea; Turner, Marsha; Systems Assessment Working Group; Sullivan, Kimberly A.; Abdullah, Laila; Abreu, Maria; Abu-Donia, Mohamed; Aenlle, Kristina; Arocho, Jimmy; Balbin, Elizabeth; Baraniuk, James; Block, Karen; Block, Michelle; DeBeer, Bryann; Engdahl, Brian; Filipov, Nikolay; Fletcher, Mary Ann; Kalasinsky, Victor; Kokkotou, Efi; Lidie, Kristy; Little, Deborah; Loging, William; Morris, Marianna; Nathanson, Lubov; Nichols, Montra Denise; Pasinetti, Giulio; Shungu, Dikoma; Waziry, Paula; VanLeeuwen, Jon; Younger, Jarred; Pharmacology and Toxicology, School of Medicine
Aims: The Gulf War Illness programs (GWI) of the United States Department of Veteran Affairs and the Department of Defense Congressionally Directed Medical Research Program collaborated with experts to develop Common Data Elements (CDEs) to standardize and systematically collect, analyze, and share data across the (GWI) research community. Main methods: A collective working group of GWI advocates, Veterans, clinicians, and researchers convened to provide consensus on instruments, case report forms, and guidelines for GWI research. A similar initiative, supported by the National Institute of Neurologic Disorders and Stroke (NINDS) was completed for a comparative illness, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), and provided the foundation for this undertaking. The GWI working group divided into two sub-groups (symptoms and systems assessment). Both groups reviewed the applicability of instruments and forms recommended by the NINDS ME/CFS CDE to GWI research within specific domains and selected assessments of deployment exposures. The GWI CDE recommendations were finalized in March 2018 after soliciting public comments. Key findings: GWI CDE recommendations are organized in 12 domains that include instruments, case report forms, and guidelines. Recommendations were categorized as core (essential), supplemental-highly recommended (essential for specified conditions, study types, or designs), supplemental (commonly collected, but not required), and exploratory (reasonable to use, but require further validation). Recommendations will continually be updated as GWI research progresses. Significance: The GWI CDEs reflect the consensus recommendations of GWI research community stakeholders and will allow studies to standardize data collection, enhance data quality, and facilitate data sharing.
A complex signature network that controls the upregulation of PRMT5 in colorectal cancer
(Elsevier, 2022-03) Wei, Han; Hartley, Antja-Voy; Motolani, Aishat; Jiang, Guanglong; Safa, Ahmad; Prabhu, Lakshmi; Liu, Yunlong; Lu, Tao; Pharmacology and Toxicology, School of Medicine
A decade of epigenetic research in Toxoplasma gondii
(Elsevier, 2010) Dixon, Stacy E.; Stilger, Krista L.; Elias, Eliana V.; Naguleswaran, Arunasalam; Sullivan, William J., Jr.; Pharmacology and Toxicology, School of Medicine
In the past 10 years, the field of parasitology has witnessed an explosion of studies investigating gene regulation. In this review, we will describe recent advances largely stemming from the study of Toxoplasma gondii, a significant opportunistic pathogen and useful model for other apicomplexan protozoa. Surprising findings have emerged, including the discovery of a wealth of epigenetic machinery in these primitive eukaryotes, unusual histone variants, and a battery of plant-like transcription factors. We will elaborate on how these unusual features impact parasite physiology and potential therapeutics as we summarize some of the key discoveries from the last decade. We will close by proposing a few questions to address in the next 10 years.
A GCN2-Like Eukaryotic Initiation Factor 2 Kinase Increases the Viability of Extracellular Toxoplasma gondii Parasites
(American Society for Microbiology, 2011) Konrad, Christian; Wek, Ronald C.; Sullivan, William J., Jr.; Pharmacology and Toxicology, School of Medicine
Toxoplasmosis is a significant opportunistic infection caused by the protozoan parasite Toxoplasma gondii, an obligate intracellular pathogen that relies on host cell nutrients for parasite proliferation. Toxoplasma parasites divide until they rupture the host cell, at which point the extracellular parasites must survive until they find a new host cell. Recent studies have indicated that phosphorylation of Toxoplasma eukaryotic translation initiation factor 2-alpha (TgIF2α) plays a key role in promoting parasite viability during times of extracellular stress. Here we report the cloning and characterization of a TgIF2α kinase designated TgIF2K-D that is related to GCN2, a eukaryotic initiation factor 2α (eIF2α) kinase known to respond to nutrient starvation in other organisms. TgIF2K-D is present in the cytosol of both intra- and extracellular Toxoplasma parasites and facilitates translational control through TgIF2α phosphorylation in extracellular parasites. We generated a TgIF2K-D knockout parasite and demonstrated that loss of this eIF2α kinase leads to a significant fitness defect that stems from an inability of the parasite to adequately adapt to the environment outside host cells. This phenotype is consistent with that reported for our nonphosphorylatable TgIF2α mutant (S71A substitution), establishing that TgIF2K-D is the primary eIF2α kinase responsible for promoting extracellular viability of Toxoplasma. These studies suggest that eIF2α phosphorylation and translational control are an important mechanism by which vulnerable extracellular parasites protect themselves while searching for a new host cell. Additionally, TgIF2α is phosphorylated when intracellular parasites are deprived of nutrients, but this can occur independently of TgIF2K-D, indicating that this activity can be mediated by a different TgIF2K.

Browse

Browsing Department of Pharmacology and Toxicology by Title

Results Per Page

Sort Options