Article
Cardiac & Cardiovascular Systems
Sean Brennan, Simona Esposito, Muhammad I. M. Abdelaziz, Christopher A. A. Martin, Samir Makwana, Mark W. W. Sims, Iain B. B. Squire, Parveen Sharma, Amy E. E. Chadwick, Richard D. Rainbow
Summary: Hyperglycemia at the time of myocardial infarction has a negative impact on prognosis, regardless of prior diabetes diagnosis. Glucose is suggested to be the damaging factor. In ex vivo models, it was demonstrated that acutely elevated glucose has harmful effects that are PKC alpha/beta-dependent. Cardioprotection can be obtained by inhibiting PKC alpha/beta. Short pretreatments with high glucose revealed time-dependent glucose cardiotoxicity, and inhibition of PKC alpha/beta was studied as a potential mechanism to reverse the toxicity. In isolated non-diabetic rat cardiomyocytes, exposure to elevated glucose for more than 7.5 minutes led to cardiotoxicity, while exposure to metabolic inhibition following 5-minute high glucose showed time-dependent protection lasting around 15 minutes. This protection was further enhanced with PKC alpha/beta inhibition. Cardioprotection was measured by delayed contractile failure, K-ATP channel activation, improved contractile and Ca2+ transient recovery, and increased cell survival. Pre-ischemic treatment with high glucose in a whole-heart coronary ligation protocol also revealed the presence of protection with PKC alpha/beta inhibition. Selective PKC alpha/beta inhibition enhances cardioprotection, suggesting that glycaemic control with PKC inhibition may be a potential therapeutic strategy for myocardial infarction and elective cardiac surgery.
FRONTIERS IN CARDIOVASCULAR MEDICINE
(2022)
Article
Biology
Domenica Ippolito, Dominique A. Glauser
Summary: The study identifies the mechanisms of nucleo-cytoplasmic shuttling and nuclear entry of calcium-dependent CMK-1 in different stress and non-stress conditions. It reveals the impact of multiple calcium-dependent regulatory mechanisms on CMK-1 nuclear localization and their role in regulating nociceptive plasticity.
Review
Biochemistry & Molecular Biology
Jessica Kimmel, Jessica Kehrer, Friedrich Frischknecht, Tobias Spielmann
Summary: In the past 10 years, proximity-dependent biotinylation (PDB) techniques have been widely used, particularly for detecting protein interactions under physiological conditions and studying cellular structures with unclear protein composition. New PDB methods offer improved temporal and spatial resolution, with broad application potential for research on apicomplexan parasites.
MOLECULAR MICROBIOLOGY
(2022)
Article
Cardiac & Cardiovascular Systems
Andrew J. Boyle, Carl Schultz, Joseph B. Selvanayagam, Stuart Moir, Richard Kovacs, Nabil Dib, David Zlotnick, Mohammed Al-Omary, Stuart Sugito, Aravinda Selvarajah, Nicholas Collins, Grant McLachlan
Summary: This study found that treatment with NP202 for 3 months after primary PCI for anterior STEMI did not improve LV remodeling in patients with residual LV dysfunction. However, the drug demonstrated good safety and tolerability.
Article
Multidisciplinary Sciences
Moustafa A. Shehata, Julia Contreras, Ana Martin-Hurtado, Aurane Froux, Hossam Taha Mohamed, Ahmed A. El-Sherif, Ivan Plaza-Menacho
Summary: This study investigates the structural and dynamic determinants of highly selective RET kinase inhibition, identifying a new druggable target called the post-lysine pocket. It demonstrates that second generation RET inhibitors exploit this vulnerability, providing important implications for future drug design and personalized therapies for RET-driven cancers.
JOURNAL OF ADVANCED RESEARCH
(2023)
Article
Biology
Tiantian Wei, Jue Wang, Ruqi Liang, Wendong Chen, Yilan Chen, Mingzhe Ma, An He, Yifei Du, Wenjing Zhou, Zhiying Zhang, Xin Zeng, Chu Wang, Jin Lu, Xing Guo, Xiao-Wei Chen, Youjun Wang, Ruijun Tian, Junyu Xiao, Xiaoguang Lei, Hening Lin
Summary: In this study, researchers developed a potent DYRK2 inhibitor, C17, and used it as a chemical probe to investigate the function of DYRK2. They discovered that DYRK2 phosphorylates 4E-BP1 and STIM1, and C17 effectively suppresses these phosphorylation reactions. These findings expand our understanding of DYRK2 and provide a valuable tool for further research.
Article
Multidisciplinary Sciences
Moshe Katz, Suraj Subramaniam, Orna Chomsky-Hecht, Vladimir Tsemakhovich, Veit Flockerzi, Enno Klussmann, Joel A. Hirsch, Sharon Weiss, Nathan Dascal
Summary: CaV1.2 channels play a crucial role in regulating cardiac muscle contraction, with 0-AR increasing contraction by enhancing calcium influx through these channels via PKA activation. A recent study identified Rad as essential for PKA regulation of CaV1.2, revealing two distinct pathways of PKA modulation of CaV1.2: Rad dependent and Rad independent.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Editorial Material
Hematology
Antonio Sacco, Aldo M. Roccaro
Summary: In this study, it is shown that cyclin-dependent kinase-7 (CDK7) affects the oncogenic programming of multiple myeloma (MM) cells through modulation of MYC and E2F transcription factors. The authors demonstrate that inhibiting CDK7 counteracts E2F activity, resulting in reduced CDKs-retinoblastoma (Rb) axis and inhibition of MYC-regulated metabolic signatures. Therefore, CDK7 inhibition is a promising therapeutic target for MM.
Article
Physiology
Pei-Pei Zhang, Liangkun Hu, You-Jia Tian, Zefu Zhang, Pei-Hua Zhang, Yan-Yan Yang, Shi-Han Li, Jihua Ma
Summary: This study found that cardiac alternans induced by high [Ca2+](i) is mediated by PKC activity, and PKC inhibitors can effectively suppress the occurrence of cardiac alternans, suggesting that inhibition of PKC activities may serve as a therapeutic target for preventing arrhythmias associated with calcium dysregulation.
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Riku Kaneshige, Satomi Ohtsuka, Yuhei Harada, Issei Kawamata, Masaki Magari, Naoki Kanayama, Naoya Hatano, Hiroyuki Sakagami, Hiroshi Tokumitsu
Summary: This study reveals that the RP-domain is required for CaMKK isoforms to recognize and phosphorylate downstream kinases, potentially providing a promising target for specific CaMKK inhibitors.
Article
Oncology
Evan K. Day, Qing Zhong, Benjamin Purow, Matthew J. Lazzara
Summary: In glioblastoma, the inhibition of SHP2 has diverse and context-dependent effects on signaling pathways, which may make them useful components of some combination therapies but not others.
Article
Biochemistry & Molecular Biology
Jie-Yu Yue, Jin-Lan Jiao, Wen-Wen Wang, Hua-Zhong Wang
Summary: TaCDPK27 is a salt-responsive gene in wheat that plays a crucial role in regulating salt tolerance by reducing ROS accumulation and NaCl-induced PCD.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Multidisciplinary
Charles W. Morgan, Ian L. Dale, Andrew P. Thomas, James Hunt, Jason W. Chin
Summary: In this study, bio-orthogonal ligand tethering (BOLT) was used to selectively target inhibitors to CRAF, showing that selective CRAF inhibition promotes paradoxical activation. This suggests that BOLT may be used to triage potential targets for drug discovery before any target-selective small molecules are known.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Microbiology
Qiang Zhang, Qian Shao, Yaqiong Guo, Na Li, Yu Li, Jiayuan Su, Rui Xu, Ziding Zhang, Lihua Xiao, Yaoyu Feng
Summary: By expressing recombinant CpCDPK4, CpCDPK5, and CpCDPK6 in Escherichia coli, this study investigated the biological characteristics and functions of these proteins in Cryptosporidium spp. It was found that these CpCDPKs exhibited differences in gene expressions, protein localizations, and neutralizing capacities, suggesting potential varied roles during the lifecycle of Cryptosporidium spp., with CpCDPK4 and CpCDPK6 showing significant inhibitory effects on host cell invasion.
FRONTIERS IN MICROBIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Lucas Bayones, Samuel Alfonso-Bueno, Mauricio Montenegro, Jose Moya-Diaz, Octavio Caspe, Luciana Gallo, Fernando D. Marengo
Summary: This study investigated the endocytosis and replenishment of the immediately releasable pool (IRP) in mice primary chromaffin cells. The researchers found that not only a fast dynamin-dependent endocytosis occurred after the release of about 50% IRP, but also a fast dynamin-independent endocytosis was activated after depolarizations lasting 25-50ms, which released over 80% of IRP. This dynamin-independent endocytosis was found to be Ca2+- and protein kinase C (PKC)-dependent. Additionally, PKC inhibition also affected the slow component of replenishment observed after total IRP exocytosis.
JOURNAL OF NEUROCHEMISTRY
(2022)
Article
Respiratory System
Taha Al-Shaikhly, Ryan C. Murphy, Andrew Parker, Ying Lai, Matthew C. Altman, Megan Larmore, William A. Altemeier, Charles W. Frevert, Jason S. Debley, Adrian M. Piliponsky, Steven F. Ziegler, Michael C. Peters, Teal S. Hallstrand
Summary: The study found that intraepithelial eosinophils are associated with asthma and endogenous AHR, while both intraepithelial and subepithelial eosinophils are linked to T2 inflammation, with a strong association between IL-5 expression and intraepithelial eosinophils. Eosinophil infiltration of the airway wall is associated with a specific mast cell phenotype described in asthma.
EUROPEAN RESPIRATORY JOURNAL
(2022)
Article
Biochemistry & Molecular Biology
Joachim Muller, Nicoleta Anghel, Dennis Imhof, Kai Hanggeli, Anne-Christine Uldry, Sophie Braga-Lagache, Manfred Heller, Kayode K. Ojo, Luis-Miguel Ortega-Mora, Wesley C. Van Voorhis, Andrew Hemphill
Summary: Neospora caninum, closely related to Toxoplasma gondii, is a parasite that can cause fetal malformations in livestock. The development of calcium-dependent protein kinase 1 inhibitors has shown promise in treating neosporosis. However, some of these inhibitors have adverse effects on fertility in pregnant mouse models and cause embryonic malformations in zebrafish models. Through affinity chromatography and mass spectrometry, it has been found that BKI-1748 interacts not only with specific targets in apicomplexans but also with targets in other eukaryotes, indicating involvement in common essential pathways.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Microbiology
Samantha A. Michaels, Matthew A. Hulverson, Grant R. Whitman, Linh T. Tran, Ryan Choi, Erkang Fan, Case W. McNamara, Melissa S. Love, Kayode K. Ojo
Summary: A phenotypic screen of the ReFRAME compound library identified Mavelertinib as a potential therapeutic for giardiasis. It showed efficacy against metronidazole-resistant strains and demonstrated good results in a mouse model.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2022)
Article
Veterinary Sciences
Dennis Imhof, William Robert Pownall, Carling Schlange, Camille Monney, Luis-Miguel Ortega-Mora, Kayode K. Ojo, Wesley C. Van Voorhis, Anna Oevermann, Andrew Hemphill
Summary: This study investigated the safety and efficacy of a combined vaccination-drug treatment approach in a pregnant neosporosis mouse model. The results showed that the combination treatment was more effective in reducing infection and improving pup survival compared to vaccination or drug treatment alone. Further evaluation is recommended.
FRONTIERS IN VETERINARY SCIENCE
(2022)
Letter
Allergy
Ryan C. Murphy, Yu-Hua Chow, Ying Lai, Taha Al-Shaikhly, Daniel H. Petroni, Michele Black, Jessica A. Hamerman, Adam Lacy-Hulbert, Adrian M. Piliponsky, Teal S. Hallstrand
Editorial Material
Critical Care Medicine
Ryan C. Murphy, Eric D. Morrell, Teal S. Hallstrand
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
(2023)
Editorial Material
Allergy
Nyssa B. Samanas, Ryan C. Murphy, Irina Miralda, Teal S. Hallstrand, Adrian M. Piliponsky
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
(2023)
Article
Allergy
Ryan C. Murphy, Ying Lai, Matthew C. Altman, Kaitlyn A. Barrow, Kimberly A. Dill-McFarland, Matthew Liu, Jessica A. Hamerman, Adam Lacy-Hulbert, Adrian M. Piliponsky, Steven F. Ziegler, William A. Altemeier, Jason S. Debley, Sina A. Gharib, Teal S. Hallstrand
Summary: This study investigated the cross talk between airway epithelial cells and mast cells in asthma. The results showed that mast cells can promote the expression of proinflammatory and antiviral genes in airway epithelial cells, thus affecting mast cell immune responses.
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Tim Aguirre, Ellen Teichmann, Florian Q. Roempp, Ruthey Vivier, Cole Bryant, Matthew A. Hulverson, Wesley C. Van Voorhis, Kayode K. Ojo, J. Stone Doggett, Dorothea Fiedler, Stefan Hecht
Summary: This study developed photoswitchable azopyrazoles as inhibitors to selectively target CDPK1 from Toxoplasma gondii. The inhibitory activity of CDPK1 is dependent on the size of the gatekeeper residue. The photoswitchable inhibitors also showed activity against T. gondii and Cryptosporidium parvum infections in a cell culture model.
ACS CHEMICAL BIOLOGY
(2023)
Article
Critical Care Medicine
Ryan C. Murphy, Ying Lai, Matthew Liu, Taha Al-Shaikhly, Matthew C. Altman, William A. Altemeier, Charles W. Frevert, Jason S. Debley, Adrian M. Piliponsky, Steven F. Ziegler, Sina A. Gharib, Teal S. Hallstrand
Summary: This study identified differentially expressed genes associated with exercise-induced bronchoconstriction in individuals with asthma using RNA-sequencing analysis. Experiments suggested that the interactions between airway epithelial cells, mast cells, and eosinophils are closely associated with indirect airway hyperresponsiveness and play a critical role in modulating airway inflammation.
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
(2023)
Article
Microbiology
Matthew A. Hulverson, Ryan Choi, Deborah A. Schaefer, Dana P. Betzer, Molly C. McCloskey, Grant R. Whitman, Wenlin Huang, Sangun Lee, Andy Pranata, Malcolm D. McLeod, Kennan C. Marsh, Dale J. Kempf, Bruce E. LeRoy, Mark T. Zafiratos, Aimee L. Bielinski, Robert C. Hackman, Kayode K. Ojo, Samuel L. M. Arnold, Lynn K. Barrett, Saul Tzipori, Michael W. Riggs, Erkang Fan, Wesley C. Van Voorhis
Summary: Recent advances in the development of bumped kinase inhibitors for treating cryptosporidiosis have focused on a specific structure known as 5-aminopyrazole-4-carboxamide scaffold, which has shown superior efficacy, reduced hERG inhibition, and excellent safety profiles in vitro. Three compounds (BKI-1770, -1841, and -1708) demonstrated strong effectiveness in mice infected with C. parvum. While BKI-1770 and BKI-1841 were effective in a C. parvum calf model, they caused limb hyperflexion. Toxicity experiments in rats and calves revealed bone toxicity at slightly higher doses than the efficacious dose for BKI-1770. Both BKI-1770 and BKI-1841 showed neurological effects in mice, and BKI-1770 also displayed bone toxicity. However, BKI-1708 showed no signs of bone toxicity or neurological effects in mice, making it a promising candidate for further evaluation.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2023)
Letter
Respiratory System
Taha Al-Shaikhly, Ryan C. Murphy, Ying Lai, Charles W. Frevert, Jason S. Debley, Steven F. Ziegler, Kit Wong, Guiquan Jia, Cecile T. J. Holweg, Michael C. Peters, Teal S. Hallstrand
Article
Virology
Anise N. N. Happi, Akeemat O. O. Ayinla, Olusola A. A. Ogunsanya, Ayotunde E. E. Sijuwola, Femi M. M. Saibu, Kazeem Akano, Uwem E. E. George, Adebayo E. E. Sopeju, Peter M. M. Rabinowitz, Kayode K. K. Ojo, Lynn K. K. Barrett, Wesley C. C. Van Voorhis, Christian T. T. Happi
Summary: This study investigated the presence of SARS-CoV-2 in various animals in Nigeria and found that the virus can infect multiple animal species, including poultry, pigs, domestic ruminants, and lizards. This highlights the ability of SARS-CoV-2 to spread among animals and emphasizes the importance of continuous monitoring and intervention.
Article
Microbiology
Matthew A. Hulverson, Samantha A. Michaels, Jin Woo Lee, Karen L. Wendt, Linh T. Tran, Ryan Choi, Wesley C. Van Voorhis, Robert H. Cichewicz, Kayode K. Ojo
Summary: In this study, natural products and fungal extracts were screened for their ability to inhibit the growth of Giardia lamblia, leading to the discovery of novel chemical scaffolds that can potentially be developed into effective antigiardial agents.
MICROBIOLOGY SPECTRUM
(2023)
Article
Biochemistry & Molecular Biology
Sarah E. Canarelli, Brooke M. Swalm, Eric T. Larson, Michael J. Morrison, Eranthie Weerapana
Summary: This study reports on an electrophilic peptide-based probe, SEC1, that directly reports on the activity of GAPDH. SEC1 has been shown to assess changes in GAPDH activity in response to oncogenic transformation, reactive oxygen species, and small-molecule GAPDH inhibitors. The study confirms that Koningic acid is a highly effective irreversible inhibitor of GAPDH, acting through a specific mechanism. Additionally, the therapeutic potential of KA was demonstrated in an autoimmune model.
RSC CHEMICAL BIOLOGY
(2022)