Pharmacology and Toxicology

In search of nonlipogenic ABCA1 inducers (NLAI): precision coregulator TR-FRET identifies diverse signatures for LXR ligands

1. Megan S Laham
2. Martha Ackerman-Berrier
3. Fahmida Alam
4. Sarah Turner
5. Ganga Reddy Velma
6. Christopher Penton
7. Soumya Reddy Musku
8. Manan Rana
9. Senthil Kumar
10. Anandhan Annadurai
11. Maha Ibrahim Sulaiman
12. Nina Ma
13. Gregory RJ Thatcher

• Curated by eLife

  eLife Assessment

  The study highlights development of a multiplex coregulator TR-FRET (CRT) assay that detects ligands with theoretical full agonist, partial agonist, antagonist, and inverse agonist signatures within the same chemical series. The findings are valuable and will have theoretical and practical implications in the subfield, with respect to guiding the design of non-lipogenic liver X receptor (LXR) agonists. The strength of the evidence is solid, whereby the methods, data, and analyses broadly support the claims with only minor weaknesses that can be dealt with through improvements in the data analysis and the discussion. This study will be of interest to experts working in the areas of pharmacology, medicinal chemistry, and drug discovery in Alzheimer's diseases and dementias.

Reviewed by eLife

In vitro pharmacokinetics and pharmacodynamics of the diarylquinoline TBAJ-587 and its metabolites against Mycobacterium tuberculosis

1. Diana Angelica Aguilar Ayala
2. Marie Sylvianne Rabodoarivelo
3. Maxime R. Eveque-Mourroux
4. Albin AM Leding
5. Lindsay Sonnekalb
6. Ana Picó Marco
7. Nicolas Willand
8. Natalya Serbina
9. Ulrika SH Simonsson
10. Ainhoa Lucía
11. Santiago Ramón-García
12. ERA4TB consortium

Reviewed by preLights

Nonspecific membrane bilayer perturbations by ivermectin underlie SARS-CoV-2 in vitro activity

1. Richard T Eastman
2. Radda Rusinova
3. Karl F Herold
4. Xi-Ping Huang
5. Patricia Dranchak
6. Ty C Voss
7. Sandeep Rana
8. Jonathan H Shrimp
9. Alex D White
10. Hugh C Hemmings
11. Bryan L Roth
12. James Inglese
13. Olaf S Andersen
14. Jayme L Dahlin

Reviewed by Rapid Reviews Infectious Diseases

Quinolines interfere with heme-mediated activation of artemisinins

1. Melissa R Rosenthal
2. Daniel E Goldberg

• Curated by eLife

  eLife Assessment

  This study is important as it demonstrates that 4-aminoquinoline antimalarials antagonize artemisinin activity under physiologically relevant conditions. Using isogenic parasite lines and a chemical probe, the authors provide mechanistic insight and compelling evidence implicating PfCRT in this antagonism. However, some weaknesses have been identified that limit full interpretation of the findings, which are based solely on in vitro assays, though the results have implications that will be of importance in optimizing future antimalarial combination strategies.

Reviewed by eLife

Mid-zone hepatocytes trade proliferation for survival via Atf4-Chop axis in early acute liver injury

1. Yaying Zhu
2. Chengxiang Deng
3. Bo Chen
4. Jia He
5. Yanan Liu
6. Cheng Peng
7. Zhao Shan

• Curated by eLife

  eLife Assessment

  This study addresses an important question in liver biology: how zonal hepatocytes balance survival and proliferation following injury; using spatial transcriptomics, mechanistic perturbations, and functional assays, the authors propose that a mid-zone Atf4-Chop axis to Btg2 program temporarily suppresses proliferation to promote survival during APAP-induced hepatotoxicity. The idea that distinct intrahepatic zones mount tailored stress responses is conceptually significant and has implications for regeneration and toxicology. The dataset is rich and the methodology modern, but several conclusions rely on assumptions about zonation under injury, limited injury models, and incomplete functional validation of the Atf4-Chop-Btg2 axis. With targeted revisions and additional experiments, the work has the potential to provide strong mechanistic insights into liver zonation and injury responses.

Reviewed by eLife

Single-cell transcriptomics identifies an increased Ly6G- neutrophil population and accentuated T-cell cytotoxicity in tobacco flavored e-cigarette exposed mouse lungs

1. Gagandeep Kaur
2. Thomas Lamb
3. Ariel Tjitropranoto
4. Irfan Rahman

• Curated by eLife

  eLife Assessment

  This manuscript by Kaur et al. identifies differential gene expression observed in distinct cell populations, namely myeloid and lymphoid cells, upon short-term exposure to e-cig aerosols with various flavors. Their findings are useful because they provide a single cell sequencing data resource for assessing which genes and cellular pathways are most affected by e-cig aerosols and their components. However, the evidence is incomplete due to limited analyses and replicates per condition, as well as the lack of in vivo validation.

Reviewed by eLife

Mechanism of SK2 channel gating and its modulation by the bee toxin apamin and small molecules

1. Samantha J Cassell
2. Weiyan Li
3. Simon Krautwald
4. Maryam Khoshouei
5. Yan Tony Lee
6. Joyce Hou
7. Wendy Guan
8. Stefan Peukert
9. Wilhelm Weihofen
10. Jonathan R Whicher

• Curated by eLife

  eLife Assessment

  In this important manuscript, Cassell and colleagues set out on a mechanistic and pharmacological exploration of an engineered chimeric small conductance calcium-activated potassium channel 2 (SK2). They show compelling evidence that the SK2 channel possesses a unique extracellular structure that modulates the conductivity of the selectivity filter, and that this structure is the target for the SK2 inhibitor apamin. The interpretations are sound and the writing is clear, and the manuscript was strengthened during review by providing more detailed information for the electrophysiological experiments and the structural analyses attempted, in addition to relating dilation of the filter to mechanisms of inactivation in other potassium channels. This high-quality study will be of interest to membrane protein structural biologists, ion channel biophysicists, and chemical biologists, and will help to inform future drug development targeting SK channels.

Reviewed by eLife

Interleukin-4 induces CD11c+ microglia leading to amelioration of neuropathic pain in mice

1. Keita Kohno
2. Ryoji Shirasaka
3. Keita Hirose
4. Takahiro Masuda
5. Makoto Tsuda

• Curated by eLife

  eLife Assessment

  This study is important as it highlighted how IL-4 regulates the reactive state of a specific microglial population by increasing the proportion of CD11c+ microglial cells and ultimately suppressing neuropathic pain. The study employs a combination of behavioral assays, pharmacogenetic manipulation of microglial populations, and characterization of microglial markers to address these questions. It provided convincing evidence for the proposed mechanism of IL-4-mediated microglial regulation in neuropathic pain.

Reviewed by eLife

Hippocampal single-cell RNA Atlas of chronic methamphetamine abuse-induced cognitive decline in mice

1. Hai Qiu
2. Xia Yue
3. Yuebing Huang
4. Ziling Meng
5. Jiahong Wang
6. Dongfang Qiao

• Curated by eLife

  eLife Assessment

  The authors proposed two hypotheses: first, that methamphetamine induces neuroinflammation, and second, that it alters neuronal stem cell differentiation. These are valuable hypotheses, and the authors provided in vivo observations of the methamphetamine response in mice. However, concerns remain regarding the interpretation of the data, and the current evidence is incomplete, requiring substantial experimental validation.

Reviewed by eLife

Transgenerational effects of perinatal cannabis exposure on female reproductive parameters in mice

1. Mingxin Shi
2. Yeongseok Oh
3. Debra A Mitchell
4. James A MacLean
5. Ryan J McLaughlin
6. Kanako Hayashi

Reviewed by preLights