Xiao-Hui Xu

Ischemic stroke currently lacks evidence-based neuroprotective agents, primarily due to the challenge of timely intervention, which often occurs after the onset of irreversible neuronal damage. To address this, this study investigates the PARthanatos pathway, a form of regulated cell death triggered by DNA damage. Utilizing MNNG-induced cellular PARthanatos models, we screened a library of 2,939 traditional Chinese medicine monomers and identified Bruceine E, a natural product derived from Brucea javanica (bitterwood), as a potent inhibitor of PARthanatos at nanomolar concentrations, acting via the inhibition of PARP-1 overactivation. Bruceine E effectively prevents the accumulation of PAR-modified proteins, mitigates mitochondrial membrane potential collapse, and inhibits AIF nuclear translocation. Mechanistically, molecular docking, molecular dynamics simulations, surface plasmon resonance (SPR), and thermal stability assays demonstrate that Bruceine E interacts with the NAD + catalytic pocket of PARP-1 through six hydrogen bonds, exhibiting fast-binding and slow-dissociation kinetics. Furthermore, PARP1 overexpression rescue experiments confirmed that PARP1 overexpression markedly reversed the neuroprotective effect of Bruceine E, indicating that its pharmacological action is specifically dependent on PARP1 regulation. In a permanent distal middle cerebral artery occlusion (pdMCAO) model of C57BL/6 mice, a single intraperitoneal injection of 10 mg/kg Bruceine E administered 4.5 h after occlusion reduced infarct volume by approximately 80.2%, histological evidence confirmed that a single intraperitoneal administration of BE provided effective neuroprotection against ischemic brain injury.

JOURNAL/nrgr/04.03/01300535-202606000-00067/figure1/v/2026-04-16T195327Z/r/image-tiff Cmyc , a proto-oncogene, is expressed at extremely low levels in mature neurons and is traditionally thought to have no function in these cells. However, recent studies suggest that Cmyc may play a crucial role in maintaining the health and function of mature dopaminergic neurons. This study assessed the role of Cmyc in dopaminergic neurons and its significance in Parkinson’s disease. We used a conditional knockout approach to specifically delete Cmyc in substantia nigra dopaminergic neurons of adult mice. Our findings showed that Cmyc deletion led to progressive neuron loss, Parkinson’s disease-like symptoms, downregulation of Klotho, and upregulation of senescence-associated inflammatory factors, along with enhanced oxidative stress and nitrated alpha-synuclein accumulation, ultimately causing neuronal death. In vitro experiments confirmed increased senescence in C-MYC knockout cells, which was partially reversible by KLOTHO overexpression. We conclude that low-level Cmyc expression is essential for maintaining the health of mature dopaminergic neurons and preventing neurodegeneration, and suggest the c-Myc/Klotho axis as a potential therapeutic target for age-related neurodegenerative diseases, including Parkinson’s disease. Our study introduces a novel mouse model for Parkinson’s disease that replicates a condition associated with normal aging, offering a valuable tool for future research into disease mechanisms and therapeutic strategies.

Introduction: Cerebral ischemic stroke (CIS) is caused by the interruption of cerebral blood circulation due to thrombosis or embolism and is the second-leading cause of mortality worldwide. The neuronal death and motor dysfunction resulting from CIS are primarily attributed to the induction of PARthanatos in neurons at the site of ischemia. Blocking parthanatos is a promising treatment for CIS.Methods: The effect of medroxyprogesterone treatment on PARthanatos in vitro was examined by CCK8 assay and flow cytometry and the target protein of medroxyprogesterone was then identified by a series of assays, including western blotting, immunofluorescence, cell thermal shift assay and molecular docking. Subsequently, the efficacy of medroxyprogesterone in the treatment of ischemic stroke was evaluated by FJC staining.Results: In our study, medroxyprogesterone was able to block the occurrence of PARthanatos in Hela cells induced by MNNG. PARP-1 activity did not change after medroxyprogesterone treatment but prevented MNNG-induced apoptosis inducing factor (AIF) release from mitochondria by improving the stability of phosphorylated extracellular signal-regulated kinase (ERK). In vivo, medroxyprogesterone significantly reduces neuronal death in mouse models of CIS by inhibiting PARthanatos.Conclusion: Our findings indicate that medroxyprogesterone effectively inhibits PARthanatos not by affecting the activity of PARP-1, but by directly binding to ERK and stabilizes the active phosphorylated ERK, thereby inhibiting AIF translocation. Furthermore, medroxyprogesterone shows potential as a neuroprotective agent for patients with CIS, potentially enhancing post-stroke recovery and reducing societal burdens.

Tingting Yu, Zirui Yuan, Jiaona Yu, Lu Chen, Wei Hao, and Xiaohui Xu. Korean J Physiol Pharmacol -0001;0:. https://doi.org/10.4196/kjpp.24.293

To combat the SARS-CoV-2 pandemic, innovative prevention strategies are needed, including reducing ACE2 expression on respiratory cells. This study screened approved drugs in China for their ability to downregulate ACE2. Daphnetin (DAP) was found to significantly reduce ACE2 mRNA and protein levels in PC9 cells. DAP exerts its inhibitory effects on ACE2 expression by targeting HIF-1α and JAK2, thereby impeding the transcription of the ACE2 gene. The SARS-CoV-2 pseudovirus infection assay confirmed that DAP-treated PC9 cells exhibited decreased susceptibility to viral infection. At therapeutic doses, DAP effectively lowers ACE2 expression in the respiratory systems of mice and humans. This suggests that DAP, already approved for other conditions, could be a new preventive measure against SARS-CoV-2, offering a cost-effective and accessible way to reduce SARS-CoV-2 spread.

Identification of translocator protein-related genes involved in bensulfuron-methyl (BSM) uptake and transport in rice could facilitate the development of herbicide-tolerant cultivars by inactivating them. This study found that the OsCNGC12 mutants not only reduced BSM uptake but also compromised the Ca² ⁺ efflux caused by BSM in the roots, regulating dynamic equilibrium of Ca² ⁺ inside the cell and conferring non-target-site tolerance to BSM.