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Lung cancer is the leading cause of cancer‐related deaths. LIM domain kinase (LIMK) 1 is a member of serine/threonine kinase family and highly expressed in various cancers. Luteolin, a polyphenolic plant flavonoid, has been reported to suppress tumour proliferation through inducing apoptosis and autophagy via MAPK activation in glioma. However, the mechanism of luteolin on suppressing lung cancer growth is still unclear. We found that luteolin targeted LIMK1 from the in silico screening and significantly inhibited the LIMK1 kinase activity, which was confirmed with pull‐down binding assay and computational docking models. Treatment with luteolin inhibited lung cancer cells anchorage‐independent colony growth and induced apoptosis and cell cycle arrest at G1 phase. Luteolin also decreased the expression of cyclin D1 and increased the levels of cleaved caspase‐3 by down‐regulating LIMK1 signalling related targets, including p‐LIMK and p‐cofilin. Furthermore, luteolin suppressed the lung cancer patient‐derived xenograft tumour growth by decreasing Ki‐67, p‐LIMK and p‐cofilin expression in vivo. Taken together, these results provide insight into the mechanism that underlies the anticancer effects of luteolin on lung cancer, which involved in down‐regulation of LIMK1 and its interaction with cofilin. It also provides valuable evidence for translation towards lung cancer clinical trials with luteolin.

All eukaryotic cells are composed of the cytoskeleton, which plays crucial roles in coordinating diverse cellular functions such as cell division, morphology, migration, macromolecular stabilization, and protein trafficking. The cytoskeleton consists of microtubules, intermediate filaments, and actin filaments. Cofilin, an actin-depolymerizing protein, is indispensable for regulating actin dynamics in the central nervous system (CNS) development and function. Cofilin activities are spatiotemporally orchestrated by numerous extra- and intra-cellular factors. Phosphorylation at Ser-3 by kinases attenuate cofilin’s actin-binding activity. In contrast, dephosphorylation at Ser-3 enhances cofilin-induced actin depolymerization. Cofilin functions are also modulated by various binding partners or reactive oxygen species. Although the mechanism of cofilin-mediated actin dynamics has been known for decades, recent research works are unveiling the profound impacts of cofilin dysregulation in neurodegenerative pathophysiology. For instance, oxidative stress-induced increase in cofilin dephosphorylation is linked to the accumulation of tau tangles and amyloid-beta plaques in Alzheimer’s disease. In Parkinson’s disease, cofilin activation by silencing its upstream kinases increases α-synuclein-fibril entry into the cell. This review describes the molecular mechanism of cofilin-mediated actin dynamics and provides an overview of cofilin’s importance in CNS physiology and pathophysiology.

Humans are commonly exposed to the representative neurotoxic heavy metals lead (Pb), cadmium (Cd), and mercury (Hg). These three substances can be detected simultaneously in the blood of the general population. We have previously shown that a low-dose mixture of these heavy metals induces rat learning and memory impairment at human exposure levels, but the pathogenic mechanism is still unclear. LIM kinase 1 (LIMK1) plays a critical role in orchestrating synaptic plasticity during brain function and dysfunction. Hence, we investigated the role of LIMK1 activity in low-dose heavy metal mixture-induced neurobehavioral deficits and structural synaptic plasticity disorders. Our results showed that heavy metal mixture exposure altered rat fear responses and spatial learning at general population exposure levels and that these alterations were accompanied by downregulation of LIMK1 phosphorylation and structural synaptic plasticity dysfunction in rat hippocampal tissues and cultured hippocampal neurons. In addition, upregulation of LIMK1 phosphorylation attenuated heavy metal mixture-induced structural synaptic plasticity, dendritic actin dynamics, and cofilin phosphorylation damage. The potent LIMK1 inhibitor BMS-5 yielded similar results induced by heavy metal mixture exposure and aggravated these impairments. Our findings demonstrate that LIMK1 plays a crucial role in neurobehavioral deficits induced by low-dose heavy metal mixture exposure by suppressing structural synaptic plasticity.

Abstract Background Depression is one of the most common forms of mental illness and also a leading cause of disability worldwide. Developing novel antidepressant targets beyond the monoaminergic systems is now popular and necessary. LIM kinases, including LIM domain kinase 1 and 2 (LIMK1/2), play a key role in actin and microtubule dynamics through phosphorylating cofilin. Since depression is associated with atrophy of neurons and reduced connectivity, here we speculate that LIMK1/2 may play a role in the pathogenesis of depression. Methods In this study, the chronic unpredictable mild stress (CUMS), chronic restraint stress (CRS), and chronic social defeat stress (CSDS) models of depression, various behavioral tests, stereotactic injection, western blotting, and immunofluorescence methods were adopted. Results CUMS, CRS, and CSDS all significantly enhanced the phosphorylation levels of LIMK1 and LIMK2 in the medial prefrontal cortex (mPFC) but not the hippocampus of mice. Administration of fluoxetine, the most commonly used selective serotonin reuptake inhibitor in clinical practice, fully reversed the effects of CUMS, CRS, and CSDS on LIMK1 and LIMK2 in the mPFC. Moreover, pharmacological inhibition of LIMK1 and LIMK2 in the mPFC by LIMKi 3 infusions notably prevented the pro-depressant effects of CUMS, CRS, and CSDS in mice. Conclusions In summary, these results suggest that LIMK1/2 in the mPFC has a role in chronic stress-induced depressive-like effects in mice and could be a novel pharmacological target for developing antidepressants.

Background/Objectives: Cofilin, a key regulator of actin cytoskeleton dynamics, contributes to neuroinflammation, synaptic damage, and blood–brain barrier disruption in ischemic stroke. Despite its established role in stroke pathology, cofilin remains largely untargeted by existing therapeutics. This study aimed to identify potential cofilin-binding molecules by repurposing LIMK1 inhibitors through an integrated computational strategy. Methods: A cheminformatics pipeline combined QSAR modeling with four molecular fingerprint sets and multiple machine learning algorithms. The best-performing QSAR model (substructure–Random Forest) achieved R2_train = 0.8747 and R2_test = 0.8078, supporting the reliability of compound prioritization. Feature importance was assessed through SHAP analysis. Top candidates were subjected to molecular docking against cofilin, followed by 300 ns molecular dynamics simulations, MM-GBSA binding energy calculations, principal component analysis (PCA), and dynamic cross-correlation matrix (DCCM) analyses. Network pharmacology identified overlapping targets between selected compounds and stroke-related genes. Results: Three compounds, CHEMBL3613624, ZINC000653853876, and Gandotinib, were prioritized based on QSAR performance, binding affinity (−6.68, −6.25, and −5.61 Kcal/mol, respectively), and structural relevance. Docking studies confirmed key interactions with Asp98 and His133 on cofilin. Molecular dynamics simulations supported the stability of these interactions, with Gandotinib showing the highest conformational stability, and ZINC000653853876 exhibiting the most favorable energetic profile. Network pharmacology analysis revealed eight intersecting targets, including MAPK1, PRKCB, HDAC1, and serotonin receptors, associated with neuroinflammatory and vascular pathways in strokes. Conclusions: This study presents a rational, integrative repurposing framework for identifying cofilin-targeting compounds with potential therapeutic relevance in ischemic stroke. The selected candidates warrant further experimental validation.

Background Hepatocellular carcinoma (HCC) is one of the leading causes of cancer‐related deaths globally. Herein, we explored the underlying mechanism by which Propofol inhibited the development of HCC. Methods 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay was carried out to detect the viability and proliferation. Quantitative real‐time polymerase chain reaction (qRT‐PCR) and Western blot were performed to detect the expression of long noncoding RNA (lncRNA) H19, microRNA‐520a‐3p (miR‐520a‐3p), LIM domain kinase 1 (LIMK1), metastasis‐associated markers (Snail, Twist, Vimentin and E‐cadherin) and exosome markers (CD9 and CD81). Transmission electron microscopy (TEM) was used to observe the morphology and structure of exosomes. The apoptosis and metastasis were measured by flow cytometry and transwell assays. StarBase software was utilized to predict the targets of H19 and miR‐520a‐3p. Dual‐luciferase reporter assay was performed to confirm the interaction between miR‐520a‐3p and H19 or LIMK1. Nude mice bearing tumors were used to validate the role of exosomal H19. RESULTS The high expression of exosomal H19 accelerated the proliferation and motility while hampering the apoptosis of HCC cells. MiR‐520a‐3p could bind with H19. Exosomal H19 exacerbated HCC through sponging miR‐520a‐3p. The 3’ untranslated region (3’UTR) of LIMK1 could bind to miR‐520a‐3p. MiR‐520a‐3p mimic transfection reversed the inhibitory effect of high expression of exosomal LIMK1 on the apoptosis of HCC cells and the promoting effects on the proliferation and metastasis of HCC cells. The mRNA and protein levels of LIMK1 were regulated by H19/miR‐520a‐3p signaling. The high level of exosomal H19 promoted the growth of HCC tumors in vivo. Conclusion Circulating H19 promoted the proliferation, migration and invasion and inhibited the apoptosis of HCC cells treated with Propofol through upregulating LIMK1 via sponging miR‐520a‐3p. Exosomal lncRNA H19 elevated the malignant potential of HCC cells treated with Propofol via miR‐520a‐3p/LIMK1 axis in vivo and in vitro. The underlying mechanism of LIMK1 on the modulation of behaviors of HCC cells needs further exploration.

This study aimed to evaluate the clinical significance and underlying biological mechanisms of LIM kinase 1 (LIMK1) in hepatocellular carcinoma (HCC). Using multi-omics data from TCGA and ICGC cohorts, we analyzed LIMK1 expression and its prognostic value. Clinical validation was performed via immunohistochemistry on tissue microarray specimens. A multivariate Cox model integrating LIMK1 and clinicopathological features was constructed and evaluated using machine learning. Tumor immune microenvironment was profiled using multiple immune deconvolution algorithms. Immunotherapy cohorts and drug sensitivity data were leveraged to assess therapeutic implications. LIMK1 was significantly overexpressed in HCC tissues across all cohorts and correlated with poor overall survival (TCGA HR = 2.26,  P  < 0.001; ICGC HR = 2.23, P  = 0.011; in-house HR = 2.09, P  = 0.004). The prognostic Cox model integrating LIMK1 achieved high accuracy (1-year AUC = 0.90) and decision curve analysis showed the potential for clinical decision making. High LIMK1 expression was linked to an immunosuppressive microenvironment, characterized by elevated immunosuppressive cells (MDSCs, M2 macrophages, fibroblasts, and regulatory T cells) and immune checkpoint markers (PDCD1, CTLA4). HCC patients with high LIMK1 expression showed poor responses to immunotherapy but increased sensitivity to chemotherapy agents, including sorafenib, paclitaxel, docetaxel and 5-fluorouracil. In conclusion, LIMK1 serves as a promising biomarker in HCC, stratifying patients by prognosis and therapeutic response.

The Rho/ROCK/LIMK pathway is central for the mediation of repulsive environmental signals in the central nervous system. Several studies using pharmacological Rho-associated protein kinase (ROCK) inhibitors have shown positive effects on neurite regeneration and suggest additional pro-survival effects in neurons. However, as none of these drugs is completely target specific, it remains unclear how these effects are mediated and whether ROCK is really the most relevant target of the pathway. To answer these questions, we generated adeno-associated viral vectors to specifically downregulate ROCK2 and LIM domain kinase (LIMK)-1 in rat retinal ganglion cells (RGCs) in vitro and in vivo . We show here that specific knockdown of ROCK2 and LIMK1 equally enhanced neurite outgrowth of RGCs on inhibitory substrates and both induced substantial neuronal regeneration over distances of more than 5 mm after rat optic nerve crush (ONC) in vivo . However, only knockdown of ROCK2 but not LIMK1 increased survival of RGCs after optic nerve axotomy. Moreover, knockdown of ROCK2 attenuated axonal degeneration of the proximal axon after ONC assessed by in vivo live imaging. Mechanistically, we demonstrate here that knockdown of ROCK2 resulted in decreased intraneuronal activity of calpain and caspase 3, whereas levels of pAkt and collapsin response mediator protein 2 and autophagic flux were increased. Taken together, our data characterize ROCK2 as a specific therapeutic target in neurodegenerative diseases and demonstrate new downstream effects of ROCK2 including axonal degeneration, apoptosis and autophagy.

LIMK1 has been demonstrated to be highly correlated with the progression and overall survival rates of colorectal cancer (CRC) patients. In this study, a series of diarylheptanoid scaffold derivatives were intentionally designed and synthesised to evaluate their potential as LIMK1 inhibitors. Among these compounds, compounds and exhibited LIMK1 inhibitory activity with IC values of 0.94 and 0.57 µM, respectively. We also disclosed the structure-activity relationship of the resulting compounds that exhibited LIMK1 inhibition. Catechol-containing diarylheptanoid was identified as a promising scaffold for LIMK1 inhibitors. Notably, compound demonstrated selectivity in inhibiting the tyrosine kinase-like family and exhibited potent inhibition of CRC cells. Moreover, compound induced an increase in the S phase and a decrease in the G0/G1 phase in a dose-dependent manner, indicating apoptosis induction. These findings establish compound as a lead compound for the further development of anti-CRC agents.

Modern concepts hold that intellectual problems in neurological brain damage are based on active forgetting, which is regulated by actin remodeling signal cascades dependent on small GTPases Rac and Rho. The key enzyme in these cascades is LIM kinase 1 (LIMK1). Changes in limk1 gene expression lead to neurocognitive pathologies. There is a need to create and validate simple animal models for rapid screening and testing of targeted therapeutic agents altering the protein–protein interactions of GTPases and components of signal cascades. One opportunity for this is provided by Drosophila, mutant strains of which allow the key points of the intersections of biochemical and neural networks which accompany active forgetting to be identifi ed.