Cyclin-dependent kinase 5 (CDK5), which belongs to the protein kinase family, regulates neuronal function but is also associated with cancer development and has been proposed as a target for cancer treatment. Indeed, CDK5 has roles in cell proliferation, apoptosis, angiogenesis, inflammation, and immune response. Aberrant CDK5 activation triggers tumour progression in numerous types of cancer. In this review, we summarise the role of CDK5 in cancer and neurons and CDK5 inhibitors. We expect that our review helps researchers to develop CDK5 inhibitors as treatments for refractory cancer.

Epidemiological studies have linked fine dust pollution to depression, yet the underlying mechanisms remain unclear. Oxidative stress and endoplasmic reticulum (ER) stress are known contributors to depression, but their induction by particulate matter (PM), particularly PM2.5, in animal models has been limited. This study aimed to establish a rat model of PM2.5-induced depression-like behaviors and elucidate the underlying molecular mechanisms. Adult male Sprague–Dawley rats received daily intranasal PM2.5 for four weeks. Behavioral assessments, including the open field test (OFT), forced swim test (FST), and light-dark box (LDB) test, were conducted weekly. PM2.5-exposed rats displayed depressive-like behaviors, particularly in the FST, reflecting decreased motivation and learned helplessness. Molecular analyses indicated a specific increase in ER stress markers (CHOP, eIF2α, GRP78, and P16) and NOX4 in the hypothalamus, while other brain regions (striatum, cortex, and hippocampus) were not as pronounced. Additionally, PM2.5 exposure reduced tyrosine hydroxylase (TH) levels in the hypothalamus, suggesting impaired dopamine synthesis. These findings indicate that PM2.5 induces depressive-like behaviors via hypothalamic ER stress and oxidative stress pathways, leading to dopaminergic dysfunction. Targeting oxidative and ER stress within the hypothalamus may offer new therapeutic strategies for treating depression associated with environmental pollutants.

LW1497 suppresses the expression of the hypoxia-inducing factor (HIF)-1α inhibiting malate dehydrogenase. Although hypoxia and HIF-1α are known to be important in cancer, LW1497 has not been therapeutically applied to cancer yet. Thus, we investigated the effect of LW1497 on the epithelial-mesenchymal transition (EMT) of lung cancer cells. A549 and H1299 lung cancer cells were induced to undergo via TGF-β1 treatment, resulting in the downregulation of E-cadherin and upregulation of N-cadherin and Vimentin concurrently with increases in the migration and invasion capacities of the cells. These effects of TGF-β1 were suppressed upon co-treatment of the cells with LW1497. An RNA-seq analysis revealed that LW1497 induced differential expression of genes related to hypoxia, RNA splicing, angiogenesis, cell migration, and metastasis in the A549 lung cancer cell lines. We confirmed the differential expression of Slug, an EMT-related transcription factor. Results from Western blotting and RT-PCR confirmed that LW1497 inhibited the expression of EMT markers and Slug. After orthotopically transplanting A549 cancer cells into mice, LW1497 was administered to examine whether the lung cancer progression was inhibited. We observed that LW1497 reduced the area of cancer. In addition, the results from immunohistochemical analyses showed that LW1497 downregulated EMT markers and Slug. In conclusion, LW1497 suppresses cancer progression through the inhibition of EMT by downregulating Slug.

Airborne fine particulate matter (PM2.5) exposure is associated with central neuroinflammation and autonomic dysfunction, but its effects on peripheral sympathetic ganglia remain poorly defined. Here, we examined the effects of central PM2.5 administration and direct PM2.5 exposure on the superior cervical ganglion (SCG), a primary sympathetic relay governing cephalic noradrenergic outflow. Intracerebroventricular (ICV) administration of PM2.5 increased hypothalamic TNF-α and IL-6 levels and reduced presynaptic synaptophysin expression, while SCG tyrosine hydroxylase expression remained unchanged. In a complementary ex vivo model, direct PM2.5 exposure reduced norepinephrine (NE) accumulation in the culture medium of isolated SCGs without significantly altering tissue NE content. Mechanistically, live-cell Ca²⁺ imaging revealed attenuated depolarization-evoked Ca²⁺ responses in SCG neurons following either 24-h direct exposure or in vivo ICV administration. Whole-cell patch-clamp recordings further demonstrated reduced voltage-gated Ca²⁺ channel (VGCC) current density in neurons isolated from ICV PM2.5-treated rats. This functional reduction was not accompanied by significant changes in the SCG mRNA levels of the examined pore-forming Ca_vα1 subunits. In parallel, ICV PM2.5 administration increased GFAP and Kir4.1 protein levels and enhanced perineuronal GFAP immunoreactivity, consistent with satellite glial cell reactivity. Together, these findings identify impaired neuronal Ca²⁺ signaling and accompanying glial alterations in the SCG following PM2.5 exposure. The reductions in extracellular NE accumulation and VGCC function across complementary exposure models support a potential contribution of impaired Ca²⁺-dependent secretion to PM2.5-associated sympathetic dysfunction.