Korean Journal of Physiology & Pharmacology最新文献

Ischemic stroke is a leading cause of death and disability worldwide. Amorfrutin A (AA), a small molecule compound found in Amorpha fruticosa L. (bastard indigo), possesses various activities, including blood glucose regulation, antiinflammatory, analgesic, and tumor suppression. In this study, we used the middle cerebral artery occlusion/reperfusion (MCAO/R) model and the oxygen glucose deprivation/ reoxygenation (OGD/R) model to mimic the ischemia/reperfusion process in vivo and in vitro, respectively. The role of AA in ischemic stroke was evaluated by CCK-8 assay, ELISA, TTC staining, hematoxylin-eosin staining and Western blot assay. AA increased the survival of BV2 or PC12 cells following OGD/R injury. Meanwhile, AA effectively suppressed the release of reactive oxygen species, nitric oxide, and tumor necrosis factor-α (TNF-α) in BV2 or PC12 cells subjected to OGD/R. After 24 h of MCAO/R surgery, AA significantly reduced the neurological deficit score, diminished the cerebral infarct volume, and attenuated brain pathological injury in rats. AA administration significantly increased superoxide dismutase and glutathione peroxidase levels, reduced malondialdehyde production, and inhibited the release of inflammatory cytokines interleukin-1β and TNF-α in the ischemic brain tissue of MCAO/R rats. In addition, AA suppressed Kelch-like ECH-associated protein 1 expression and promoted nuclear factor erythroid 2-related factor 2 (Nrf2), NAD(P)H quinone oxidoreductase 1, and heme oxygenase 1 (HO-1) expression in rat ischemic brain. AA may be a potential drug for the treatment of ischemic stroke. Its antioxidant and anti-inflammatory effects in cerebral ischemia-reperfusion injury may be related to Nrf2/HO-1 signaling pathway.

Several molecules in human body exhibit light-dependent diurnal expression rhythms, and their disruption impairs physiological functions and health. Normal aging alters these rhythms, contributing to aging processes and age-related brain disorders. Chronic low-grade inflammation is a hallmark of aging (inflammaging), and age-related changes in the diurnal expression of proinflammatory cytokines have been reported in the suprachiasmatic nucleus (SCN) and peripheral blood. However, it remains unclear which genes show diurnal expression changes in brain with the SCN regions removed (extra-SCN) and whether these changes are reflected in peripheral blood. To address this, we analyzed the diurnal expression of genes in extra-SCN brain regions and cytokines in the peripheral blood of young and aged male and female mice. Samples were collected during the light (10 AM) and the dark (10 PM) phases and analyzed using RNA sequencing and cytokine array analysis. In the aged brain, the number of genes displaying diurnal variation in expression was reduced, whereas genes related to inflammation and immune responses, especially Ccl21, were upregulated regardless of phase, suggesting age-associated immune dysregulation. However, peripheral blood levels of CCL21 protein did not differ between age groups. Instead, CXCL13 and IGFBP1 showed age-related diurnal alterations in the blood, but their expression patterns in the aged brain differed from those in the blood. These findings indicate that diurnal expression of inflammation-related molecules is altered with aging in both the brain and blood, with differences observed. These diurnal changes may contribute to the underlying mechanism of inflammaging and age-related diseases.

Xuefu Zhuyu decoction (XFZY) has therapeutic effects on diabetic kidney disease (DKD)-induced renal interstitial fibrosis (RIF), but the mechanisms are unclear. This study investigates XFZY's molecular mechanisms through network pharmacology and experimental validation. Ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) and database screening was used to identify XFZY bioactive compounds. Common targets between these compounds and DKD-induced RIF were analyzed. A protein-protein interaction network was constructed, followed by gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Molecular docking validated interactions between XFZY compounds and targets. In vivo, a mouse model of DKD-induced RIF was established using streptozotocin and a high-fat diet. In vitro, human kidney-2 cells were treated with advanced glycation end products. Renal function and pathology were assessed, along with key protein expression levels. Using UPLC-Q-TOF-MS technology and database screening, seven bioactive components of XFZY were identified. Network pharmacology identified 61 common targets, including core targets like AKT1, MTOR, ULK1, and MMP9. Enrichment analysis indicated the AMPK signaling pathway is closely related to XFZY's therapeutic effects on DKD-induced RIF. Molecular docking demonstrated the seven bioactive components exhibited high binding affinities with key targets in the AMPK pathway (AMPK, mTOR, ULK1). In vivo, XFZY improved renal function, ameliorated renal pathology, reduced tubular injury, and alleviated RIF. Both in vivo and in vitro, XFZY increased phosphorylated AMPK and phosphorylated ULK1 expression, decreased phosphorylated MTOR, and reduced LC3 and p62 expression in the autophagy pathway. XFZY may alleviate DKD-induced RIF by modulating autophagy via the AMPK/MTOR/ULK1 pathway.

Aplastic anemia (AA) is a rare bone marrow failure syndrome marked by hypocellular bone marrow and pancytopenia, typically without abnormal infiltration or reticulin fiber increase. It often presents as acute, severe cytopenia in young adults and can have high mortality if untreated. Recent advancements, including immunosuppressive therapy (IST) combined with eltrombopag and hematopoietic stem cell transplantation (HSCT), have improved patient outcomes. This review discusses current etiopathogenesis involving immune dysregulation, genetic mutations, and environmental triggers. Accurate differential diagnosis, distinguishing AA from myelodysplastic syndromes and paroxysmal nocturnal hemoglobinuria, is essential for effective treatment. We also highlight emerging therapies, such as mismatched unrelated donor (MMUD) transplantation and precision medicine targeting genetic abnormalities. AA, with an incidence of 2-4 per million annually, peaks at ages 15-25 and over 60. These insights continue to reshape AA prognosis and management. This disease typically manifests as acute, severe cytopenia, particularly in young adults, and has a high mortality rate if untreated. Advances in treatment, including IST combined with eltrombopag and HSCT, have significantly improved outcomes. In this review, we explore the current etiopathogenesis, including immune dysregulation, genetic mutations, and environmental factors. The differential diagnosis of AA, distinguishing it from conditions such as myelodysplastic syndromes and paroxysmal nocturnal hemoglobinuria, is critical for tailored treatment. AA remains a rare disease, with an annual incidence of 2-4 per million, and peaks in occurrence during the ages of 15-25 and over 60. These advancements in understanding and managing AA continue to transform its prognosis and patient care.

Pulmonary arterial hypertension (PAH) is a fatal disease marked by increased pulmonary vascular resistance and right ventricular (RV) failure. Impaired vascular relaxation and vasoconstrictive signaling, including Rho-associated kinase (ROCK2) upregulation and myosin phosphatase target subunit 1 (MYPT1) downregulation, contribute to disease progression. We investigated the therapeutic effects of URO-K10, a novel K_v7.4 channel activator, in a monocrotaline-induced rat model of PAH (PAH-MCT). In PAH-MCT rats, chronic URO-K10 administration improved body weight gain, and significantly reduced RV hypertrophy. Functional studies revealed enhanced pulmonary artery relaxation, while relaxation after high K+-induced contraction showed only partial recovery. Immunoblot analysis demonstrated that ROCK2 upregulation was reversed by URO-K10, but MYPT1 remained downregulated and MLC2 diphosphorylation persisted. Interestingly, treatment with 8-Br-cGMP restored delayed relaxation and reduced MLC2 phosphorylation in URO-K10-treated PAH-MCT while not in the untreated PAH-MCT rats, suggesting that cGMP supplementation can compensate for the recovery from impaired endogenous signaling by the URO-K10 application. These findings suggest that URO-K10 improves pulmonary hemodynamics and RV remodeling via K_v7.4 activation and downregulation of ROCK2. However, incomplete recovery of MYPT1 and MLC2 phosphorylation highlights the complexity of contractile regulation in PAH. K_v7.4 activation represents a promising therapeutic approach but may require combination strategies to fully restore vascular function in PAH.

Olanzapine, an atypical antipsychotic, is widely used in the treatment of schizophrenia and bipolar disorder due to its modulation of dopamine and serotonin receptor systems. While its primary action involves antagonism of dopamine D2 and serotonin 5-HT (5-hydroxytryptamine)₂A receptors, recent evidence suggests that olanzapine also inhibits 5-HT₃ receptors, which are ligand-gated ion channels involved in synaptic transmission in central and peripheral nervous systems. The present study aimed to investigate the action of olanzapine on 5-HT₃ receptor-mediated currents using whole-cell voltage-clamp recordings in NCB-20 neuroblastoma cells. Results of this study indicated that olanzapine could act as a non-competitive antagonist of the 5-HT₃ receptor, exhibiting concentration-dependent inhibition of ion currents. Moreover, olanzapine facilitated both deactivation and desensitization kinetics, accelerating decay of 5-HT₃ receptor-mediated currents. Recovery from desensitization was significantly delayed by olanzapine, whereas recovery from deactivation was largely unaffected by it. Current-voltage relationship analysis revealed that olanzapine reduced the amplitude of 5-HT₃ receptor-mediated currents across all holding potentials without altering reversal potential, suggesting a voltage-independent inhibition. Furthermore, olanzapine exhibited use-dependent inhibition, with a greater reduction in current observed during more frequent 5-HT application. These findings provide novel insights into a non-competitive and allosteric inhibition of 5-HT₃ receptors by olanzapine, contributing to a deeper understanding of its pharmacological profile in neuropsychiatric and gastrointestinal conditions where serotonergic neurotransmission is implicated.

Melanoma is a common and aggressive tumor, characterized by a high incidence rate and extensive metastasis. Chelidonine exhibits a broad range of biological properties including anti-inflammatory, antimicrobial, and anticancer effects. Our study is intended to explore the effects chelidonine of on melanoma cells. In detail, CCK-8 assay was used for detection of cell viability. The colony formation assay was carried out to measure cell proliferation. Wound healing assay and Transwell assay were employed to evaluate cell migration and invasion, respectively. Cell apoptosis was determined by flow cytometry analysis, and protein level was measured by Western blotting. The experimental results demonstrated that chelidonine treatment inhibited cell viability and cell proliferation but facilitated cell apoptosis of melanoma cells. Besides, chelidonine suppressed melanoma cancer cell migration and invasion by attenuating epithelial-mesenchymal transition process. Moreover, chelidonine inhibited the activation of TLR4/NF-κB and PI3K/AKT pathways by downregulation of the protein level of TLR4, phosphorylated p65, phosphorylated PI3K, and phosphorylated AKT in melanoma cells. Furthermore, TAK-242 or LY294002 further enhanced the inhibitory effects chelidonine of on malignant cell behavior. In conclusion, our findings demonstrate that chelidonine effectively suppresses the malignancy of melanoma cells through the inhibition of TLR4/NF-κB and PI3K/AKT signaling pathways, suggesting its potential as a promising therapeutic agent for melanoma treatment.

Melittin (MEL) is the main bioactive component of bee venom and has been reported to have various pharmacological effects. This study investigates the protective effect of MEL on MPP⁺-injured HT22 cells and the possible mechanisms involved. We treated the cells with 4 mM MPP⁺ for 24 h to induce a cellular injury model. HT22 cells were pretreated with 0.1 μM MEL for 6 h and then exposed to 4 mM MPP⁺ for 24 h. We measured cell viability, the expression of Bax, the indicators and protein levels associated with apoptosis and parthanatos, and the co-localisation of MEL and mitochondria, and mitochondrial function-related indices such as the mitochondrial membrane potential (MMP) and mito-SOX. We show that PAR protein expression was significantly increased in the MPP⁺-treated cell model and that the parthanatos inhibitor DPQ significantly reduced MPP⁺-induced cell death, suggesting that MPP⁺ can cause PARP1-dependent cell death. MEL significantly inhibited cell death, increased cell viability as well as NAD+ and ATP levels, increased the expression of Bcl-2 and suppressed the activation of Bax, cleaved-caspase3, and cleaved-PARP1. Moreover, MEL was found to be localised on the mitochondria of HT22 cells and to improve mitochondrial functions including increased MMP and decreased mitochondrial reactive oxygen species. We speculate that MEL may protect neurons against MPP⁺-induced HT22 cell injury by inhibiting Bax activation, suppressing changes in mitochondrial permeability, and improving mitochondrial function, thereby preventing cell parthanatos and apoptosis.

Syringetin inhibits bone metastasis in cancer, but its action in breast cancer-related bone pain is unknown. This study aims to analyze the action of Syringetin in breast cancer-related bone pain. Based on network pharmacology analysis, estrogen receptor 1 (ESR1) was identified as the core gene between Syringetin and bone pain associated with breast cancer, with the binding energy of -7.5 kcal/mol to ESR1 protein. Syringetin exhibited a dose-dependent inhibition of breast cancer cell viability, suppressed cell migration and expression of ESR1 and PRDM2 protein, and promoted cell apoptosis. In the Syringetin intervention group of rats, the bone trabeculae and cortical bone were slightly intact, along with an elevation in AS and PWT scores, a decrease expression of ESR1 and PRDM2 proteins. There was a clearly positive correlation between ESR1 protein and the GFAP, IBA1, and NeuN levels. Syringetin alleviated the disease characteristics of breast cancer-related bone pain by downregulating the ESR1/PRDM2 proteins.

Acute myocardial infarction (AMI) represents a significant global mortality factor. Alterations in nicotinamide metabolism within the myocardium post-AMI can influence the progression of the condition. Additionally, melanin plays a crucial role in nicotinamide metabolism and exhibits anti-inflammatory properties. Nevertheless, the diagnostic biomarkers for AMI that are based on nicotinamide metabolism and melanin-associated genes remain poorly defined. In this study, the AMI transcriptomic data from the Gene Expression Omnibus were analyzed to identify differentially expressed genes (DEGs) intersecting with nicotinamide metabolism and melatonin-related genes. Machine learning algorithms, including RandomForest, least absolute shrinkage and selection operator, and support vector machine-recursive feature elimination, were applied to select feature genes. Diagnostic markers were further evaluated based on area under the curve from receiver operating characteristic analysis. We identified 14 candidate genes, refined to 4 key genes, with NAMPT and BST1 ultimately selected as diagnostic biomarkers. These were used to classify AMI into two molecular subtypes. Immune landscape analysis revealed increased infiltration of monocytes, neutrophils, macrophages, and parainflammation in AMI. Enrichment analyses showed DEGs were mainly involved in innate immune response and cytokine production. Additionally, hsa-miR-34a-5p and hsa-miR-181b-5p were identified as potential regulators of NAMPT and BST1. In summary, NAMPT and BST1 are promising diagnostic biomarkers associated with nicotinamide metabolism and melatonin in AMI. The molecular subtyping based on these genes will enhance the management and hierarchical treatment of AMI, offering significant implications for clinical diagnosis and therapeutic strategies.