Korean Journal of Physiology & Pharmacology最新文献

Recent research indicates that mitofusin 2 (MFN2) plays a pivotal role in the neuroprotective effects achieved by silencing nuclear receptor subfamily 6 group A member 1 (NR6A1) during cerebral ischemia. While NR6A1 is known to inhibit octamer-binding transcription factor 4 (OCT4), the regulatory relationship between OCT4 and MFN2 remains unknown. This study explores the neuroprotective effects of OCT4-activating compound 1 (OAC1), an OCT4 activator, against cerebral ischemia/reperfusion injuries and its underlying mechanism. In a murine stroke model, administration of OAC1 (3 mg/kg) significantly reduced brain infarction of mice and loss of MFN2. Notably, OAC1 treatment mitigated neuronal injury induced by oxygen-glucose deprivation/reoxygenation (OGD/R) in a dose-dependent manner. Additionally, OAC1 treatment also alleviated dysfunction of mitochondria and endoplasmic reticulum stress. Moreover, OAC1 application preserved both OCT4 and MFN2 expression following OGD/R, and MFN2 facilitate protective function of OAC1 against neuronal damage induced by OGD/R. Our results demonstrate that OAC1 can alleviate neuronal damage in cerebral ischemia by activating the OCT4/MFN2. These findings offer novel insights into MFN2 regulation and highlight OCT4's potential as a therapeutic target for cerebral ischemia.

Hemistepsin A is a sesquiterpene lactone isolated from plants of the family. Recently, this compound was reported to be a bioactive compound that is beneficial for numerous health problems without side effects; however, its effect on lung cancer cells has not yet been studied. Therefore, in this study, we investigated the anticancer activity of hemistepsin A in human lung carcinoma A549 cells. This study showed that treatment with hemistepsin A induces apoptosis by activating caspase cascade and reducing the expression of inhibitors of apoptotic protein family members. Additionally, hemistepsin A disrupted mitochondrial integration by altering the levels of Bcl-2 family proteins to increase the cytoplasmic release of cytochrome c. Moreover, hemistepsin A reduced the activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway, and pretreatment with a PI3K inhibitor markedly augmented the cytotoxic effect of hemistepsin A on A549 cells. Furthermore, hemistepsin A significantly enhanced the production of intracellular and mitochondrial reactive oxygen species (ROS), whereas ROS scavengers restored the reduced viability by attenuating DNA damage and apoptosis by blocking the hemistepsin A-mediated inactivation of the PI3K/Akt pathway. Our findings demonstrate that hemistepsin A induces apoptosis in A549 cells by generating ROS, which subsequently inhibits the PI3K/Akt pathway, suggesting that ROS generation is involved as an early inducer of hemistepsin A-mediated anticancer activity.

Skeletal muscle differentiation is a complex process regulated by a network of genes and transcription factors. Recent studies have revealed the roles of circular RNAs (circRNAs) and microRNAs (miRNAs) in modulating gene expression during myogenesis. In this study, we focused on the functional interplay between circAtxn10, miR-143-3p, and the nicotinic acetylcholine receptor subunit alpha 1 (Chrna1) in skeletal muscle differentiation. Our results demonstrate that circAtxn10 expression increases during myogenic differentiation and acts as a sponge for miR-143-3p through direct binding. We identified Chrna1 as a direct target of miR-143-3p through three binding sites in its 3'-UTR and showed that both miR-143-3p mimic and Chrna1 knockdown significantly impair myogenesis. Notably, Chrna1 overexpression dramatically enhanced myogenic marker expression and myotube formation. Our findings establish a regulatory axis involving circAtxn10, miR-143-3p, and Chrna1 that plays a critical role in modulating skeletal muscle differentiation, providing new insights into the complex molecular mechanisms regulating myogenesis.

The substantia gelatinosa (SG) of the trigeminal subnucleus caudalis (Vc) serves as the primary relay point for orofacial nociceptive inputs transmitted via thin myelinated Aδ and unmyelinated C primary afferent fibers. Citronellol is a monoterpenoid alcohol found in the essential oil of various medicinal plants, such as Cymbopogon citratus. It has been shown to be able to alleviate orofacial pain. However, the precise mechanism by which citronellol modulates SG neurons in the Vc remains unclear. To investigate this, the whole-cell patch-clamp technique was used to examine antinociceptive effects of citronellol on SG neurons in the Vc of mice. In a high-chloride pipette solution, citronellol consistently induced inward currents which persisted even in the presence of tetrodotoxin (a voltage-gated Na⁺ channel blocker), 6-cyano-7-nitroquinoxaline-2,3-dione (a non-N-methyl-d-aspartate glutamate receptor antagonist), and DL-2-amino-5-phosphonopentanoic acid (an N-methyl-d-aspartate receptor antagonist). Nevertheless, citronellol-induced inward currents were partially inhibited by picrotoxin, a GABA_A receptor antagonist, or strychnine, a glycine receptor antagonist. Citronellol-induced inward currents were almost fully blocked when both strychnine and picrotoxin were applied together. In addition, citronellol enhanced both GABA-induced inward currents and glycine-induced inward currents. These findings suggest that citronellol can mediate inhibitory effects of GABA and glycine on SG neurons in the Vc and serve as a potential herbal treatment for orofacial pain.

Diabetic nephropathy (DN), a primary cause of end-stage renal disease, stems from hyperglycemia-induced vascular dysfunction and aberrant angiogenesis. Sodium-glucose cotransporter 2 inhibitors, such as dapagliflozin, improve glycemic control and provide renal protection yet fall short of fully halting DN progression. This study explores 4E2, a Tie2 receptor activator that mimics angiopoietin-1 to stabilize the vascular endothelium, as a novel DN therapy-both independently and in combination with dapagliflozin. In a streptozotocin (STZ)-induced DN mouse model (DBA/2J strain), male mice were treated with weekly intravenous 4E2, daily oral dapagliflozin, or a combination of both for 4 weeks following STZ administration. Dapagliflozin primarily reduced fasting blood glucose with modest renoprotective effects, whereas 4E2 significantly lowered kidney weight, blood urea nitrogen, and urinary albumin while elevating serum albumin, indicating greater renal protection. Histological analysis showed that 4E2 more effectively attenuated glomerular hypertrophy and lesions compared to dapagliflozin. Immunohistochemistry revealed that 4E2 markedly increased VE-cadherin and CD31 expression while decreasing PDGFR-β, reflecting enhanced endothelial stability and reduced vascular remodeling through Tie2-mediated mechanisms. Combination therapy synergistically enhanced these outcomes, achieving superior reductions in glucose levels, glomerular damage, and vascular pathology compared to either treatment alone. In contrast to anti-VEGF therapies, which can worsen proteinuria, 4E2-mediated Tie2 activation normalizes vascular stability without disrupting physiological angiogenesis, providing a safer therapeutic option. These findings establish 4E2 as a promising treatment for DN, especially when combined with dapagliflozin, by leveraging Tie2-driven stabilization and synergistic benefits to meet this critical unmet need.

Agmatine, a decarboxylation product of L-arginine, has been proposed as a novel neurotransmitter/neuromodulator with diverse neuroprotective and antidepressant-like effects. Although its therapeutic potential has been explored, the precise mechanisms by which agmatine modulates synaptic transmission and plasticity in the hippocampus remain unclear. In this study, we investigated the effects of agmatine on the induction and maintenance of long-term potentiation (LTP) in the CA1 region of mouse hippocampal slices, its ability to counteract amyloid-β (Aβ1-42)-induced LTP impairment, and the receptor systems involved. Bath application of agmatine significantly suppressed the maintenance phase of LTP. Notably, agmatine reversed Aβ-induced deficits in LTP, suggesting a protective effect against synaptic dysfunction. Pharmacological experiments demonstrated that these effects were mediated via α2-adrenergic and imidazoline type I receptors. Paired-pulse facilitation and input-output analyses revealed that agmatine did not alter presynaptic release probability but selectively modulated postsynaptic transmission, particularly under AMPA receptor blockade, indicating a potential regulation of NMDA receptor-mediated signaling. Together, these findings suggest that agmatine modulates hippocampal synaptic plasticity through receptor-specific, postsynaptic mechanisms, and highlight its potential as a therapeutic agent against synaptic impairments in neurodegenerative diseases.

Alprenolol is a nonselective β-adrenoceptor antagonist used in treating cardiovascular diseases by stabilizing elevated heart rates and myocardial contractility through the inhibition of sympathetic nerve transmissions alongside its role as an antagonist of 5-HT_1A and 5-HT_1B receptors. This study aimed to examine whether alprenolol can affect human Kv1.3 channel (hKv1.3) currents, which contribute to the proliferation and activation of T lymphocytes by regulating the driving force of Ca²⁺ influx. We investigated the acute effects of alprenolol on hKv1.3 channel currents using two-microelectrode voltage clamp recordings in Xenopus oocytes. Alprenolol exhibited concentration-dependent biphasic effects on hKv1.3 currents: it increased the current amplitudes at 1-100 μM but decreased them at 300-1,000 μM during a +50 mV depolarization step. A significant difference was found in alprenolol's effects on the peak and steady-state currents after 6 min of treatment with 10 μM, 50 μM, and 100 μM and 12 min of treatment with 10 μM and 50 μM. Furthermore, alprenolol affected the time constants of intrinsic inactivation and ultrarapid activation. However, no significant changes in V_1/2 and k value were found for steady-state activation and inactivation curves, except for the k value between 50 μM and 1,000 μM of the inactivation curve. At 1,000 μM, alprenolol suppressed hKv1.3 currents more rapidly during 5 sec inter-stimulus intervals compared to 15 sec intervals, indicating use-dependent blockade. Therefore, the effects of alprenolol on the biphasic and various biophysical properties of hKv1.3 channels could cause drug concentration-dependent changes in immune function.

Vascular smooth muscle cell (VSMC) proliferation contributes to intimal thickening in atherosclerosis and restenosis diseases. As a proanthocyanidin type B, procyanidin B2 (PB2) is abundantly found in cocoa, apples, and grapes and is reported to have vascular protective effects. However, the mechanisms by which PB2 inhibits proliferation of VSMCs are not clearly understood. Therefore, the purpose of this study was to investigate the underlying mechanism of PB2-induced inhibition of cell proliferation in VSMCs. We found that PB2 dose- and time-dependently increased phosphorylation of liver kinase B1 (LKB1) and AMP-activated protein kinase (AMPK) in VSMCs. AMPK is a serine-threonine kinase and serves as a key sensor of cellular energy. PB2 induced LKB1 translocation from nucleus to cytosol which led to AMPK activation. In addition, PB2-induced AMPK activation decreased cell proliferation and cell cycle progression by inhibiting mammalian target of rapamycin signaling pathway. Transfection with LKB1 or AMPK siRNA and transduction of dominant-negative isoforms of the α1 and α2 subunits of AMPK eliminated anti-proliferative effects of PB2. These results demonstrate that PB2 might be a preventive agent for cardiovascular disorders such as atherosclerosis and hypertension.

Axl, a receptor tyrosine kinase, plays a critical role in various cellular processes, such as survival, proliferation, migration, and immune response regulation. Dysregulation of Axl, particularly its overexpression and activation, is implicated in several cancers, where it has been found to facilitate tumor growth, metastasis, and the development of resistance to chemotherapy. Consequently, the inhibition of Axl has garnered significant interest as a potential strategy for cancer treatment. Natural compounds, known for their structural diversity and inherent bioactivity, are a valuable resource for drug discovery. These compounds offer a vast array of chemical structures that can serve as potential inhibitors of Axl, thereby providing novel approaches to modulate its activity. Researchers have identified various natural compounds that exhibit inhibitory effects on Axl, which underscore their potential for developing effective therapies. This review strives to provide a comprehensive overview of natural compounds that have been identified as Axl inhibitors. It will examine the mechanisms through which these natural compounds exert their inhibitory effects on Axl and discuss their potential applications in therapeutic settings. By compiling and analyzing existing research, this review seeks to advance the understanding of natural compounds as viable candidates in the development of effective Axl-targeted therapies, ultimately contributing to improved outcomes in diseases marked by Axl dysregulation.