Korean Journal of Physiology & Pharmacology最新文献

Tricyclic antidepressants (TCAs) have been widely used for the treatment of major depressive disorder and other psychiatric conditions. However, their clinical application has declined due to adverse side effects and the availability of newer antidepressants with improved safety profiles. TCAs primarily target serotonin and norepinephrine receptors but also interact with a variety of other receptors and ion channels, contributing to both their therapeutic and adverse effects. We previously reported that TCAs regulate transient receptor potential canonical type 4 (TRPC4) channels. In this study, we investigated whether TCAs similarly modulate TRPC5 channels. Using HEK293 cells overexpressing TRPC5, we measured TRPC5 currents and intracellular calcium levels. Without altering TRPC5 expression levels, TCAs (amitriptyline, desipramine, and imipramine) dose-dependently reduced inward currents through TRPC5, with IC₅₀ values of 2.9, 10.3, and 11.7 μM, respectively. Given that TCAs can act as off-target agonists at opioid receptors (ORs), we co-expressed TRPC5 with various OR subtypes (μ-, δ-, and κ-ORs). Our results revealed that at low concentrations, TCAs enhanced TRPC5 activation through OR stimulation, whereas at higher concentrations, competitive inhibition of TRPC5 activity predominated. The biphasic modulation of TRPC5 by TCAs may contribute to a wide spectrum of cardiovascular and neurological manifestations, depending on the dosage and clinical application. Overall, these findings enhance the pharmacological understanding of the molecular mechanisms underlying the actions of TCAs and emphasize the need for more targeted therapeutic approaches.

Wogonin has been shown to exhibit anti-tumor effects by regulating the growth and inducing cell death in hepatocellular carcinoma (HCC) cells. However, its impact on radiotherapy for HCC remains unclear. This study aimed to elucidate the mechanisms and effects of wogonin in enhancing radiotherapy for HCC. The viability and cell cycle of HCC cells were assessed using CCK-8, trypan blue dye exclusion, and flow cytometry. RNA sequencing was performed to explore the genomic effects of wogonin on HCC cells. Immunofluorescence staining was employed to detect γ-H2AX distribution, and Western blot was used to evaluate the expression of γ-H2AX and p21. Wogonin induced cell cycle arrest and inhibited DNA damage repair in SMMC-7721 and HCC-LM3 cells following irradiation. RNA sequencing analysis of wogonin-and radiation-treated cells revealed significant enrichment of genes related to cell cycle progression, with notable changes in CDK inhibitor expression. Furthermore, wogonin in combination with irradiation increased the expression of γ-H2AX and p21 in HCC cells. Notably, p21 interference partially abrogated the anti-tumor effects of wogonin and radiation. Wogonin enhances the efficacy of radiotherapy in HCC by promoting cell cycle arrest and inhibiting DNA damage repair through upregulation of p21.

Transient receptor potential vanilloid 3 (TRPV3)-mediated Ca²⁺ signaling in keratinocytes plays a crucial role in epidermal keratinocyte differentiation and triggers the release of pro-inflammatory cytokines, causing inflammation and itching. However, the regulation of skin barrier recovery by TRPV3 and its expression during keratinocyte differentiation remain unexplored. This study aimed to investigate the role and expression levels of TRPV3 in keratinocyte differentiation and skin barrier recovery, focusing on the effects of varying TRPV3 activation using pharmacological agents. Differentiation of primary human keratinocytes was induced in high-calcium media, and TRPV3 activity and expression were assessed using patch-clamp, fura-2 fluorimetry, and immunoblotting. The effects of TRPV3 agonists on skin barrier recovery following tape stripping were evaluated by measuring transepidermal water loss in mice. Results showed that TRPV3 expression, current density, and agonist-induced [Ca²⁺]_i changes increased with keratinocyte differentiation. The TRPV3 antagonist, ruthenium red, inhibited both keratinocyte differentiation and TRPV3 upregulation. TRPV3 agonists (2-APB/carvacrol) facilitated early differentiation but paradoxically downregulated TRPV3 expression at higher concentrations. Moderate TRPV3 activation by lower agonist concentrations enhanced skin barrier recovery, while higher concentrations hindered recovery and induced immune cell infiltration. These findings highlight the dual role of TRPV3 in skin homeostasis and suggest that targeted modulation of TRPV3 could be a promising strategy for treating skin disorders.

Hyperphosphatemia is a potentially life altering condition in end-stage renal disease patients who are on regular hemodialysis that can lead to cardiovascular calcification, metabolic bone disease and secondary hyperparathyroidism. Bile acid sequestrants are anion exchange resins bind to bile acids and phosphate in the intestine resulting in preventing intestinal absorption of dietary phosphate, interruption of bile acid homeostasis and reduction in low-density lipoprotein cholesterol levels. Cholestyramine is chosen for study in hemodialysis patients based on the effectiveness and safety of bile acid sequestrants such colestilan and colestipol in the treatment of hyperphosphatemia and hypercholesterolemia in hemodialysis patients. A prospective, interventional, randomized, double blinded, placebo-controlled two arm study was carried out to assess the efficacy of oral cholestyramine on reduction of serum phosphate level in adult hemodialysis patients. 76 eligible patients were randomly assigned to either a drug group or a placebo group for the 2-month study period. The protocol was approved by the institutional review board of the faculty of pharmacy Ain Shams University Ethical committee and has been registered on ClinicalTrials.gov: NCT05577507. Over the 2-month treatment period, patients in cholestyramine group showed a significant decline in serum phosphorus levels versus placebo group (4.6 mg/dl vs. 6.6 mg/dl; p < 0.001) and serum calcium-phosphorus product (40 mg²/dl² vs. 59.8 mg²/dl²; p < 0.001). Median serum triglyceride and low-density lipoprotein cholesterol levels had decreased significantly versus baseline values in the cholestyramine group. Cholestyramine used with phosphate binders effectively lowers phosphorus levels, improves the lipid profile, and has mild adverse effects.

Postmenopausal osteoporosis (PMOP) is characterized by estrogen depletion, leading to skeletal demineralization and fractures. This study examines the impact of Colla Carapacis et Plastri (CCP) on PMOP in ovariectomized rats. Within this research, we replicated a rat model of PMOP through ovariectomy. The model rats were then intervened with low-dose CCP, high-dose CCP, and estrogen (positive control). The body weight was recorded, and the uterine index (UMI) was calculated. After intervention with CCP and the receptor activator of nuclear factor Κb (RANK) ligand (RANKL) inhibitor denosumab in PMOP rats, the bone microstructure, bone metabolism, macrophage M1/M2, and RANK/RANKL/Osteoprotegerin (OPG) signaling pathway-related factors were examined. These were conducted through hematoxylin and eosin staining, Biochemical kits and immunohistochemistry, respectively. The ovariectomized rat model was successfully established. Compared to the Sham group, rats in the Model group exhibited increased body weight, reduced UMI, and extensive damage to the microstructure of the femur. After intervention with CCP, the bone tissue microstructure of PMOP rats was repaired, as observed in increased levels of blood calcium level. Furthermore, CCP intervention led to reduced M1 macrophage levels (iNOS and CD86) and increased M2 macrophage levels (CD163 and CD206). Additionally, CCP treatment decreased RANK and RANKL expression levels and increased expression of OPG. The addition of denosumab further enhanced the effects of CCP. CCP can improve PMOP and regulate macrophage immunity in ovariectomized rats by modulating the RANK/RANKL/OPG signaling pathway.

Diabetic retinopathy (DR), a significant complication that affects the retina of individuals with diabetes, poses a severe threat to their visual health. DR is classified into stages ranging from non-proliferative to proliferative forms. As the disease progresses, pathological neovascularization and hemorrhage in the retina or vitreous can occur, potentially leading to vision impairment or blindness. Current treatments for DR include intravitreal injections of anti-vascular endothelial growth factor drugs and surgical interventions such as laser photocoagulation. However, these treatments are associated with various complications and side effects. Therefore, cellular and epigenetic studies are necessary to better understand the pathogenesis of DR, which may lead to the development of novel therapeutic strategies. Several studies have demonstrated the role of circular RNAs (circRNAs) in the pathogenesis and progression of DR. CircRNAs have been shown to regulate the expression of genes involved in the proliferation, differentiation, or angiogenesis of different retinal cells, thereby influencing their function. Therefore, this review aims to investigate the role of circRNAs in different retinal cell types in DR and evaluate their potential as diagnostic and therapeutic targets for the disease.

The 5-hydroxytryptamine type₃ (5-HT₃) receptor, a ligand-gated ion channel, plays a critical role in synaptic transmission. It has been implicated in various neuropsychiatric disorders. This study aimed to elucidate the mechanism by which quetiapine, an atypical antipsychotic, could inhibit 5-HT₃ receptor-mediated currents in NCB20 neuroblastoma cells. Whole-cell patch-clamp recordings were used to study effects of quetiapine on receptor ion channel kinetics and its competitive antagonism. Co-application of quetiapine shifted 5-HT concentration-response curve rightward, significantly increasing the EC50 without altering the maximal response (E_max), suggesting a competitive inhibition. Quetiapine's IC₅₀ varied with 5-HT concentration and treatment condition. The IC₅₀ value of quetiapine was 0.58 μM with 3 μM 5-HT and 25.23 μM with 10 μM 5-HT, indicating an inverse relationship between quetiapine efficacy and agonist concentration. Pretreatment of quetiapine significantly enhanced its inhibitory potency, reducing its IC₅₀ from 25.23 μM to 0.20 μM. Interaction kinetics experiments revealed an IC₅₀ of 5.17 μM for an open state of the 5-HT₃ receptor, suggesting weaker affinity during receptor activation. Quetiapine also accelerated receptor deactivation and desensitization, suggesting that it could stabilize the receptor in non-conducting states. Additionally, quetiapine significantly prolonged recovery from desensitization without affecting recovery from deactivation, demonstrating its selective impact on receptor kinetics. Inhibition of the 5-HT₃ receptor by quetiapine was voltage-independent, and quetiapine exhibited no use-dependency, further supporting its role as a competitive antagonist. These findings provide insights into inhibitory mechanism of quetiapine on 5-HT₃ receptor and suggest its potential therapeutic implications for modulating serotonergic pathways in neuropsychiatric disorders.

The role of acetylated apurinic/apyrimidinic endonuclease 1/redox factor 1 (APE1/Ref-1) in ovarian cancer remains poorly understood. Therefore, this study aimed to investigate the combined effect of recombinant human APE1/Ref-1 (rhAPE1/Ref-1) and aspirin (ASA) on two ovarian cancer cells, PEO-14, and CAOV3. The viability and apoptosis of ovarian cancer cells treated with rhAPE1/Ref-1 or ASA were assessed. Our results demonstrated that ASA induced rhAPE1/Ref-1 acetylation and widespread hyperacetylation in PEO-14 cells. Additionally, co-treatment with rhAPE1/Ref-1 and ASA substantially reduced cell viability and induced PEO-14 cell apoptosis, not CAOV3, in a dose-dependent manner. ASA increased the expression and membrane localization of the receptor for advanced glycation endproducts (RAGEs). Acetylated APE1/Ref-1 showed enhanced binding to RAGEs. In contrast, RAGE knockdown reduced cell death and poly(ADP-ribose) polymerase cleavage caused by rhAPE1/Ref-1 and ASA combination treatment, highlighting the importance of the APE1/Ref-1-RAGE interaction in triggering apoptosis. Moreover, combination treatment with rhAPE1/Ref-1 and ASA effectively induced apoptosis in 3D spheroid cultures of PEO-14 cells, a model that better mimics the tumor microenvironment. These results demonstrate that acetylated APE1/Ref-1 and its interaction with RAGE is a potential therapeutic target for ovarian cancer. Thus, the combination of ASA and APE1/Ref-1 may offer a promising new strategy for inducing cancer cell death.

Geraniin, a polyphenol derived from the fruit peel of Nephelium lappaceum L., has been shown to possess anti-inflammatory and antioxidant properties in the cardiovascular system. The present study explored whether geraniin could protect against an isoproterenol (ISO)-induced cardiac hypertrophy model. Mice in the ISO group received an intraperitoneal injection of ISO (5 mg/kg) once daily for 9 days, and the administration group were injected with ISO after 5 days of treatment with geraniin or spironolactone. Potential therapeutic effects and related mechanisms analysed by anatomical coefficients, histopathology, blood biochemical indices, reverse transcription-PCR and immunoblotting. Geraniin decreased the cardiac pathologic remodeling and myocardial fibrosis induced by ISO, as evidenced by the modifications to anatomical coefficients, as well as the reduction in collagen I/III á1mRNA and protein expression and cross-sectional area in hypertrophic cardiac tissue. In addition, geraniin treatment reduced ISO-induced increase in the mRNA and protein expression levels of interleukin (IL)-6, IL-1β and tumor necrosis factor-α, whereas ISO-induced IL-10 showed the opposite behaviour in hypertrophic cardiac tissue. Further analysis showed that geraniin partially reversed the ISO-induced increase in malondialdehyde and nitric oxide, and the ISO-induced decrease in glutathione, superoxide dismutase and glutathione. Furthermore, it suppressed the ISO-induced cellular apoptosis of hypertrophic cardiac tissue, as evidenced by the decrease in B-cell lymphoma-2 (Bcl-2)-associated X/caspase-3/caspase-9 expression, increase in Bcl-2 expression, and decrease in TdT-mediated dUTP nick-end labeling-positive cells. These findings suggest that geraniin can attenuate ISO-induced cardiac hypertrophy by inhibiting inflammation, oxidative stress and cellular apoptosis.

Colorectal cancer ranks third in global incidence and is the second leading cause of cancer-related mortality. Doxorubicin, an anthracycline chemotherapeutic drug, is integral to current cancer treatment protocols. However, toxicity and resistance to doxorubicin poses a significant challenge to effective therapy. Panobinostat has emerged as a critical agent in colorectal cancer treatment due to its potential to overcome doxorubicin resistance and enhance the efficacy of existing therapeutic protocols. This study aimed to evaluate the capability of panobinostat to surmount doxorubicin toxicity and resistance in colorectal cancer. Specifically, we assessed the efficacy of panobinostat in enhancing the therapeutic response to doxorubicin in colorectal cancer cells and explored the potential synergistic effects of their combined treatment. Our results demonstrate that the combination treatment significantly reduces cell viability and colony-forming ability in colorectal cancer cells compared to individual treatments. The combination induces significant apoptosis, as evidenced by increased levels of cleaved PARP and cleaved caspase-9, while also resulting in a greater reduction in p-Akt/p-GSK-3β/mTOR expression, along with substantial decreases in c-Myc and SREBP-1 levels, compared to monotherapies. Consistent with the in vitro experimental results, the combination treatment significantly inhibited tumor formation in colorectal cancer xenograft nude mice compared to the groups treated with either agent alone. In conclusion, our research suggests that the panobinostat effectively enhances the effect of doxorubicin and combination of two drugs significantly reduced colorectal cancer tumor growth by targeting the Akt/GSK-3β/mTOR signaling pathway, indicating a synergistic therapeutic potential of these two drugs in colorectal cancer treatment.