Korean Journal of Physiology & Pharmacology最新文献

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.

Lung adenocarcinoma (LUAD) is a global malignancy with significant chemoresistance impacting patient prognosis. The pro-tumorigenic role of hyaluronan- mediated motility receptor (HMMR) in LUAD is recognized. This study was designed to investigate the underlying mechanisms by which HMMR affects chemoresistance in LUAD. Bioinformatics presented the expression patterns of HMMR in LUAD patients and the association between HMMR levels and patient survival, followed by qRT-PCR to verify HMMR expression in LUAD tissues and cells. Further, bioinformatics was leveraged to identify the signaling pathways enriched by HMMR and its relevance to glycolytic genes, we also analyzed changes in the glycolytic activity of LUAD cells by manipulating HMMR expression. Stemness was evaluated through cell aggregation assays and Western blot, and drug responsiveness was gauged using CCK-8 assays, alongside flow cytometry for apoptosis analysis. HMMR was highly expressed in LUAD tissues and cells, and this overexpression correlated with poorer prognoses in patients. GSEA showed that HMMR was notably enriched in the glycolysis and gluconeogenesis pathways, correlating positively with the expression of key glycolytic genes. Cellular experiments confirmed that HMMR knockdown notably suppressed aerobic glycolysis in LUAD cells. Moreover, overexpression of HMMR could further enhance the stemness and cisplatin resistance of LUAD cells by stimulating glycolysis. In brief, this study has validated that high levels of HMMR in LUAD are predictive of poor patient prognosis, and that overexpression of HMMR can catalyze aerobic glycolysis, thus promoting stemness and chemoresistance in LUAD cells. Thus, HMMR could be a target for improving chemosensitivity in LUAD.

Haloperidol is a typical antipsychotic drug effective in alleviating positive symptoms of schizophrenia by blocking dopamine receptor 2 (DR2). However, it is also known to produce neuropsychiatric effects by acting on various targets other than DR. In this study, we investigated effect of haloperidol on function of 5-hydroxytryptamine (5-HT)₃ receptor, a ligand-gated ion channel belonging to the serotonin receptor family using the whole-cell voltage clamp technique and NCB20 neuroblastoma cells. When co-applied with 5-HT, haloperidol inhibited 5-HT₃ receptormediated currents in a concentration-dependent manner. A reduction in maximal effect (E_max) and an increase in EC₅₀ observed during co-application indicated that haloperidol could act as a non-competitive antagonist of 5-HT₃ receptors. Haloperidol inhibited the activation of 5-HT₃ receptor, while also accelerating their deactivation and desensitization. The inhibitory effect of haloperidol showed no significant difference between pre- and co-application. Haloperidol did not alter the reversal potential of 5-HT₃ receptor currents. Furthermore, haloperidol did not affect recovery from deactivation or desensitization of 5-HT₃ receptors. It did not show a use-dependent inhibition either. These findings suggest that haloperidol can exert its inhibitory effect on 5-HT₃ receptors by allosterically preventing opening of ion channels. This mechanistic insight enhances our understanding of relationships between 5-HT₃ receptors and pharmacological actions of antipsychotics.

Osteoarthritis (OA) is one of the most prevalent joint disorders, with aging considered a primary, irreversible factor contributing to its progression. Telomere-related cellular senescence may be a crucial factor influencing the OA process, yet biomarkers for OA based on telomere-related genes have not been clearly identified. The datasets GSE51588, GSE12021, and GSE55457 were retrieved from the Gene Expression Omnibus database. Initially, R software was utilized to identify differentially expressed genes between OA and normal samples. Subsequently, differentially expressed telomere-related genes (DETMRGs) were obtained, and their functional enrichment was analyzed. Feature genes for OA diagnosis were selected from DETMRGs using a combination of least absolute shrinkage and selection operator, support vector machine-recursive feature elimination, and Random Forest algorithms. The diagnostic value of these feature genes was then validated through receiver operating characteristic (ROC) curves and decision curve analysis. Additionally, CIBERSORT and xCell were employed to assess the infiltration of immune cells in OA tissues. Finally, potential drugs targeting candidate genes were predicted. Three telomere-related genes, PGD, SLC7A5, and TKT, have been identified as biomarkers for OA diagnosis and were confirmed through ROC diagnostic tests. The immune infiltration of mast cells, neutrophils, common lymphoid precursors, and eosinophils associated with PGD, SLC7A5, and TKT was reduced. Recognizing telomere-related genes PGD, SLC7A5, and TKT as potential diagnostic biomarkers for OA is significant, as it offers valuable insights into the role of telomere-related genes in OA. This discovery also provides valuable information for the diagnosis and treatment of OA.