Korean Journal of Physiology & Pharmacology最新文献

Renal cell carcinoma (RCC) is heterogeneous and frequently refractory to cytotoxic therapy. We investigated whether contexts with elevated DDR2-a collagenactivated receptor tyrosine kinase-are preferentially sensitive to regorafenib, a multikinase inhibitor with activity against DDR2. DDR2 mRNA was quantified by quantitative PCR in Caki1 (clear cell), ACHN (papillary), and Caki2 (papillary) relative to HK2. Shortterm viability was assessed by a tetrazolium (MTT) assay with fourparameter logistic fits to estimate the lowest observed effect concentration (LOEC) and halfmaximal inhibitory concentration (IC₅₀). In an ACHN xenograft model, mice were randomized to vehicle or regorafenib (10 mg/kg, intraperitoneally) every 3 days for 21 days. ACHN and Caki1 expressed higher DDR2 than HK2, whereas Caki2 was modest; ACHN xenografts retained elevation, whereas Caki2 xenografts did not. Regorafenib reduced ACHN viability with LOEC 1 μM and IC₅₀ 6.93 μM, while Caki2 first declined at 30 μM without reaching 50% inhibition. In vivo, regorafenib attenuated ACHN tumor growth with a significant difference by day 14. Clinically, higher DDR2 associated with inferior overall survival in The Cancer Genome Atlas papillary cohort (KIRP), with no consistent association in the clear cell cohort (KIRC). Across in vitro, in vivo, and in silico analyses, DDR2-high papillary contexts exhibit preferential regorafenib sensitivity, nominating DDR2-enriched papillary RCC for biomarker‑guided repurposing and motivating protein‑level and genetic validation.

Volume-regulated anion channels (VRACs) and TMEM16A calciumactivated chloride channels (CaCCs) are distinct but share some features and can co-immunoprecipitate. Currently, there are no specific inhibitors for these channels exist. Our prior research showed Flavoxate inhibits VRAC currents in HEK293 cells under hypotonic conditions. MFCA (3-methylflavone-8-carboxylic acid, a primary active metabolite of Flavoxate) and 3-methylflavone are two structural analogues of Flavoxate. To further elucidate the specific inhibitory effects of the three flavonoids on VRACs and TMEM16A/CaCCs, the current study used patch-clamp techniques to explore their effects on the two chloride channels. Additionally, we investigated the effects of the three flavonoids on action potential (AP) firing in small dorsal root ganglion (DRG) neurons utilizing the current-clamp technique. Our findings indicate that the inhibition rates of 30 μM Flavoxate, MFCA, and 3-methylflavone on VRAC currents approximately were 78%, 46%, and 35%, with corresponding half-maximal concentration (IC₅₀) values of 1.8 μM, 18.5 μM, and 37.2 μM, respectively. In contrast, the inhibition rates of these compounds on TMEM16A/CaCC currents approximately were 14%, 15%, and 24%, with IC₅₀ values of 32.8 μM, 28.3 μM, and 26.5 μM, respectively. These results suggest that Flavoxate is highly efficient and selective for VRAC inhibition, with the 8-substituent on its flavonoid core being crucial for this selectivity. All three flavonoids strongly inhibit AP firing, indicating that their core structure contributes to analgesic effects. In summary, Flavoxate is a selective VRAC inhibitor and a potential neuropathic pain inhibitor by suppressing AP firing in small DRG neurons.

Heart failure (HF) is a leading cause of morbidity and mortality worldwide, with mitochondrial dysfunction and impaired mitophagy recognized as key contributors to its progression. Astragaloside IV (AS-IV), a major active component of Astragalus membranaceus, has shown multiple biological effects, but its role in mitochondrial homeostasis in HF remains unclear. In this study, a rat model of HF was induced by abdominal aortic constriction, and AS-IV was administered at doses of 20 mg/kg and 80 mg/kg. We found AS-IV treatment significantly reduced myocardial fibrosis and hypertrophy, improved mitochondrial function by increasing ATP and manganese superoxide dismutase levels, reducing reactive oxygen species, and upregulating PGC-1α and TFAM. It also enhanced mitochondrial autophagy. Moreover, AS-IV markedly inhibited the activation of the p38 MAPK pathway. AS-IV suppresses autophagy and mitochondrial function via targeting MAPK pathway in H9c2 cells. These findings suggest that AS-IV alleviates HF by promoting mitophagy and preserving mitochondrial function through suppression of the MAPK pathway, highlighting its potential as a novel therapeutic agent for HF.

Despite advances in the understanding of muscle degeneration, the mechanisms governing muscle regeneration under stress conditions remain poorly defined. Sestrin2 (Sesn2) is a stress-inducible gene that plays a crucial role in metabolic balance, nutrient sensing, and redox homeostasis, while protecting against muscle atrophy through multiple pathways. However, its precise role in skeletal muscle differentiation and regeneration, particularly under injury conditions, remains incompletely understood. In this study, we investigated the role of Sesn2 in skeletal muscle homeostasis and regeneration using in vitro and in vivo models, complemented by transcriptome analyses. Sesn2 knockdown in C2C12 myoblasts induced senescence-like morphological changes, accompanied by upregulation of nicotinamide adenine dinucleotide phosphate oxidase 4 and transforming growth factor-beta, leading to impaired myogenic differentiation. Intriguingly, Sesn2-knockout mice developed normally under basal conditions but exhibited regenerative defects, characterized by prolonged inflammation, necrosis, and delayed muscle regeneration, following cardiotoxininduced injury. Transcriptomic analysis of Sesn2 transgenic mice further supported this conditional role, revealing that genes involved in mitochondrial function and myogenesis were preferentially upregulated under immobilized conditions compared to basal conditions. These findings underscore that the context-dependent role of Sesn2 is essential for effective muscle regeneration under injury, positioning it as a potential therapeutic target for degenerative muscle diseases.

Pulmonary arterial hypertension (PAH) is referred to as a tumor of the cardiovascular system and is a major cause of death. It is urgent to develop safe and effective drugs to combat PAH. Eupatilin, a flavonoid extracted from Artemisia, has multiple pharmacological activities. However, the role of Eupatilin in PAH-induced right heart failure is not clear. This study was aimed to investigate the effects of Eupatilin on the PAH via monocrotaline (MCT)-induced rat models and platelet-derived growth factor-BB (PDGF-BB)-induced pulmonary artery smooth muscle cell (PASMC) model. We found Eupatilin inhibits PDGF-BB-induced proliferation of PASMCs in vitro. In addition, Eupatilin affects pulmonary blood flow and right ventricular function induced by MCT in rats. We further revealed Eupatilin alleviates pulmonary artery remodeling induced by MCT. Also, it alleviates myocardial fibrosis induced by MCT. Mechanically, Eupatilin inhibits the JNK/p38 MAPK pathway. Collectively, Eupatilin alleviates MCT-induced pulmonary vascular remodeling as well as right ventricular hypertrophy via JNK/p38 MAPK pathway and could serve as a promising drug to combat PAH.

Cardiopulmonary dysfunction is a critical complication following spinal cord injury (SCI), yet conventional rehabilitation often focuses narrowly on inspiratory training. This study aimed to evaluate a novel, multicomponent program that integrates respiratory, strength, and aerobic training to improve overall cardiopulmonary health in this population. In this randomized controlled trial, 22 individuals with chronic SCI were assigned to an experimental (EXP) or a no-intervention control (CON) group. The EXP group underwent a 4-week supervised program of progressive, integrated exercises. Key outcomes included changes in respiratory function (spirometry), isometric shoulder strength, and exercise capacity (NetVO₂). The EXP group demonstrated significantly greater improvements than the CON group in all measured domains. Key respiratory outcomes, including maximal inspiratory pressure and peak expiratory flow, increased significantly, with a notable increase in forced vital capacity of 0.5 ± 0.6 L. Upper limb strength also improved substantially; for example, shoulder flexion strength increased by up to 3.2 ± 1.2 N. Furthermore, exercise capacity, measured by NetVO₂, increased by 2.7 ± 1.3 ml/kg/min (all p < 0.05). A structured, multidimensional exercise program that combines respiratory, strength, and aerobic training is a highly effective strategy for concurrently enhancing cardiopulmonary function, muscle strength, and aerobic capacity in individuals with SCI. These findings advocate for a holistic, integrated approach over single-modality training to optimize functional recovery. Clinical Research Information Service (CRIS; KCT0010320).

SMK-002, a novel derivative of proguanil, has higher inhibitory activity against cancer than proguanil. We previously found that SMK-002 significantly inhibited the proliferation of bladder cancer (BC) cells. In this study, we creatively found that the sensitivity of BC cells to SMK-002 was positively correlated with the expression of epidermal growth factor receptor (EGFR). Mechanistically, SMK-002 specifically targeted EGFR and inhibited its binding to the deubiquitination protein USP11, facilitated the ubiquitination degradation of EGFR in lysosomes by post-translational modification. Further studies suggested that SMK-002 significantly inhibited the p-EGFR/p-c-Raf/p-ERK downstream pathway. Osimertinib, one commonly used representative of the clinically approved third-generation EGFR inhibitors, has been rarely reported to apply on BC. Furthermore, we found that SMK-002 synergized with Osimertinib further downregulated EGFR signal pathway and reduced growth of BC both in vivo and in vitro without any detectable toxicities. Taken together, this study revealed that SMK-002 inhibited proliferation and migration of BC cells by promoting EGFR ubiquitination degradation in lysosomes. Moreover, SMK-002 synergized with Osimertinib and further inhibited the growth of BC cells both in vitro and in vivo, providing a novel strategy for the potential treatment of BC.

Androsin is a phenolic acid compound extracted from Picrorhiza kurroa with apocynin as its aglycone. Early studies have shown that apocynin exhibits specific inhibition towards NADPH oxidases (NOXs) and has some therapeutic effects on colorectal cancer (CRC). However, the effects and mechanisms of androsin on CRC remain unexplored. Based on the network pharmacology analysis, this study investigates the mechanisms of androsin on CRC at molecular, cellular, and animal tissue levels. Results indicate that in the high-concentration range, androsin induces apoptosis and inhibits the proliferation of CRC cell in a concentration-dependent manner, with IC₅₀ values of 56 μM and 41 μM after 48 h and 72 h, respectively. Although androsin do not affect cell viability in the low-concentration range, they significantly inhibit cell invasion, migration, and reactive oxygen species (ROS) production. In animal models, androsin suppresses tumor growth in nude mice and disrupts tumor tissues, as shown by hematoxylin-eosin staining, immunohistochemical analysis of Ki-67, and TUNEL assays. Mechanistically, androsin promotes apoptosis via the PI3K/Akt/mTOR/caspase3/PARP pathway in the high-concentration range, and inhibits invasion and migration via the NOX2/ROS/FAK/PI3K/Akt/NF-κB/MMP7 pathway in the low-concentration range. These findings not only verified the prediction from network pharmacology, but also provided a preliminary basis for exploring androsin's anti-CRC mechanisms and its potential as a therapeutic molecule or lead compound.

Heart failure with preserved ejection fraction (HFpEF), defined by clinical heart failure with left ventricular ejection fraction ≥ 50%, represents more than half of heart failure cases in Asia and carries a one-year composite hospitalization and mortality rate of approximately 12.1%. Recent landmark trials have transformed the therapeutic landscape: Sodium-glucose cotransporter 2 inhibitors emerged as treatment for HFpEF, shown beneficial in EMPEROR-preserved and DELIVER. Empagliflozin significantly reduced the risk of cardiovascular death or heart failure hospitalization and dapagliflozin demonstrated comparable efficacy across regions. Furthermore, glucagon-like peptide-1 receptor agonist such as semaglutide have shown promising improvements in functional capacity and symptom burden in obesity-related HFpEF. Asian HFpEF phenotypes often exhibit high rates of hypertension and diabetes, alongside lower average body mass index compared to Western cohorts. In numerous respects, the clinical and pathophysiological features of HFpEF in Asian populations diverge from those traditionally observed in Western cohorts. In this brief review, we will focus on therapeutics approved for HFpEF and agents currently under clinical trial, as well as the distinctive characteristics of HFpEF patients observed in Asia and the key considerations for future therapeutic development in this region.

Ovarian cancer (OV) remains a leading cause of gynecologic cancer mortality, this is primarily attributed to the absence of early symptoms and reliable diagnostic biomarkers. Recent studies suggest that zinc dysregulation reshapes the tumor microenvironment, impairs immune surveillance, and promotes tumor progression. However, the prognostic implications of zinc homeostasis-related genes in OV remain poorly understood. Patients with OV were stratified into molecular subtypes based on the expression profiles of prognostic zinc homeostasis-related genes. Differential gene expression analysis was conducted using the limma package. Subsequently, we constructed a zinc homeostasis-based risk score model employing univariate Cox regression, least absolute shrinkage and selection operator regression, and multivariate Cox regression analyses. The prognostic model was validated using external datasets. Additionally, immune cell infiltration and drug sensitivity analyses were conducted to evaluate the clinical relevance of the model. Two molecular subtypes of OV were identified, each associated with distinct biological pathways. A prognostic model comprising four zinc homeostasis-related genes was developed, demonstrating robust predictive capability for overall survival and significant correlation with immune cell infiltration patterns. Drug sensitivity analysis revealed potential therapeutic targets and candidate drugs, offering insights for OV treatment strategies. This study identifies novel OV subtypes driven by zinc homeostasisrelated genes, providing insights into the genetic heterogeneity, immune landscape, and therapeutic strategies of OV. The developed prognostic model and identified candidate therapeutic agents offer valuable references for personalized treatment approaches in OV.