Korean Journal of Physiology & Pharmacology最新文献

Frozen shoulder (FS) and osteoporosis (OP) are common age-related degenerative diseases, occurring more frequently in females, which suggests potential molecular links between them. This study aimed to identify shared genetic features and pathways of OP and FS using bioinformatics and machine learning approaches. Gene expression data for OP and FS were obtained from the Gene Expression Omnibus database. Common differentially expressed genes (DEGs) were identified. Functional enrichment analysis, protein-protein interaction (PPI) networks construction, and machine learning algorithms were applied to screen key genes. Diagnostic value was evaluated by receiver operating characteristic (ROC) curve analysis. Immune infiltration and regulatory networks involving transcription factors and miRNAs were explored. Potential therapeutic compounds were also predicted. A total of 111 common DEGs were identified, enriched in pathways related to neurological development, cellular signaling, and immune regulation. PPI analysis revealed 14 hub genes, with SDC1 and ELN identified as key diagnostic markers by machine learning. ROC curves confirmed their diagnostic efficacy for both OP and FS. Immune infiltration analysis revealed distinct immune cell patterns in OP, correlating with the expression of key gene. Regulatory network analysis demonstrated complex transcriptional regulation of SDC1 and ELN. Drug prediction identified five candidate small molecules targeting these genes. This study uncovered shared genetic features of FS and OP through comprehensive bioinformatics analysis, enhancing understanding of their co-morbidity mechanisms. These findings provide a theoretical basis for identifying novel diagnostic biomarkers and therapeutic targets, facilitating the development of precise diagnostic strategies for OP with FS.

Hypertrophic scarring (HS) is a dermal fibroproliferative disorder accompanied by pain. Sildenafil (SIL) has been shown to have a protective effect against fibrosis. This study aimed to determine the effects and mechanisms of SIL on the proliferation, migration, and extracellular matrix (ECM) production of HS fibroblasts. The expression levels of Krüppel-like factor 15 (KLF15) and lysyl oxidase-like 1 (LOXL1) in human dermal fibroblasts (HDFbs) and HS-derived fibroblasts (HSFbs) were determined using reverse transcription-quantitative polymerase chain reaction and Western blotting. The effect of SIL on cell proliferation, migration, ECM production, and SMAD expression was assessed using Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine staining, transwell, and Western blotting assays, respectively. The effect of KLF15 on LOXL1 transcriptional activity was examined using chromatin immunoprecipitation and dual-luciferase reporter assays. Compared with HDFbs, HSFbs showed greater migration and ECM deposition. SIL inhibited cell proliferation, migration, ECM deposition, and SMAD activation in HSFbs, whereas these effects were inhibited by KLF15 knockdown. KLF15 inhibited LOXL1 transcription in HSFbs. LOXL1 silencing abrogated the effect of KLF15 knockdown on SIL-inhibited proliferation, migration, and ECM deposition. SIL inhibited the transcriptional activity of LOXL1 by upregulating KLF15, eventually inactivating SMAD signaling and suppressing the proliferation, migration, and ECM deposition of HSFbs.

Glioblastoma, an aggressive brain tumor that largely depends on angiogenesis, has limited treatment options and poor prognosis. This study explores the therapeutic potential of fimepinostat, a dual HDAC/PI3K inhibitor, as a single agent alone and in combination of temozolomide in glioblastoma using preclinical tumor and angiogenesis models. We show that fimepinostat at nanomolar concentrations inhibited proliferation and induced apoptosis in a panel of glioblastoma cell lines. In addition, fimepinostat inhibited capillary network formation of microvascular endothelial cells derived from patients, indicating that fimepinostat inhibits glioblastoma angiogenesis. Combination index analysis indicates that fimepinostat and temozolomide is synergistic in inhibiting glioblastoma. Consistent with the in vitro findings, fimepinostat significantly inhibited glioblastoma growth in mice without causing any toxicity. The combination of fimepinostat and temozolomide significantly inhibited tumor growth and prolonged survival compared to monotherapy or control. Mechanism studies confirmed that fimepinostat acts on glioblastoma cells through suppressing Akt/MYC. Our findings suggest that dual targeting of tumor and angiogenesis by fimepinostat may provide an alternative approach for anti-glioblastoma therapy.

Xerostomia, a pathological condition resulting from hyposalivation due to salivary gland (SG) dysfunction, severely affects a patient's health, quality of life, and healthcare costs. Despite its high prevalence, long-term curative treatments remain unavailable, leaving patients with lifelong symptom management. Permanent SG damage caused by disease or injury exacerbates this condition, highlighting the urgent need for regenerative solutions. Salivary gland organoids (SGOs) have emerged as promising in vitro models for studying SG homeostasis and pathology. SGOs serve as physiologically relevant three-dimensional models, enabling the study of tissue renewal, stem cell-niche interactions, and responses to genetic mutations, drugs, or injury. Additionally, advances in regenerative medicine, including stem cell-or organoid-based therapies integrated with bioengineering approaches, have the potential to develop future treatments. In this review, we summarize the latest progress in SGO development, explore its potential for modeling diseases and injuries, and discuss emerging regenerative strategies for restoring SG function. By deepening our understanding of SG physiology and diseases, these studies pave the way for therapeutic or regenerative approaches that have the potential to provide lasting relief for patients with xerostomia.

Diabetes mellitus is a major global health concern associated with micro-and macrovascular complications. Among the diverse mechanisms that contribute to vascular dysfunction in diabetes, endothelial to mesenchymal transition (EndMT) has emerged as a key pathological process. EndMT involves the loss of endothelial cell characteristics and the acquisition of mesenchymal features, resulting in impaired endothelial function, increased fibrosis, and inflammation. In addition to findings from preclinical models, recent human studies support the clinical relevance of End-MT. This review summarizes the molecular mechanisms governing EndMT, including key signaling pathways such as TGF-β, Notch, and Wnt, and examines how environmental, metabolic, and inflammatory cues influence this process. Furthermore, we discuss the maladaptive role of EndMT in diabetic complications, including nephropathy, retinopathy, atherosclerosis, and impaired wound healing, highlighting recent advances in anti-EndMT therapies and the clinical implications. Understanding the mechanisms of EndMT in the diabetic milieu may reveal novel therapeutic targets for preventing or reversing diabetic vascular diseases.

The progression of renal fibrosis is difficult to reverse, and Poria cocos, one of the main components of Wenyang Zhenshuai Granules, has been shown to be crucial to the development of the epithelial-mesenchymal transition (EMT). This study aimed to examine the molecular mechanism by which Poricoic Acid A (PAA) inhibited the advancement of EMT in renal tubular epithelial (RTE) cells. The protein levels of sprouty RTK signaling antagonist 2 (SPRY2) extracellular regulated protein kinases (ERK), and p-ERK were measured. The EMT progression of RTE cells was evaluated by a series of experiments. The regulatory relationship of PAA to SPRY2 was determined by cycloheximide, molecular docking and drug affinity target stability and immunoprecipitation. The overexpression of SPRY2 or PAA intervention suppressed the HK-2 and NRK-52E cell's viability, proliferation and migration ability of TGF-β1-induced while raising the levels of E-cadherin and decreasing those of collagen I, collagen III, Fibronectin1, α-SMA, Vimentin, ZEB1, Twist, Snail and Slug. PAA was able to be combined with SPRY2 protein. Besides, we found that PAA intervention increased the stability of SPRY2 through the ubiquitin-proteasome pathway, did not affect ERK levels, and reduced the levels of p-ERK. Finally, we found that inhibiting SPRY2 negated the beneficial effect of PAA on TGF-β1-stimulated RTE cells. PAA alleviated the EMT of RTE cells by modulating the SPRY2/ERK pathway.

Acute lung injury (ALI) and acute respiratory distress syndrome are major causes of acute respiratory failure and even death. Acute pneumonia can be accompanied by damage to the alveolar epithelium. In vitro functional experiments were performed by constructing inflammatory models in human alveolar epithelial cells. It was found that the chick early amniotic fluid (ceAF) extracted from SPF-grade early chicken embryos could significantly reduce the inflammation of human lung epithelial cells (Calu-3) induced by lipopolysaccharide (LPS) and COVID-19 protein pseudovirus, and reduce the gene expression of inflammatory factors. Pneumonia is one of the most common risk factors for causing ALI. An acute pneumonia model was constructed by LPS inhalation. Tail vein injection of ceAF significantly improved inspiratory and expiratory resistance, enhanced lung compliance, and reduced death rate due to acute pneumonia in mice. Neutrophil recruitment is an important feature of both acute inflammation and ALI. HE staining and immunohistochemical staining showed that ceAF treatment significantly reduced lung inflammatory edema and neutrophil cell aggregation, and promoted the resolution of inflammation in ALI, while reducing the inflammatory response in the blood. Further mass spectrometry experiments revealed that nicotinamide adenine dinucleotide (NAD⁺), guanosine and deoxyinosine were the primary components of ceAF. While each compound partially alleviated LPS-induced acute pneumonia, their effects were slightly weaker than those of ceAF, suggesting that ceAF's anti-inflammatory properties may arise from the synergistic action of these molecules.

Cardiac fibrosis, characterized by excessive extracellular matrix accumulation and perpetual fibroblast activation, represents a common pathological endpoint across diverse cardiovascular diseases. Despite its central role in adverse cardiac remodeling and heart failure progression, targeted antifibrotic therapies remain largely elusive. This review synthesizes recent breakthroughs in understanding the molecular and cellular drivers of cardiac fibrosis, highlighting the complex interplay between fibrogenic signaling pathways, immune mechanisms, and extracellular matrix dynamics. We critically evaluate emerging diagnostic modalities from advanced imaging techniques to novel biomarker panels, emphasizing their translational potential and limitations. Current pharmacological approaches achieve only modest antifibrotic effects, whereas emerging targeted therapies such as small-molecule drugs, immunomodulatory agents, and cell-based strategies have shown promising results in preclinical models. The integration of precision medicine approaches with bioengineered platforms represents a paradigm shift in developing personalized antifibrotic interventions. This review provides a comprehensive framework for understanding the translational landscape of cardiac fibrosis and identifies critical gaps that must be addressed to advance effective therapies from bench to bedside.

Coronary microembolization (CME) is a prevalent and refractory complication of coronary revascularization, resulting in perioperative myocardial injury, cardiac dysfunction, and unfavorable prognosis. Vericiguat represents a novel therapeutic agent for chronic heart failure; however, further investigation is warranted to explore its potential cardioprotective effects beyond improving cardiac function in CME-induced myocardial injury. Therefore, the objective of this study is to evaluate the impact of vericiguat on pyroptosis in cardiomyocytes induced by CME and elucidate the underlying mechanism. The CME model was created in 40 Sprague-Dawley rats by injecting microspheres into the left ventricle, with the exception of the sham group. Vericiguat or CC (AMPK inhibitor), was given before creating CME models. Four groups were created for the rats: sham, CME, CME+VER, and CME+VER+CC, with random assignment. The CME+VER and CME+VER+CC groups received oral administration of vericiguat for a duration of two weeks before undergoing CME modeling. Echocardiography, myocardial histopathology, and serum markers of myocardial injury were assessed following induction of CME. Pyroptosis-related molecules and the adenosine monophosphate-activated protein kinase (AMPK)/nuclear factor erythroid 2-like (Nrf2)/NOD-like receptor pyrin containing 3 (NLRP3) pathway were evaluated using qRT-PCR, Western blotting, ELISA, and immunofluorescence. Vericiguat pretreatment attenuated cardiac dysfunction and myocardial injury following CME. Furthermore, vericiguat ameliorates mitochondrial damage, facilitated AMPK activation, upregulated the expression of Nrf2, suppressed the initiation of the NLRP3 inflammasome and alleviated cardiomyocyte pyroptosis levels. However, the cardioprotective effects of vericiguat were reversed when co-treatment with CC. Vericiguat pretreatment reduces cardiomyocyte pyroptosis and myocardial injury after CME by activating the AMPK/Nrf2/NLRP3 pathway.