查找使用阿拉丁产品的科研文献

Terazosin Stimulates Pgk1 to Remedy Gastrointestinal Disorders

Jingjing Liu,Wenyang Zhao,Chun Li,Tongyu Wu,Liang Han,Zhuozhou Hu,Xiangxiang Li,Jing Zhou,Xinping Chen

Gastrointestinal disease is the most common health concern that occurs due to environmental, infectious, immunological, psychological, and genetic stress. Among them, the most frequent diseases are gastric ulcer (GU) and ulcerative colitis (UC). DSS-induced UC and ethanol-stimulated GU models resemble the pathophysiology of human gastrointestinal disease. The current study was designed to explore the anti-oxidation, anti-inflammation, anti-cell death properties of terazosin, an α-adrenergic receptor antagonist, in vivo and in vitro. Our results indicate that terazosin dramatically activates Pgk1, and upregulates glycose metabolism, evidenced by the enhanced ATP production and higher LDH enzymatic activity. Also, terazosin significantly enhances p-AKT expression and inhibits NF-κB p65 activation through abrogating the phosphorylation of IKBα, as well as lowers Caspase-1 and GSDMD expression. The findings in this study demonstrate that terazosin exhibits anti-inflammatory effects by downregulating NF-κB-GSDMD signal pathway, along with enhancing glycolysis for gastrointestinal disease treatment. Meanwhile, we also find terazosin ameliorates ethanol-induced gastric mucosal damage in mice. Collectively, as a clinical drug, terazosin should be translated into therapeutics for gastrointestinal disease soon.Keywords:terazosin;gastrointestinal disease;anti-inflammation;Pgk1;cell death

Isochlorogenic Acid A Attenuated Periodontitis by Inhibiting Inflammation via ACE/PGK1/STAT1 Signaling

Xin Huang,Hong Shen,Zirui Li,Tingting Fu,Xin Wei,Sainan Qiu

The purpose of the present study was to evaluate the effect of isochlorogenic acid A (IAA) on periodontitis and explore its potential mechanism. A ligature/LPS procedure was employed to induce periodontitis in rats. LPS-induced HPDLF was used as the in vitro model. Bioinformatic analyses indicated that angiotensin-converting enzyme (ACE) might be the target of IAA in periodontitis. PGK1/STAT1 might be the related molecules of ACE. Treatment with IAA inhibited inflammatory cytokines, inflammatory molecule transcriptions in gingival tissues and HPDLFs. MicroCT, H&E, TRAP and Runx2 staining showed that IAA relieved periodontitis. Immunofluorescence observation and WB revealed that IAA inhibited ACE/PGK1/STAT1 in dental papilla, parodontium, gingival tissues and HPDLFs. IAA suppressed glycolysis, mitochondrial fission, oxidative stress and promoted oxidative phosphorylation, mitochondrial fusion. The application of the ACE-overexpression plasmid, PGK1 SiRNA, the ACE inhibitor captopril, the PGK1 inhibitor NG52 suggested that ACE and PGK1 were involved in IAA-mediated anti-inflammatory response. Molecular docking, molecular dynamics, DARTS and CETSA indicated that IAA might combine with ACE. It was also found that MYC governed ACE transcription. The Y195 residue of PGK1 was conservative and critical for the combination between PGK1 and ACE. ACE and PGK1 were also upregulated in gingival tissues of periodontitis patients. In conclusion, IAA ameliorated periodontitis by inhibiting inflammation via ACE/PGK1/STAT1 signaling.

Lamivudine protects mice from gastric ulcer by activating PGK1 to suppress ferroptosis

Xinrui Meng,Jingjing Liu,Jia Kang,Menghan Wang,Zhanghui Guan,Dong Tian,Xinping Chen

Gastric ulcer is a highly prevalent digestive tract disease across the world, which is recurrent and hard to cure, sometimes transforming into gastric cancer if left untreated, posing great threat to human health. To develop new medicines for gastric ulcer, we ran a series of screens with ethanol stress model in GES-1 cells, and we uncovered that lamivudine rescued cells from ethanol toxicity. Then, we confirmed this discovery using the well-established ethanol-induced gastric ulcer model in mice and our findings suggest that lamivudine can directly activate phosphoglycerate kinase 1 (PGK1, EC 2.7.2.3), which binds and stimulates superoxide dismutase 1 (SOD1, EC 1.15.1.1) to inhibit ferroptosis and ultimately improve gastric ulcer. Moreover, AAV-PGK1 exhibited comparable gastroprotective effects to lamivudine. The findings are expected to offer novel therapeutic strategies for gastric ulcer, encompassing both lamivudine and AAV-PGK1.

PP2C phosphatases Ptc1 and Ptc2 dephosphorylate PGK1 to regulate autophagy and aflatoxin synthesis in the pathogenic fungus Aspergillus flavus

Zhuo Zhu,Mingkun Yang,Guang Yang,Bei Zhang,Xiaohong Cao,Jun Yuan,Feng Ge,Shihua Wang

Perturbation of phosphoglycerate kinase 1 (PGK1) only marginally affects glycolysis in cancer cells

Chengmeng Jin,Xiaobing Zhu,Hao Wu,Yuqi Wang,Xun Hu

Phosphoglycerate kinase 1 (PGK1) plays important roles in glycolysis, yet its forward reaction kinetics are unknown, and its role especially in regulating cancer cell glycolysis is unclear. Here, we developed an enzyme assay to measure the kinetic parameters of the PGK1-catalyzed forward reaction. The Km values for 1,3-bisphosphoglyceric acid (1,3-BPG, the forward reaction substrate) were 4.36 μm (yeast PGK1) and 6.86 μm (human PKG1). The Km values for 3-phosphoglycerate (3-PG, the reverse reaction substrate and a serine precursor) were 146 μm (yeast PGK1) and 186 μm (human PGK1). The Vmax of the forward reaction was about 3.5- and 5.8-fold higher than that of the reverse reaction for the human and yeast enzymes, respectively. Consistently, the intracellular steady-state concentrations of 3-PG were between 180 and 550 μm in cancer cells, providing a basis for glycolysis to shuttle 3-PG to the serine synthesis pathway. Using siRNA-mediated PGK1-specific knockdown in five cancer cell lines derived from different tissues, along with titration of PGK1 in a cell-free glycolysis system, we found that the perturbation of PGK1 had no effect or only marginal effects on the glucose consumption and lactate generation. The PGK1 knockdown increased the concentrations of fructose 1,6-bisphosphate, dihydroxyacetone phosphate, glyceraldehyde 3-phosphate, and 1,3-BPG in nearly equal proportions, controlled by the kinetic and thermodynamic states of glycolysis. We conclude that perturbation of PGK1 in cancer cells insignificantly affects the conversion of glucose to lactate in glycolysis.

Icariside II inhibits Epithelial-Mesenchymal transition in metastatic osteosarcoma by antagonizing the miR-194/215 cluster via PGK1

Jianping Hu,Jinhu Chen,Caili Zhao,Pei Yu,Wenjun Xu,Yong Yin,Lei Yang,Zhenzhen Zhang,Lingyi Kong,Chao Zhang

Osteosarcoma, the most prevalent malignant bone tumor in adolescents, is characterized by its aggressiveness and tendency to metastasize. Despite the advancements in treatment that have improved survival rates for localized cases, metastatic osteosarcoma remains challenging to treat due to the limited efficacy of current therapies and the severe side effects of chemotherapy. Epithelial-mesenchymal transition (EMT) is a key factor in osteosarcoma metastasis, and the miR-194/215 cluster, which is upregulated in osteosarcoma, promotes this process. This study sought to investigate natural compounds that could counteract the miR-194/215 cluster’s effects and inhibit osteosarcoma metastasis. By analyzing miRNA databases and clinical data, a signature gene set for the miR-194/215 cluster was established, and the LINCS database was screened to find natural compounds with antagonistic effects. Icariside II, an active component of Epimedium, was identified as a potential inhibitor and was shown to reduce the migration and invasion of osteosarcoma cells in vitro and lung metastasis in vivo . The study utilized various techniques, including Gene Set Enrichment Analysis (GSEA), Drug Affinity Responsive Target Stability (DARTS), Cellular Thermal Shift Assay (CETSA), molecular docking, and enzyme activity assays, to identify phosphoglycerate kinase 1 (PGK1) as the target protein of Icariside II. It was found that Icariside II competitively inhibits PGK1 by binding to its ADP binding pocket, reducing its activity and thus antagonizing the miR-194/215 cluster’s promotion of EMT in metastatic osteosarcoma. The results suggest that Icariside II could be a promising therapeutic agent for metastatic osteosarcoma, providing new targets and strategies for clinical treatment.

Alfuzosin ameliorates diabetes by boosting PGK1 activity in diabetic mice

Jing Zhou,Tongyu Wu,Chun Li,Zhuozhou Hu,Liang Han,Xiangxiang Li,Jingjing Liu,Wenyang Zhao,Jia Kang,Xinping Chen

Aims Diabetes mellitus (DM) has become a global problem, causing a huge economic burden. The purpose of this study is to find a new potential method and mechanism for the treatment of DM. Main methods The oxidation, glycation and insulin resistance cell models were built to screen the potential anti-diabetic chemicals. Then the DM mice were induced by the combination of high-fat diet (HFD) and intraperitoneal injection of streptozotocin (50 mg/kg) for five days. The alfuzosin (1.2 mg/kg) was administered by intraperitoneal injection once daily for sequential 12 weeks. Fasting blood glucose, blood lipid, oxidative stress and key markers of glucose metabolism were detected. PGK1/AKT/GLUT4 pathway related proteins were analyzed by Western blot. Key findings Alfuzosin ameliorated oxidative stress, glycative stress and insulin resistance in HepG2 cells. Further, in a high-fat diet/streptozotocin (HFD/STZ)-induced diabetic mouse model, alfuzosin reduced fasting blood glucose, improved insulin sensitivity. Mechanically, alfuzosin activated PGK1 directly to stimulate the protein kinase B (AKT) signaling pathway, thus facilitating glucose uptake as well as improving insulin resistance. Significance The present finding has shed a new light on the treatment of DM and provides validation for PGK1 as a therapeutic target for DM.

Pharmacological inhibition of PGK1 by genipin reduces inflammation and oxidative damage in osteoarthritis

Meichen Li,Yi Peng,Qingqing Xiao,Siyi Chen,Chunjie Zhang,Hongyu Chen,Yue Zhao,Shan Chang,Lu Qiu,Lele Zhang,Xiaoqiang Guo,Qiang Fu

Background Osteoarthritis (OA) is a chronic degenerative joint disease characterized by the degeneration of articular cartilage and synovial inflammation. Due to the ambiguity of its therapeutic targets, there are currently no effective interventions targeting the core mechanisms. Genipin is one of the main active components of the fruits of Gardenia jasminoides Ellis and shows great application potential in anti-inflammation and cartilage protection. Purpose This study aims to elucidate the direct molecular targets and underlying mechanisms of genipin in mitigating cartilage damage associated with osteoarthritis. Methods The in vitro curative effect of genipin was evaluated in the TNF- α -induced C28/I2 cell model. Potential therapeutic targets of genipin in OA was identified using CC-ABPP, SPR and other experiments. The binding sites of genipin were investigated by LC-MS/MS, molecular docking analysis and other methods. The therapeutic mechanism of genipin was further elucidated through the detection of changes in downstream metabolites and proteins. Results PGK1 has been identified as a key therapeutic target of genipin in OA. Genipin covalently binds to lysine 216 of PGK1, occupying its nucleotide-binding domain (NBD) domain and blocking ATP interaction, thereby competitively inhibiting PGK1 activity. Further studies revealed that genipin enhances methylglyoxal (MGO) levels, an upstream metabolite of PGK1, activating the Keap1-Nrf2 antioxidant pathway while suppressing NF- κ B-mediated inflammation, downregulating matrix metalloproteinase (MMPs) expression, reducing extracellular matrix (ECM) degradation, and ultimately protecting cartilage. Conclusion Genipin is a covalent PGK1 inhibitor. Genipin exerts its anti-OA effects by specifically targeting the NBD domain of PGK1 and regulating the Keap1-Nrf2/NF- κ B signaling pathway.

PGK1 Lactylation-Driven Self-Reinforcing Loop Orchestrates Glycolytic Reprogramming in FSP1+ Macrophages in Liver Fibrosis

Min Tang,Mengxue Sun,Hui Zhang,Jinwei Chen,Yuanben Wang,Yan Jiang,Linhua Qin,Hao Wang,Fengshang Zhu,Changqing Yang

Liver fibrosis shows limited treatment efficacy, driven by metabolic reprogramming and epigenetics, while the role of lactate-mediated lactylation in hepatic microenvironment remains unclear. Here, through integrative analysis of public databases and human cirrhotic liver tissues, we identified a pathogenic FSP1 + (fibroblast specific protein 1) macrophage subset as a key therapeutic target. We uncovered a novel FSP1–glycolysis–lactylation axis that drives fibrotic progression through metabolic–immune crosstalk. Expanded FSP1 + macrophage infiltration was observed in human cirrhotic liver tissues and myeloid-specific Fsp1 knockout markedly attenuates inflammation and fibrosis. Mechanistic investigations reveal that FSP1 physically interacts with pyruvate kinase M2 (PKM2) in macrophages, inhibiting its ubiquitin–proteasome degradation to stabilize the enzyme. This FSP1–PKM2 interaction enhances glycolytic flux and lactate production, which in turn promotes KAT2B-dependent lactylation of phosphoglycerate kinase 1 (PGK1) at lysine 353 (K353). The posttranslational modification creates a positive feedback loop by concurrently activating PGK1 and pyruvate dehydrogenase kinase 1, which blocks mitochondrial pyruvate metabolism, thereby amplifying glycolysis and PGK1 lactylation. Notably, we developed a cell-penetrating peptide targeting PGK1-K353 lactylation that effectively attenuates the progression of liver fibrosis. Our findings establish lactate-mediated lactylation of PGK1 as a critical node in fibrotic metabolism and reveal a previously unrecognized FSP1–glycolysis axis that sustains the pro-fibrotic microenvironment. Targeting PGK1-K353 lactylation represents a promising therapeutic strategy for chronic liver diseases.

Diallyl trisulfide regulates PGK1/Nrf2 expression and reduces inflammation to alleviate neurological damage in mice after traumatic brain injury

Yafei Chen,Jianliang Pang,Yulong Chen,Ying Liang,Zhengbo Zhang,Zhangquan Wang

Background Diallyl trisulfide (DATS) has a direct antioxidant capacity and emerges as a promising neuroprotective agent. This study was designed to investigate the role of DATS in traumatic brain injury (TBI). Methods TBI mouse models were established using the controlled weight-drop impact, followed by DATS administration. The effects of DATS on neurological deficit, brain damage, inflammation and phosphoglycerate kinase 1 (PGK1) expression were detected using mNSS test, histological analysis, TUNEL assay, enzyme-linked immunosorbent assay and immunofluorescence. PC12 cells were subjected to H 2 O 2 -induced oxidative injury after pre-treatment with DATS, followed by cell counting kit-8 assay, flow cytometry and ROS production detection. Apoptosis-related proteins and the PGK1/nuclear factor erythroid-2 related factor 2 (Nrf2) pathway were examined using Western blot. Results DATS ameliorated the cerebral cortex damage, neurological dysfunction and apoptosis, as well as decreased PGK1 positivity and expressions of pro-inflammatory cytokines (IL-6, IL-1β, TNF-α) in mice after TBI. DATS also enhanced viability, blocked apoptosis and inhibited ROS production in H 2 O 2 -induced PC12 cells. DATS downregulated Cleaved-Caspase3, Bax and PGK1 levels, and upregulated Bcl-2 and Nrf2 levels in TBI mouse models and the injured cells. Conclusion DATS regulates PGK1/Nrf2 expression and inflammation to alleviate neurological damage in mice after TBI.