查找使用阿拉丁产品的科研文献

Matrine inhibits synovial angiogenesis in collagen-induced arthritis rats by regulating HIF-VEGF-Ang and inhibiting the PI3K/Akt signaling pathway

Limei Ao,Han Gao,Lifen Jia,Shimin Liu,Jie Guo,Bingzhen Liu,Qiumei Dong

Matrine (Mat) is an alkaloid of tetracycline quinazine, and previous studies have demonstrated its specific effect on relieving rheumatoid arthritis (RA). However, the effect of Mat on joint synovial angiogenesis in the pathogenesis of RA has not been elucidated. In this study, body weight, joint swelling, arthritis index (AI) score, histopathological changes, immunohistochemical, and western blot- were used in collagen-induced arthritis (CIA) rats to detect pro-inflammatory factors and, - expression levels of key cytokines and proteins along the hypoxia-inducible factor (HIF)-endothelial growth factor (VEGF)-angiopoietin (Ang) axis and VEGF-phosphoinositide 3-kinase (PI3K) / protein kinase B (Akt) pathway. In vitro experiments were conducted to observe the effect of Mat on the proliferation, migration and lumen formation of RA-fibroblast-like synovial cells (FLS) and human umbilical vein endothelial cells (HUVECs). Results showed that Mat reduced the degree of paw swelling and AI score in CIA rats, joint synovial tissue proliferation, inflammatory cell infiltration, and neovascularization; moreover, it down-regulated the expression levels of inflammatory factors interleukin-1β, interferon-γ, and pro-angiogenic factors VEGF, placental growth factor, HIF-α, Ang-1, Ang-2, Tie-2, and phosphorylation-Akt in the ankle joint of CIA rats. In addition, the in vitro experiments showed that Mat inhibited the proliferation and migration of RA-FLS and inhibited the proliferation and lumen formation of HUVECs. Therefore, Mat exerts an anti-angiogenesis effect by regulating the HIF-VEGF-Ang axis and inhibiting the PI3K/Akt signaling pathway. This inhibits the pathogenesis and improve the symptoms of RA, and may be offered as a candidate drug for the treatment of RA.

Resveratrol dual efficacy in high-altitude hypoxia and NAFLD: inhibits ferroptosis by modulating key proteins, including HIF-1α, ACSL4, and TfR1

Minghui Zhao,Hongfang Mu,Qian Ji,Jiale Song,Fuyixuan Zheng,Tianlong Liu,Wenbin Li,Rong Wang

Background The effects of persistent hypoxic conditions in high-altitude regions on metabolic disorders remain poorly understood and in-depth investigation into its underlying molecular mechanisms is notably insufficient. As a metabolism-associated liver disease, the pathogenesis of non-alcoholic fatty liver disease (NAFLD) under hypoxic conditions urgently requires clarification. Previous studies have demonstrated that resveratrol (Rsv) possesses significant anti-inflammatory, antioxidant, and lipid metabolism-modulating properties, and it can act as an inhibitor of ferroptosis. Yet its precise therapeutic efficacy and mechanism in hypoxic NAFLD remain to be further explored. Objective This study aims to explore the potential mechanism by which Rsv improves the deterioration of NAFLD under hypoxia exposure. Methods Herein, we performed concurrent interventions in both in vivo and in vitro models of NAFLD, comprehensively detecting biochemical indicators (inflammatory factors, oxidative stress markers, liver function), liver histopathological changes, and nucleic acid levels to assess the effects of Rsv. By introducing ferroptosis modulators, we measured core ferroptosis parameters (mitochondrial ultrastructure, Fe²⁺, 4-HNE, LPO levels, and key protein expressions) to define disease progression patterns. By HIF-1α silencing was employed to verify its regulatory roles in ferroptosis-related factors and NAFLD pathogenesis. Co-Immunoprecipitation assays and immunofluorescence co-localization were used to explore protein interactions among ACSL4, TfR1, and HIF-1α. Conclusion Our results demonstrated that high-altitude hypoxia exacerbates NAFLD via inducing ferroptosis; HIF-1α upregulates the expression of key ferroptosis mediators (ACSL4, TfR1), and HIF-1α silencing attenuates ferroptosis. Rsv exerts therapeutic effects against hypoxia-related NAFLD by targeting the HIF-1α-mediated ferroptosis pathway. This study elucidates the pivotal role of HIF-1α-dependent ferroptosis in hypoxia-aggravated NAFLD, identifies the therapeutic targets and mechanisms of Rsv, and provides novel theoretical foundations and potential intervention strategies for clinical management of hypoxia-related NAFLD in high-altitude areas.

GLP-1 regulates osteo-adipogenic fate of BMSCs via HIF-2-AKT signaling and supports trabecular bone in glucocorticoid-induced osteoporosis

Zhe Yang,Xin Li,Niujian Wu,Ling Wang,Zhanjin Lu,Lingling Wang,Shisong Han,Hongyun Lu

Bone marrow mesenchymal stem cell (BMSC) lineage commitment contributes to metabolic bone diseases, but whether glucagon-like peptide-1 (GLP-1) regulates osteo-adipogenic fate remains unclear. Here, RNA sequencing was performed to identify potential pathways regulated by GLP-1 in BMSCs, followed by gain- and loss-of-function experiments. Furthermore, BMSC-specific Hif-2α knockout mice with glucocorticoid-induced osteoporosis were treated with semaglutide to evaluate skeletal effects. GLP-1 suppressed adipogenesis and promoted osteogenesis of BMSCs in a dose-dependent manner. Transcriptomic analysis identified PI3K-AKT and hypoxia signaling as major GLP-1-regulated pathways. Mechanistically, GLP-1 inhibited AKT activation during adipogenesis and reshaped AKT signaling dynamics during osteogenesis. Loss of HIF-2α largely abolished GLP-1-mediated regulation of AKT activity. In vivo , semaglutide improved trabecular bone mass in osteoporotic mice, whereas this bone-protective effect was markedly diminished in Hif-2α -knockout mice. Our findings suggest that GLP-1 modulates BMSC lineage commitment by inhibiting adipogenesis and enhancing osteogenesis through HIF-2α-associated regulation of AKT signaling.

A piezoelectrically driven hierarchical biomimetic architecture promotes diabetic bone defect repair by bidirectionally regulating HIF-1α to restore immunometabolic-vascular homeostasis

Lv Nanning,Dong He,Sun Haifu,Shi Jing,Wu Xinhui,Chen Xiaofan,Li Hongye,Feng Xiaoxiao,Guo Xuran,Dong Xieping,Hu Ying,Zheng Longpo,Liu Mingming

Diabetic bone defects are difficult to repair because chronic hyperglycemia disrupts local immunometabolic and vascular homeostasis, leading to persistent inflammation, poor angiogenesis, and impaired osteogenesis. Here we report a piezoelectrically driven hierarchical biomimetic architecture that promotes diabetic bone defect repair through spatially bidirectional regulation of HIF-1α. The system comprises an ultrasound-responsive PLLA/ZnO/DFO biomimetic periosteum and a conductive GelMA/MXene/Ce-MOF@Arg defect-filling hydrogel. Under ultrasound stimulation, the upper layer generates piezoelectric microcurrents and releases deferoxamine, which is associated with activation of endothelial HIF-1α/VEGF signaling and angiogenic responses, whereas the lower layer relays electrical cues into the defect core and is associated with reduced macrophage HIF-1α expression and glycolytic activity in parallel with arginine delivery and Ce-MOF nanozyme-mediated redox regulation. This design promotes recovery toward a more favorable immunometabolic-vascular state by coupling superficial pro-angiogenic activation with deep anti-inflammatory metabolic remodeling. The scaffold shows favorable piezoelectric, conductive, mechanical, degradation, and release properties, promotes endothelial migration, drives macrophage polarization toward a reparative phenotype, enhances osteogenic-angiogenic coupling, and substantially accelerates critical-sized calvarial defect healing in diabetic rats. Our findings provide an electroactive and spatially coordinated strategy for diabetic bone regeneration.

Oxygen-Generating Biomimetic Nano-Herb System for Synergistic Therapy & Pain Relief in Triple-Negative Breast Cancer via HIF-1α/VEGF Pathway

Dian-Chao Cao,Yan Liang,Yang Guo,Dong-Yang Wu,Na-Na Wang,Yan-Mei Li,Hong-Fang Sun,Qin Wang,Xia Zhang,Yong-Liang Chi,Pei-Pei Sun,You-Jie Li,Ran-Ran Wang,Ping-Yu Wang,Shu-Yang Xie,Ning Xie

Purpose This study aims to develop an innovative delivery system, (Q+M/MnOx)@Clip, to enhance the bioavailability and therapeutic efficacy of quercetin both in tumor treatment and pain alleviation.Methods The (Q+M/MnOx)@Clip system was evaluated to enhance the release of quercetin, investigate its ability to target cancer cells, alleviate tumor hypoxia, and improve the efficacy of chemodynamic therapy (CDT). Tumor hypoxia markers and immune response activation were assessed, along with the impact on pain relief biomarkers.Results (Q+M/MnOx)@Clip successfully mitigated tumor hypoxia, facilitated controlled Q release, and enhanced CDT in vitro and in vivo. The system demonstrated a dual therapeutic effect: anti-tumor immunity and significant cancer pain relief by reducing HIF-1α and VEGF-A levels.Conclusion The novel (Q+M/MnOx)@Clip system represents a promising advancement in nanomedicine, improving the bioavailability of quercetin and offering a more effective approach to cancer treatment by downregulation of HIF-1α and VEGF-A. This study demonstrates the potential for combining anti-tumor immunity with pain relief for triple-negative breast cancer therapy.

A pH-responsive metal-organic framework for the co-delivery of HIF-2α siRNA and curcumin for enhanced therapy of osteoarthritis

Zhang Zi-Jian,Hou Ying-Ke,Chen Ming-Wa,Yu Xue-Zhao,Chen Si-Yu,Yue Ya-Ru,Guo Xiong-Tian,Chen Jin-Xiang,Zhou Quan

The occurrence of osteoarthritis (OA) is highly correlated with the reduction of joint lubrication performance, in which persistent excessive inflammation and irreversible destruction of cartilage dominate the mechanism. The inadequate response to monotherapy methods, suboptimal efficacy caused by undesirable bioavailability, short retention, and lack of stimulus-responsiveness, are few unresolved issues. Herein, we report a pH-responsive metal-organic framework (MOF), namely, MIL-101-NH2, for the co-delivery of anti-inflammatory drug curcumin (CCM) and small interfering RNA (siRNA) for hypoxia inducible factor (HIF-2α). CCM and siRNA were loaded via encapsulation and surface coordination ability of MIL-101-NH2. Our vitro tests showed that MIL-101-NH2 protected siRNA from nuclease degradation by lysosomal escape. The pH-responsive MIL-101-NH2 gradually collapsed in an acidic OA microenvironment to release the CCM payloads to down-regulate the level of pro-inflammatory cytokines, and to release the siRNA payloads to cleave the target HIF-2α mRNA for gene-silencing therapy, ultimately exhibiting the synergetic therapeutic efficacy by silencing HIF-2α genes accompanied by inhibiting the inflammation response and cartilage degeneration of OA. The hybrid material reported herein exhibited promising potential performance for OA therapy as supported by both in vitro and in vivo studies and may offer an efficacious therapeutic strategy for OA utilizing MOFs as host materials.

N-formyl methionine mediates NETosis of neutrophil to promote sepsis-induced cardiomyopathy via the FPR1 pathway

Sen Chen,Hui Lin,Haodi Gu,Xinrou Yu,Junjie Xiang,Lili Xu,Gang Ye,Yue Shan,Yun Wang

Introduction Sepsis-induced cardiomyopathy (SIC) is a rapidly advancing condition associated with a poor prognosis due to the lack of effective treatments. Neutrophil extracellular traps (NETs), however, act as a double-edged sword in the innate immune response during sepsis. N-formyl methionine (fMet) has been documented to induce NETs in inflammatory conditions, yet its clinical significance and biological function in SIC remain unclear. In this study, we investigated whether fMet induces excessive NETs, thereby promoting SIC. Methods and results Clinically, serum fMet levels were quantified using ELISA, revealing a significant elevation in patients with SIC compared to non-sepsis patients and healthy controls. The fMet levels were positively correlated with the NETs-related markers myeloperoxidase (MPO) and double-stranded DNA (dsDNA) in patients with SIC. Treatment with lipopolysaccharide and fMet increased NET formation in human neutrophils and upregulated the expression of formyl peptide receptor 1 (FPR1) and hypoxia-inducible factor 1-alpha (HIF-1α). Furthermore, bone marrow-derived neutrophils (BMDNs) were isolated from global FPR1 knockout mice, and FPR1 deficiency in BMDNs was found to suppress NETosis. The cecal ligation and puncture (CLP) model was employed to induce SIC in mice and we found knockout of FPR1 improved outcomes in CLP mice, as evidenced by survival benefit, increased cardiac function, attenuated cytokine storm, reduced neutrophil infiltration, improved mitochondrial function and suppressed NETosis, compared with those of wild-type (WT) mice. In addition, treatment with FPR1 inhibitor HCH6–1 improved cardiac outcome and inhibits NETosis in CLP mice. Conclusion These data reveal the role of fMet-mediated FPR1/HIF-1α activation in promoting SIC through the NETosis, indicating novel therapeutic strategy for SIC.

Bromodomain-containing protein 4 activates androgen receptor transcription and promotes ovarian fibrosis in PCOS.

Wang D,Zhu Z,Fu Y,Zhang Q,Zhang Y,Wang T,Weng Y,Wen Y,Cao W,Tao G,Wang Y

Polycystic ovary syndrome (PCOS) is an endocrine disorder and the main cause of anovulatory infertility, in which persistent activation of androgen receptor (AR) due to aberrant acetylation modifications of transcription is a potential trigger; however, the precise mechanisms of AR activation are poorly understood. In this study, AR activation in dehydroepiandrosterone- and letrozole-induced rat PCOS ovaries coincided with a marked increase of a chromatin acetylation "reader" BRD4. Further bioinformatic analysis showed that the AR promoter contained highly conserved binding motifs of BRD4 and HIF-1α. BRD4 and HIF-1α inducibly bound to the histone 3/4 acetylation-modified AR promoter, while administration of a BRD4-selective inhibitor JQ1 reduced the binding and AR transcription and improved the adverse expression of the core fibrotic mediators in PCOS ovaries and DHT-treated granulosa cells. Our data indicate that BRD4 upregulation and the resultant AR transcriptional activation constitute an important regulatory pathway that promotes ovarian fibrosis in PCOS.

Trigonelline regulates glycolysis and energy metabolism during hepatic fibrosis via Glut-1-HIF-1α axis: Focusing the interaction of macrophages and HSCs

Chong Gao,Wei Liu,Sai-Hu Liu,Shuang Zheng,Chen-Yu Wang,Xu Dai,Li-Hua Lian,Zhen-Yu Cui,Ji-Xing Nan,Yan-Ling Wu

Background Reprogramming of aerobic glycolysis occurs with HSCs activation and is associated with regression of liver fibrosis. Trigonelline (TRG), a plant alkaloid extracted from Trigonella foenum-graecum L seeds, has a variety of pharmacological effect. Purpose The current study investigated the hepatoprotective effect and mechanism of TRG against hepatic fibrosis by regulating glycolysis. Methods Anti-hepatic fibrosis effects of TRG were detected in thioacetamide (TAA)-induced hepatic fibrosis mice. HSCs or LX-2 were stimulated with TGF-β or conditioned medium (CM) from LPS-stimulated THP-1, then incubated with TRG, phloretin (PHL), rosiglitazone (RGZ), siRNA Glut-1 or plasmid with Glut-1. Results TRG significantly reduced serum transaminase levels, liver histopathological changes, excessive collagen deposition, inflammatory response, and neutrophil recruitment in TAA-induced mice. TAA increased hepatic Glut-1, HIF-1α and key enzymes of glycolysis expressions, while TRG completely reversed this effect. TRG also obviously regulated the combination of Glut-1 and HIF-1α to affect glycolysis in activated HSCs. TRG could inhibit α-SMA, IL-6, IL1R1, and HIF-1α expressions accompanying inhibition of Glut-1, function as PHL (Glut-1 inhibitor). Glut-1 silencing weakened α-SMA, IL-6, IL1R1, and HIF-1α expressions and enhanced the effect of TRG in activated LX-2. TRG inhibited LX-2 activation caused by Glut-1 overexpression, even demonstrated in interaction between LX-2 and macrophages. Further, TRG shown that improved fibrogenesis and inflammatory response by inhibiting Glut-1 compared with PHL in vivo . Conclusion TRG could ameliorate hepatic fibrosis through inhibiting ECM excessive deposition and inflammatory response. Inhibiting Glut-1-HIF-1α axis and glycolysis was a potential therapeutic strategy for TRG ameliorating liver microenvironment, further against hepatic fibrosis.

Oxygen tension regulating hydrogels for vascularization and osteogenesis via sequential activation of HIF-1α and ERK1/2 signaling pathways in bone regeneration

Xianzhen Yin,Yihao Wei,Haotian Qin,Jin Zhao,Yixiao Chen,Sen Yao,Nan Li,Ao Xiong,Deli Wang,Peng Zhang,Peng Liu,Hui Zeng,Yingqi Chen

Angiogenesis plays a crucial role in bone regeneration. Hypoxia is a driving force of angiogenesis at the initial stage of tissue repair. The hypoxic microenvironment could activate the hypoxia-inducible factor (HIF)-1α signaling pathway in cells, thereby enhancing the proliferation, migration and pro-angiogenic functions of stem cells. However, long-term chronic hypoxia could inhibit osteogenic differentiation and even lead to apoptosis. Therefore, shutdown of the HIF-1α signaling pathway and providing oxygen at later stage probably facilitate osteogenic differentiation and bone regeneration. Herein, an oxygen tension regulating hydrogel that sequentially activate and deactivate the HIF-1α signaling pathway were prepared in this study. Its effect and mechanism on stem cell differentiation were investigated both in vitro and in vivo . We proposed a gelatin-based hydrogel capable of sequentially delivering a hypoxic inducer (copper ions) and oxygen generator (calcium peroxide). The copper ions released from the hydrogels significantly enhanced cell viability and VEGF secretion of BMSCs via upregulating HIF-1α expression and facilitating its translocation into the nucleus. Additionally, calcium peroxide promoted alkaline phosphatase activity, osteopontin secretion, and calcium deposition through the activation of ERK1/2. Both Cu 2+ and calcium peroxide demonstrated osteogenic promotion individually, while their synergistic effect within the hydrogels led to a superior osteogenic effect by potentially activating the HIF-1α and ERK1/2 signaling pathways.

Salvianolic Acid B Enhances Motor Function Recovery after Spinal Cord Injury in Association with AKT/mTOR/HIF-1α Pathway Activation and Angiogenesis

Jiange Yao,Yingfeng Chen,Fengjun Pan,Susu Zhang

Hypoxia-induced AFAP1L1 regulates pathological neovascularization via the YAP-DLL4-NOTCH axis

Ren Jun-Song,Bai Wen,Ding Jing-Juan,Ge Hui-Min,Wang Su-Yu,Chen Xi,Jiang Qin

Background Pathological neovascularization plays a pivotal role in the onset and progression of tumors and neovascular eye diseases. Despite notable advancements in the development of anti-angiogenic medications that target vascular endothelial growth factor (VEGF) and its receptors (VEGFRs), the occurrence of adverse reactions and drug resistance has somewhat impeded the widespread application of these drugs. Therefore, additional investigations are warranted to explore alternative therapeutic targets. In recent years, owing to the swift advancement of high-throughput sequencing technology, pan-cancer analysis and single-cell sequencing analysis have emerged as pivotal methodologies and focal areas within the domain of omics research, which is of great significance for us to find potential targets related to the regulation of pathological neovascularization.Methods Pan-cancer analysis and scRNA-seq data analysis were employed to forecast the association between Actin filament-associated protein 1 like 1 (AFAP1L1) and the development of tumors and endothelial cells. Tumor xenograft model and ocular pathological neovascularization model were constructed as well as Isolectin B4 (IsoB4) staining and immunofluorescence staining were used to assess the effects of AFAP1L1 on the progression of neoplasms and neovascular eye diseases in vivo. Transwell assay, wound scratch assay, tube forming assay, three-dimensional germination assay, and rhodamine-phalloidin staining were used to evaluate the impact of AFAP1L1 on human umbilical vein endothelial cells (HUVECs) function in vitro; Dual luciferase reporting, qRT-PCR and western blot were used to investigate the upstream and downstream mechanisms of pathological neovascularization mediated by AFAP1L1.Results Our investigation revealed that AFAP1L1 plays a crucial role in promoting the development of various tumors and demonstrates a strong correlation with endothelial cells. Targeted suppression of AFAP1L1 specifically in endothelial cells in vivo proves effective in inhibiting tumor formation and ocular pathological neovascularization. Mechanistically, AFAP1L1 functions as a hypoxia-related regulatory protein that can be activated by HIF-1α. In vitro experiments demonstrated that reducing AFAP1L1 levels can reverse hypoxia-induced excessive angiogenic capacity in HUVECs. The principal mechanism of angiogenesis inhibition entails the regulation of tip cell behavior through the YAP-DLL4-NOTCH axis.Conclusion In conclusion, AFAP1L1, a newly identified hypoxia-related regulatory protein, can be activated by HIF-1α. Inhibiting AFAP1L1 results in the inhibition of angiogenesis by suppressing the germination of endothelial tip cells through the YAP-DLL4-NOTCH axis. This presents a promising therapeutic target to halt the progression of tumors and neovascular eye disease.