EXPERIMENTAL CELL RESEARCH
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2023
·
IF 3.7
Lirong Zou,Xinling Wang,Xiao Han
The retina may undergo structural and functional damage as a result of hypoxia, which could lead to permanent blindness. As competing endogenous RNAs (ceRNAs), lncRNAs are essential in eye disorders. The biological function of lncRNA MALAT 1 and its potential mechanisms in hypoxic-ischemic retinal diseases are still unknown. MALAT 1 and miR-625–3p expression alterations in hypoxia-treated RPE cells were examined using qRT-PCR. The target binding relationships between MALAT 1 and miR-625–3p, as well as between miR-625–3p and HIF-1α, were identified utilizing bioinformatics analysis and dual luciferase reporter assay. We observed that si-MALAT 1 and miR-625–3p mimic both reduced apoptosis and epithelial-mesenchymal transition (EMT) in hypoxic RPE cells, whereas si-MALAT 1 was reversed by miR-625–3p inhibitor. Further, we carried out a mechanistic investigation, and rescue assays demonstrated that MALAT 1 sponging miR-625–3p influenced HIF-1α expression and consequently took part in the NF-κB/Snail signaling pathway , which regulated apoptosis and EMT. In conclusion, our research had shown that the MALAT 1/miR-625–3p/HIF-1α axis drove the progression of hypoxic-ischemic retinal disorders and may serve as a promising predictive biomarker for their therapeutic and diagnostic targets.
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Nutrients
·
2022
·Vol. 14
·期 13
·2591
·
IF 6.706
Cuicui Zhang,Hai Niu,Chengyu Wan,Xiuxian Yu,Guang Xin,Yuda Zhu,Zeliang Wei,Fan Li,Yilan Wang,Kun Zhang,Shiyi Li,Yuman Dong,Yangying Li,Wen Huang
Acute pancreatitis (AP) is one of the most common causes of hospitalization for gastrointestinal diseases, with high morbidity and mortality. Endoplasmic reticulum stress (ERS) and Gasdermin D (GSDMD) mediate AP, but little is known about their mutual influence on AP. Diosgenin has excellent anti-inflammatory and antioxidant effects. This study investigated whether Diosgenin derivative D (Drug D) inhibits L-arginine-induced acute pancreatitis through meditating GSDMD in the endoplasmic reticulum (ER). Our studies were conducted in a mouse model of L-arginine-induced AP as well as in an in vitro model on mouse pancreatic acinar cells. The GSDMD accumulation in ER was found in this study, which caused ERS of acinar cells. GSDMD inhibitor Disulfiram (DSF) notably decreased the expression of GSDMD in ER and TXNIP/HIF-1α signaling. The molecular docking study indicated that there was a potential interaction between Drug D and GSDMD. Our results showed that Drug D significantly inhibited necrosis of acinar cells dose-dependently, and we also found that Drug D alleviated pancreatic necrosis and systemic inflammation by inhibiting the GSDMD accumulation in the ER of acinar cells via the TXNIP/HIF-1α pathway. Furthermore, the level of p-IRE1α (a marker of ERS) was also down-regulated by Drug D in a dose-dependent manner in AP. We also found that Drug D alleviated TXNIP up-regulation and oxidative stress in AP. Moreover, our results revealed that GSDMD-/-mitigated AP by inhibiting TXNIP/HIF-1α. Therefore, Drug D, which is extracted from Dioscorea zingiberensis, may inhibit L-arginine-induced AP by meditating GSDMD in the ER by the TXNIP /HIF-1α pathway.Keywords:acute pancreatitis;L-arginine;Gasdermin D;endoplasmic reticulum stress;TXNIP
研究领域:
药理学
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炎症
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分子生物学
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细胞生物学
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CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY
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2019
·Vol. 47
·期 1
·85-94
·
IF 2.336
Ning Han,Haitao Xu,Na Yu,Yazhen Wu,Li Yu
Proliferative diabetic retinopathy (PDR) is a common complication of diabetes mellitus, characterized by abnormal retinal angiogenesis. MicroRNA-203-3p (miR-203-3p) was found to be down-regulated in a murine model of proliferative retinopathy. This study was performed to explore the role of miR-203a-3p in retinal angiogenesis of PDR. Firstly, a rat OIR model, which was used to mimic PDR, was established and the OIR rats were treated with scrambled control or miR-203a-3p agomir by intravitreal injection. The results showed that the level of miR-203a-3p was decreased in OIR rats, and forced over-expression of miR-203a-3p inhibited OIR-induced retinal angiogenesis as evidenced by reduced blood vessel profiles and CD31 expression. OIR-induced up-regulation of VEGFA, HIF-α, PCNA, and MMPs in the retina was also counteracted by miR-203a-3p. Additionally, high glucose (HG)-induced proliferation, migration and tube formation of human retinal microvascular endothelial cells (HRMECs) were also dampened by the up-regulation of miR-203a-3p. Dual-luciferase reporter assay showed that miR-203a-3p could specifically bind to the 3′UTR of VEGFA and HIF-1α. Over-expression of VEGFA or HIF-1α restored the tube formation activity of HRMECs suppressed by miR-203a-3p. In conclusion, our findings demonstrate that up-regulation of miR-203a-3p might inhibit pathological retinal angiogenesis of PDR by targeting VEGFA and HIF-1α.
研究领域:
分子生物学
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眼科学
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糖尿病研究
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微小RNA
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2023
·
IF 5.6
Pingchuan Wang,Tianming Li,Changping Niu,Siyu Sun,Dongyan Liu
Reactive oxygen species (ROS) damage to the intestinal barrier is a side effect of prolonged hyperoxia therapy in neonates, which impairs growth and development of the intestine and promotes intestinal diseases. However, the research on clinical prevention and treatment is lacking. Therefore, we investigated the molecular mechanisms of the neonate intestinal response against hyperoxia-derived ROS to find targets for intestinal barrier damage prevention. Human intestinal epithelial cells were incubated under hyperoxia (85% oxygen) to build an in vitro model. ROS and the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway were inhibited to detect the MAPK/ERK pathway, nuclear factor erythroid factor 2-related factor 2 (Nrf2), hypoxia-inducible factor-1α (Hif-1α), and interleukin-17D (IL-17D) expression. Nrf2 was inhibited to detect Hif-1α and IL-17D expression. Hif-1α was inhibited to detect Nrf2, IL-17D, and tight junction proteins expression and apoptosis. Cells were treated with human recombinant IL-17D to detect TNF-α, IL-1β, IL-10, and tight junction proteins expression. ROS, Nrf2, Hif-1α, and IL-17D were upregulated and the MAPK/ERK pathway was activated under hyperoxia. But ROS inhibition downregulated the MAPK/ERK pathway, Nrf2, Hif-1α, and IL-17D. MAPK/ERK pathway inhibition downregulated Nrf2, Hif-1α, and IL-17D. Nrf2 inhibition downregulated Hif-1α and IL-17D. Hif-1α inhibition downregulated Nrf2, IL-17D, tight junction proteins, and exacerbated apoptosis. The recombinant IL-17D downregulated TNF-α, IL-1β, but upregulated IL-10 and tight junction proteins. We concluded that Hyperoxia-generated ROS activated the MAPK/ERK pathway to regulate Nrf2, Hif-1α, and IL-17D expression. Nrf2 and Hif-1α were interdependent and promoted IL-17D. Importantly, Hif-1α and IL-17D expression protected the intestinal epithelial barrier.
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Chemical Biology & Drug Design
·
2025
·Vol. 105
·期 6
·e70133
·
IF 3.3
Lin Xu,Dongsheng Yao,Tianying Lan,Yurou Chen,Dongping Chen,Minghai Shao,Yijing Zhou,Chaoyang Ye,Di Huang
Ferulic acid (FA), a natural phenolic compound, shows potential therapeutic effects on renal interstitial fibrosis, although its antifibrotic mechanism remains unclear. This study investigated the molecular mechanisms of FA by focusing on epithelial-mesenchymal transition (EMT) and related signaling pathways. By using a hypoxia-induced HK2 cell model, the optimal FA concentration was determined by CCK-8 assay, and the cells were assigned to low-, medium-, and high-FA groups. Renal fibrosis-associated protein and mRNA levels were evaluated by western blotting (WB) and reverse transcription-quantitative polymerase chain reaction. In a 5/6 nephrectomy-induced chronic renal failure rat model, renal oxygen consumption, serum creatinine, and blood urea nitrogen levels were measured, while ultrastructural and morphological changes in renal tissues were examined by transmission electron microscopy (TEM), hematoxylin–eosin (HE) staining, and Masson's trichrome staining. Renal fibrosis-related indicators were further assessed by Western Blot (WB) and immunofluorescence assay. The results showed that FA treatment significantly reduced fibronectin, HIF-1α, and α-SMA expression; inhibited partial EMT in vivo and in vitro; improved renal function; and attenuated fibrosis in kidney tissues. Combining siTwist or oe-HIF-1α transfection with FA treatment revealed that FA targeted the HIF-1α/Twist signaling pathway, impeding EMT and delaying renal fibrosis. In conclusion, FA inhibited partial EMT of tubular epithelial cells and suppressed the HIF-1α/Twist pathway, thereby mitigating renal interstitial fibrosis and providing a foundation for FA-based treatment of chronic kidney disease.
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JOURNAL OF NANOBIOTECHNOLOGY
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2022
·Vol. 20
·期 1
·1-16
·
IF 9.429
Liu Jie,Hu Xiaochun,Feng Lei,Lin Yun,Liang Shujing,Zhu Zhounan,Shi Shuo,Dong Chunyan
Background Non-redundant properties such as hypoxia and acidosis promote tumor metabolic adaptation and limit anti-cancer therapies. The key to the adaptation of tumor cells to hypoxia is the transcriptional and stable expression of hypoxia-inducible factor-1 alpha (HIF-1α). The phosphorylation-activated tumorigenic signal PI3K/AKT/mTOR advances the production of downstream HIF-1α to adapt to tumor hypoxia. Studies have elucidated that acid favors inhibition of mTOR signal. Nonetheless, carbonic anhydrase IX (CAIX), overexpressed on membranes of hypoxia tumor cells with pH-regulatory effects, attenuates intracellular acidity, which is unfavorable for mTOR inhibition. Herein, a drug delivery nanoplatform equipped with dual PI3K/mTOR inhibitor Dactolisib (NVP-BEZ235, BEZ235) and CAIX inhibitor 4‐(2‐aminoethyl) benzene sulfonamide (ABS) was designed to mitigate hypoxic adaptation and improve breast cancer treatment. Results ABS and PEG-NH 2 were successfully modified on the surface of hollow polydopamine (HPDA), while BEZ235 and Chlorin e6 (Ce6) were effectively loaded with the interior of HPDA to form HPDA-ABS/PEG-BEZ235/Ce6 (H-APBC) nanoparticles. The release of BEZ235 from H-APBC in acid microenvironment could mitigate PI3K/mTOR signal and resist HIF-1α-dependent tumor hypoxia adaptation. More importantly, ABS modified on the surface of H-APBC could augment intracellular acids and enhances the mTOR inhibition. The nanoplatform combined with phototherapy inhibited orthotopic breast cancer growth while reducing spontaneous lung metastasis, angiogenesis, based on altering the microenvironment adapted to hypoxia and extracellular acidosis. Conclusion Taken together, compared with free BEZ235 and ABS, the nanoplatform exhibited remarkable anti-tumor efficiency, reduced hypoxia adaptation, mitigated off-tumor toxicity of BEZ235 and solved the limited bioavailability of BEZ235 caused by weak solubility. Graphical Abstract
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Frontiers in Bioengineering and Biotechnology
·
2021
·
IF 5.89
Dong Wenpei,Song Zhicheng,Liu Suihong,Yu Ping,Shen Zhipeng,Yang Jianjun,Yang Dongchao,Hu Qinxi,Zhang Haiguang,Gu Yan
Application of synthetic or biological meshes is the main therapy for the repair and reconstruction of abdominal wall defects, a common disease in surgery. Currently, no ideal materials are available, and there is an urgent need to find appropriate ones to satisfy clinical needs. Electrospun scaffolds have drawn attention in soft tissue reconstruction. In this study, we developed a novel method to fabricate a composite electrospun scaffold using a thermoresponsive hydrogel, poly (N-isopropylacrylamide)-block-poly (ethylene glycol), and a biodegradable polymer, polylactic acid (PLA). This scaffold provided not only a high surface area/volume ratio and a three-dimensional fibrous matrix but also high biocompatibility and sufficient mechanical strength, and could simulate the native extracellular matrix and accelerate cell adhesion and proliferation. Furthermore, rat adipose-derived stem cells (ADSCs) were seeded in the composite electrospun scaffold to enhance the defect repair and regeneration by directionally inducing ADSCs into endothelial cells. In addition, we found early vascularization in the process was regulated by the hypoxia inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) pathway. In our study, overexpression of HIF-1α/VEGF in ADSCs using a lentivirus system promoted early vascularization in the electrospun scaffolds. Overall, we expect our composite biomimetic scaffold method will be applicable and useful in abdominal wall defect regeneration and repair in the future.
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Arabian Journal of Chemistry
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2022
·
IF 6.212
Zizhen Zhao,Chen Fu,Yuping Zhang,Yingying Zhang,Xiaoxi Yang,Ailing Fu
The incidence of HCC continues to increase rapidly in recent years. the principle of developing anti-HCC drugs is to specifically kill tumor cells, without affecting the function of normal cells. Here we synthesized a novel protonic compound bis(5-amino-1,10-phenanthroline) (P-BAP), and the antitumor activity was explored in vitro and in vivo . The results showed that P-BAP could selectively inhibit the proliferation of tumor cells, and induce HCC apoptosis. In HCC-bearing mice, P-BAP could effectively retard the tumor growth, even completely eliminate the tumors at the dose of 5 mg/kg, and meanwhile P-BAP had no significant effect on mouse body weight. Mechanism analysis revealed that P-BAP could down-regulate the protein expressions of pleomorphic adenoma gene like-2 (PLAGL2), HIF-1α and β-catenin, and up-regulate the levels of pro-apoptotic protein BAX and BNIP3. In addition, P-BAP could reduce mitochondrial respiratory chain complex activities, leading to insufficient ATP production. The study provides a new approach for designing selective antitumor drugs, and suggests that P-BAP would be a potential candidate for HCC therapy.
研究领域:
肿瘤学
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药理学
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分子生物学
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JOURNAL OF PHARMACY AND PHARMACOLOGY
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2023
·
IF 3.3
Zeng Xiangfeng,Liu Shengyao,Yang Hua,Jia Menglei,Liu Wei,Zhu Wenting
ObjectivesThe most common cause of osteosarcoma (OS) death is lung metastasis. Currently, doxorubicin is the primary chemotherapy drug used to treat OS, however, it is not effective in inhibiting metastasis, and it has obvious cardiotoxicity. The anticancer activity of ginsenoside Rg3 has been demonstrated in a variety of malignant tumours. The aim of this study was to determine the potential role of ginsenoside Rg3 and doxorubicin in OS and the possible mechanism.MethodsThe potential synergistic effects of ginsenoside Rg3 and doxorubicin on human osteosarcoma cells 143B and U2OS, human umbilical vein endothelial cells, and mice receiving 143B xenografts and lung metastases were investigated.Key findingsOur study demonstrated that the combination of ginsenoside Rg3 and doxorubicin significantly inhibited cell proliferation, metastasis and angiogenesis in vitro. Mechanically, the anti-tumour activity of ginsenoside Rg3 and doxorubicin by modulating mTOR/HIF-1α/VEGF and EMT signalling pathways. Furthermore, ginsenoside Rg3 combined with doxorubicin inhibits tumour growth and lung metastasis in 143B-derived murine osteosarcoma models. More importantly, ginsenoside Rg3 can effectively ameliorate doxorubicin-induced weight loss and cardiotoxicity in mice.ConclusionsConsequently, we concluded that the combination of ginsenoside Rg3 and doxorubicin displayed an evidently synergistic effect, which has the potential to be used as an effective and safe therapeutic approach for OS treatment.
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CHEMICAL ENGINEERING JOURNAL
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2025
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IF 13.2
Xudong Xie,Weixian Hu,Yue An,Yuheng Liao,Shengming Zhang,Yanzhi Zhao,Kangkang Zha,Wenqian Zhang,Zhenhe Zhang,Fan Xia,Bobin Mi,Benjie Zhou,Hankun Hu,Mengfei Liu,Guohui Liu
Diabetic wounds are characterized by an imbalance between impaired angiogenesis and persistent pro-inflammatory immune responses, leading to chronic non-healing. Under hyperglycemic and oxidative stress conditions, the glycolytic function of endothelial cells is significantly compromised. However, solely enhancing angiogenesis does not effectively promote diabetic wound healing due to concomitant dysregulation of the local immune microenvironment, which further suppresses vascularization. Notably, Th1 cells dominate the diabetic wound immune milieu and exacerbate inflammatory responses, thereby aggravating immune imbalance. Thus, an optimal therapeutic strategy should simultaneously target both inflammatory dysregulation and vascular dysfunction. To address the phenomenon of cell-specific metabolic reprogramming within diabetic wounds, where glycolytic activity is impaired in endothelial cells yet enhanced in Th1 cells, this study developed a glucose-responsive NG@B87@HA hydrogel system designed to reprogram the local metabolic network and modulate Th1 cell metabolism while restoring endothelial function. The hydrogel incorporates nanoparticles functionalized with CXCR3 antibody to specifically target Th1 cells and deliver the glycolysis inhibitor Bay87-2243 (B87), thereby suppressing their glycolytic flux and inflammatory activity via inhibition of the HIF-1α–GLUT1 signaling axis. Simultaneously, naringin (NG), which acts as a crosslinker, forms dynamic boronic ester bonds with HA-PBA and PVA, enabling glucose-dependent responsiveness. This mechanism not only mitigates local oxidative stress but also enhances the tube-forming capacity of endothelial cells, ultimately promoting angiogenesis. The results demonstrated that the NG@B87@HA hydrogel effectively restores the dysregulated metabolic network in diabetic wounds. By concurrently rectifying immune microenvironment imbalance and endothelial dysfunction, this system provides a novel therapeutic strategy for accelerating diabetic wound healing.
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Journal of Agriculture and Food Research
·
2026
·
IF 7.2
Yizhu Chen,Yi Liu,Yurong Fang,Huixue Huang,Zhihong Long,Bomi Ryu,Haisheng Xie,Zhong-Ji Qian
Age related macular degeneration (AMD) is one of the main causes of blindness in. elderly patients, and its treatment methods include intraocular injection and oral. administration, requiring long-term treatment and suboptimal efficacy. Tilapia skin-derived oligopeptides, characterized by high safety and bioactivity, emerge as a promising source of functional food ingredients. Here, we investigated the protective mechanism of TBP-1 (Ser-Val-Val-Ala-Ile), a pentapeptide isolated from tilapia skin, against hypoxia-induced damage in retinal pigment epithelial (ARPE-19) cells and angiogenesis in human umbilical vein endothelial cells (HUVECs). In the functional evaluation, TBP-1 notably attenuated ROS overproduction in CoCl 2 -induced ARPE-19 cells, simultaneously suppressing the stabilization of hypoxia-inducible factor-1α (HIF-1α), which was associated with reduced vascular endothelial growth factor (VEGF) transcription, diminished inflammatory factor levels, and restoration of normal autophagic flux. To validate the ROS-dependent nature of this regulatory pathway, we performed a rescue experiment using N-acetylcysteine (NAC), a well-characterized ROS scavenger. In HUVECs activated by VEGF, TBP-1 decreased the phosphorylation of VEGFR-2 and dampened the activation of the MAPK signaling pathway, resulting in dose-dependent inhibition of cell migration, invasion, and the formation of capillary-like tubular structures. Molecular docking and quantum chemical analyses suggested that the bioactivity of TBP-1 may rely on the electron-donating property of the Ser residue and hydrophobic interactions mediated by Ile, both of which are critical for its ROS scavenging ability and predicted interaction with HIF-1α. Collectively, these findings suggest that TBP-1 is a multi-target functional food supplement for preventing AMD by targeting the ROS/HIF-1α/VEGF axis, providing a theoretical basis for the high-value utilization of tilapia skin.
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Acta Biomaterialia
·
2022
·
IF 10.633
Yifan Li,Qiangwei Liang,Liyue Zhou,Yongjing Cao,Jiayu Yang,Juan Li,Jinxia Liu,Jiawei Bi,Yanhua Liu
The signaling cascade between nuclear factor-kappa B (NF-κB) and hypoxia-inducible factor-1α (HIF-1α) can be activated by proinflammatory M1 macrophages in rheumatoid arthritis (RA), which produces reactive oxygen species (ROS) and enhances M1 macrophage polarization, thus aggravating the development of RA. Therefore, an ROS-responsive artesunate prodrug micellar nanosystem for co-delivery of dexamethasone (DEX/HA-TK-ART micelles , abbreviated as DEX/HTA) was developed for synergistic inhibition of the HIF-1α/NF-κB cascade to regulate ROS scavenging and macrophage repolarization in RA combination therapy. DEX/HTA micelles displayed prolonged circulation in blood and efficiently co-delivered ART&DEX in the inflamed joints of adjuvant-induced arthritis (AIA) rats; moreover, they were specifically recognized and internalized into M1 macrophages through CD44 receptor-mediated endocytosis . ROS-responsive co-released ART&DEX then exerted a synergistic action to efficiently perform ROS scavenging and repolarization of M1 to M2 macrophages by inhibition of the HIF-1α/NF-κB cascade. The intravenous administration of DEX/HTA micelles into AIA rat models significantly alleviated inflammatory cell infiltration and repaired cartilage injury in the joint. Collectively, our study highlights the therapeutic potential of DEX/HTA micelles for treating RA through synergistic inhibition of the HIF-1α/NF-κB signaling cascade to regulate ROS scavenging and macrophage repolarization. Statement of significance An ROS-responsive artesunate (ART) prodrug micellar nanosystem for co-delivering dexamethasone (DEX), abbreviated as DEX/HA-TK-ART micelle, was developed for synergistic cascade regulation of the HIF-1α/NF-κB pathway on ROS scavenging and macrophage repolarization in combination therapy for rheumatoid arthritis. The well-designed nanosystem showed prolonged circulation in blood and superior ART&DEX accumulation in the inflamed joints of AIA rats; moreover, the micelles were specifically internalized into M1 macrophages and co-released ART&DEX, subsequently leading to inhibition of the HIF-1α/NF-κB pathway for ROS scavenging and macrophage repolarization, thus generating synergistic anti-inflammatory effects in RAW 264.7 cells and AIA rats. The HIF-1α/NF-κB cascade regulation on ROS scavenging and macrophage repolarization based on ART&DEX combination with smart nanotechnology could serve as a promising approach for rheumatoid arthritis therapy.
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