ACS Applied Nano Materials
·
2024
·
IF 5.3
Zhi-Hang He,Han-Xiao Tang,Yan-Zheng Pan,Min Cen,Zhi-Juan Zhang
The oxygen consumption during chemodynamic therapy (CDT) can lead to severe cellular hypoxia, resulting in an increase in the hypoxia inducible factor-1α (HIF-1α) level, which hinders the effectiveness of CDT and induces tumor metastasis. Here, we propose a strategy of synergistic therapy between CDT and the HIF-1α inhibitor to avoid the limitations of CDT and reduce the risk of metastasis. Herein, based on the coordination between Fe3+ and apigenin (API, HIF-1α inhibitor), we constructed a hyaluronic acid (HA)-modified API-Fe nanoparticles (AF@HA NPs) for synergetic chemotherapy and glutathione (GSH)-activated self-enhancing CDT. AF@HA NPs have high drug loading capacity, stability, and biocompatibility. Furthermore, the overexpressed GSH in cancer cells can reduce Fe3+ to Fe2+, weakened the coordination between API and Fe, and promoted the release of API for chemotherapy. Fe2+ could react with endogenous H2O2 to generate hydroxyl groups for CDT. In addition, the released API could inhibit the expression of HIF-1α and increase the sensitivity of cells to reactive oxygen species (ROS), thereby achieving a synergistic effect between self-enhancing CDT and chemotherapy. The results of in vitro and in vivo experiments indicated that AF@HA NPs could effectively inhibit tumor growth and suppress the lung metastasis of tumor cells.
研究领域:
纳米技术
·
癌症治疗
·
药理学
·
生物医学工程
·
分子生物学
✓ 已验证
产品关联
DOI
高影响因子
PHYTOMEDICINE
·
2024
·
IF 6.7
Maoxing Pan,Yuanjun Deng,Yebei Qiu,Dajin Pi,Chuiyang Zheng,Zheng Liang,Jianwei Zhen,Wen Fan,Qingliang Song,Jinyue Pan,Yuanyou Li,Haizhen Yan,Qinhe Yang,Yupei Zhang
Background Non-alcoholic fatty liver disease (NAFLD) has emerged as a burgeoning health problem worldwide, but no specific drug has been approved for its treatment. Shenling Baizhu powder (SL) is extensively used to treat NAFLD in Chinese clinical practice. However, the therapeutic components and pharmacological mechanisms of SL against NAFLD have not been thoroughly investigated. Purpose This study aimed to investigate the pharmacological impact and molecular mechanism of SL on NAFLD. Methods First, we established an animal model of NAFLD by high-fat diet (HFD) feeding, and evaluated the therapeutic efficacy of SL on NAFLD by physiological, biochemical, pathological, and body composition analysis. Next, the effect of SL on autophagic flow in NAFLD rats was evaluated by ultrastructure, immunofluorescence staining, and western blotting. Moreover, an integrated strategy of targeted energy metabolomics and network pharmacology was performed to characterize autophagy-related genes and explore the synergistic effects of SL active compounds. UPLC-MS/MS, molecular docking combined with in vivo and in vitro experiments were conducted to verify the key compounds and genes. Finally, a network was established among SL-herb-compound-genes-energy metabolites-NAFLD, which explains the complicated regulating mechanism of SL on NAFLD. Results We discovered that SL decreased hepatic lipid accumulation, hepatic steatosis, and insulin resistance, and improved systemic metabolic disorders and pathological abnormalities. Subsequently, an integrated strategy of targeted energy metabolomics and network pharmacology identified quercetin, ellagic acid, kaempferol, formononetin, stigmasterol, isorhamnetin and luteolin as key compounds; catalase (CAT), AKT serine/threonine kinase 1 (AKT), nitric oxide synthase 3 (eNOS), NAD(P)H quinone dehydrogenase 1 (NQO1), heme oxygenase 1 (HO-1) and hypoxia-inducible factor 1 subunit alpha (HIF-1α) were identified as key genes; while nicotinamide adenine dinucleotide phosphate (NADP) and succinate emerged as key energy metabolites. Mechanistically, we revealed that SL may exert its anti-NAFLD effect by inducing autophagy activation and forming a comprehensive regulatory network involving key compounds, key genes, and key energy metabolites, ultimately alleviating oxidative stress, endoplasmic reticulum stress, and mitochondrial dysfunction. Conclusion Our study demonstrated the therapeutic effect of SL in NAFLD models, and establishes a basis for the development of potential products from SL plant materials for the treatment of NAFLD.
研究领域:
药理学
·
分子生物学
·
代谢组学
·
营养学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Yanzhu Wang,Linghe Zang,Liyuan Guan,Xihang Ren,Zongmin Xia,Zhou Li,Zhaoxu Meng,He Lian
The efficacy of αPD-L1, an immune checkpoint inhibitor, in the treatment of melanoma is limited by individual patient variations and tumor immunosuppressive cells. Consequently, current immunotherapy of melanoma is far from satisfactory. In this study, bispolyphenol nanoparticles (Phl-CaCO 3 @Lut-Cu NPs) were constructed by wrapping a luteolin-copper (Lut-Cu) network around the surface of phloretin-loaded calcium carbonate (Phl-CaCO 3 ) nanoparticles. Upon entering tumor cells, Phl-CaCO 3 @Lut-Cu nanoparticles efficiently released Cu 2+ , phloretin (Phl), and luteolin (Lut) due to the acid-responsive properties of calcium carbonate and the metal-phenolic network. The copper ions mediated cuproptosis by binding to dihydrolipoamide acetyltransferase and induced cellular immune responses by promoting release of damage-associated molecular patterns (DAMPs). In addition, Phl blocked glucose transport by inhibiting glucose transporter 1 activity, thereby disrupting the energy supply process in tumor cells. Simultaneously, Lut inhibited expression of hypoxia-inducible factor-1α, negatively regulating aerobic glycolysis. This study aimed to reshape the tumor microenvironment by exploring the synergistic effects of cuproptosis and dual glycolysis inhibition, enhancing the T cell-mediated immune response, and suppressing tumor cell growth when combined with αPD-L1. This study provides a new perspective and strategy for melanoma immunotherapy.
研究领域:
肿瘤学
·
免疫学
·
纳米医学
·
药理学
✓ 已验证
产品关联
DOI
高影响因子
International Journal of Nanomedicine
·
2024
·
IF 6.6
Min Chen,Tao Liu,Wenqiang Li,Yingting Li,Puxin Zhong,Huanchen Yan,Jingyin Kong,Weixiang Liang
Background Cartilage-related diseases, such as hypoplastic chondrodysplasia a rare genetic disorder that affects newborns, causing abnormal cartilage development and restricted skeletal growth. However, the development of effective treatment strategies for chondrodysplasia still faces significant challenges due to limitations in the controlled drug delivery, biocompatibility, and biodegradability of nanomedicines.Methods A biodegradable magnesium doped-silicon based-nanoplatforms based on silicon nanoparticles (MON) was constructed. Briefly, the MON was modified with sulfhydryl groups using MPTMS to form MOS. Further engineering of MOS was achieved by incorporating Mg2+ ions through the “dissolution-regrowth” method, resulting in MMOS. Ica was effectively loaded into the MMOS channels, and HA was anchored on the surface of MOS to obtain MMOS-Ica@HA nanoplatforms. Additionally, in vitro cell experiments and in vivo zebrafish embryo models were used to evaluate the effect of the nanoplatforms on cartilage differentiation or formation and the efficiency of treating chondrodysplasia.Results A series of characterization tests including TEM, SEM, DLS, XPS, EDX, and BET analysis validate the successful preparation of MOS-Ica@HA nanoplatforms. The prepared nanoplatforms show excellent dispersion and controllable drug release behavior. The cytotoxicity evaluation reveals the good biocompatibility of MOS-Ica@HA due to the sustained and controllable release of Ica. Importantly, the presence of Ica and Mg component in MOS-Ica@HA significantly promote chondrogenic differentiation of BMSCs via the Smad5/HIF-1α signaling pathway. In vitro and in vivo experiments confirmed that the nanoplatforms improved chondrodysplasia by promoting cartilage differentiation and formation.Conclusion The findings suggest the potential application of the developed biodegradable MMOS-Ica@HA nanoplatforms with acceptable drug loading capacity and controlled drug release in chondrodysplasia treatment, which indicates a promising approach for the treatment of chondrodysplasia.
研究领域:
生物医学工程
·
纳米技术
·
组织工程
·
再生医学
·
药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Pharmaceutics
·
2024
·Vol. 16
·期 5
·619
·
IF 4.9
Huaying Xie,Xuhua Xiao,Xiaoyuan Yi,Kunzhao Huang,Liyan Wang
Chemodynamic therapy (CDT) employs hydrogen peroxide (H2O2) within the tumor microenvironment (TME) to initiate the Fenton reaction and catalyze the generation of hydroxyl radicals (·OH) for targeted therapy. Metal ion-based nanomaterials have garnered significant attention as catalysts due to their potent anti-tumor effects. Hypoxia in the TME is often associated with cancer cell development and metastasis, with HIF-1α being a pivotal factor in hypoxia adaptation. In this study, an organic framework called MIL-101 (Fe) was designed and synthesized to facilitate H2O2-induced ·OH production while also serving as a carrier for the HIF-1α inhibitor Acriflavine (ACF). A biomimetic nanomedical drug delivery system named MIL-101/ACF@CCM was constructed by encapsulating liver cancer cell membranes onto the framework. This delivery system utilized the homologous targeting of tumor cell membranes to transport ACF, inhibiting HIF-1α expression, alleviating tumor hypoxia, and catalyzing ·OH production for effective tumor eradication. Both in vivo and in vitro experiments confirmed that combining ACF with chemotherapy achieved remarkable tumor inhibition by enhancing ROS production and suppressing HIF-1α expression.
研究领域:
肿瘤学
·
纳米医学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2024
·
IF 10
Ming-Xuan Liu,Yan-Chao Liu,Yu-Ting Cai,Ying-Ying Gu,Ya-Qi Zhu,Nan Zhang,Wei-Zhong Zhu,Yong-Hong Liu,Lei Yu,Qi-Tao Zhang,Xiao-Ling Zhang
Hypoxia can aggravate tumor occurrence, development, invasion, and metastasis, and greatly inhibit the photodynamic therapy (PDT) effect. Herein, carbon nitride (CNs)-based DNA and photosensitizer co-delivery systems (BPSCNs) with oxygen-producing functions are developed to address this problem. Selenide glucose (Seglu) is used as the dopant to prepare red/NIR-active CNs (SegluCNs). The tumor-targeting unit Bio-PEG 2000 is utilized to construct BPSCNs nanoparticles through esterification reactions. Furthermore, DNA hydrophobization is realized via mixing P53 gene with a positively charged mitochondrial-targeted near-infrared (NIR) emitting photosensitizer (MTTPY), which is encapsulated in non-cationic BPSCNs for synergistic delivery. Ester bonds in BPSCNs@MTTPY-P53 complexes can be disrupted by lipase in the liver to facilitate P53 release, upregulated P53 expression, and promoted HIF-1α degradation in mitochondria. In addition, the oxygen produced by the complexes improved the hypoxic microenvironment of hepatocellular carcinoma (HCC), synergistically downregulated HIF-1α expression in mitochondria, promoted mitochondrial-derived ferroptosis and enhanced the PDT effect of the MTTPY unit. Both in vivo and in vitro experiments indicated that the transfected P53-DNA, produced O 2 and ROS by these complexes synergistically led to mitochondrial-derived ferroptosis in hepatoma cells through the HIF-1α/SLC7A11 pathway, and completely avoiding PDT resistance caused by hypoxia, exerting a significant therapeutic role in HCC treatment.
研究领域:
癌症生物学
·
药学
·
生物医学工程
·
分子生物学
·
治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2024
·
IF 6.9
Lei Wang,Yufeng Tao,Xuesong Wang,Yuhan Gan,Yuting Zeng,Shasha Li,Qing Zhu
Phellinus igniarius is an important medicinal and edible fungus with diverse biological activities. This study aimed to investigate the effects of aqueous extract from P. igniarius (API) on the treatment of hyperuricemia (HUA) and related kidney damage. The chemical constituents of API were determined. The therapeutic effects of API on HUA and renal injury were assessed in adenine/potassium oxonate (PO)-treated mice. The constituent analysis of API revealed a predominance of polysaccharides (33.4 %), followed by total flavonoids (9.1 %), and total triterpenoids (3.5 %). Compared to control, the adenine/PO treatment greatly elevated serum uric acid (UA) levels but this elevation was attenuated by API. In the liver, the expression and activity of xanthine oxidase (XOD) were increased by HUA which were diminished by API. Furthermore, API was found to enhance the expression of UA transporter ABCG2 in the kidney and intestine of HUA mice, suggesting elevating UA excretion. Additionally, API ameliorated HUA-induced renal injury, as indicated by reduced serum BUN/creatinine levels, decreased glomerular and tubular damage, and lowered fibrotic levels. Network pharmacology analysis predicted that P. igniarius may regulate mitochondrial function to improve HUA-related renal injury. This prediction was then substantialized by the API-induced upregulation of NAD+/NADH ratio, ATP level, SOD2 activity, and expression of SOD2/PCG-1α/PPARγ in the kidney of HUA mice. Our results demonstrate that API may effectively ameliorate HUA by reducing UA production in the liver and enhancing UA excretion in the kidney and intestine, and it might be a potential therapy to HUA-related renal injury.
研究领域:
药理学
·
医学
·
生物化学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2024
·
IF 9.4
Yongsheng Zheng,Dong Yang,Botao Gao,Shuai Huang,Yubo Tang,Qingde Wa,Yong Dong,Shan Yu,Jun Huang,Sheng Huang
Chronic diabetic wounds are a severe complication of diabetes, often leading to high treatment costs and high amputation rates. Numerous studies have revealed that nitric oxide (NO) therapy is a promising option because it favours wound revascularization. Here, base-paired injectable adhesive hydrogels (CAT) were prepared using adenine- and thymine-modified chitosan (CSA and CST). By further introducing S-nitrosoglutathione (GSNO) and binary L-arginine (bArg), we obtained a NO sustained-release hydrogel (CAT/bArg/GSON) that was more suitable for the treatment of chronic wounds. The results showed that the expression of HIF-1α and VEGF was upregulated in the CAT/bArg/GSON group, and improved blood vessel regeneration was observed, indicating an important role of NO. In addition, the research findings revealed that following treatment with the CAT/bArg/GSON hydrogel, the viability of Staphylococcus aureus and Escherichia coli decreased to 14 ± 2% and 6 ± 1%, respectively. Moreover, the wound microenvironment was improved, as evidenced by a 60 ± 1% clearance of DPPH. In particular, histological examination and immunohistochemical staining results showed that wounds treated with CAT/bArg/GSNO exhibited denser neovascularization, faster epithelial tissue regeneration, and thicker collagen deposition. Overall, this study proposes an effective strategy to prepare injectable hydrogel dressings with dual NO donors. The functionality of CAT/bArg/GSON has been thoroughly demonstrated in research on chronic wound vascular regeneration, indicating that CAT/bArg/GSON could be a potential option for promoting chronic wound healing. Statement of significance This article prepares a chitosan hydrogel utilizing the principle of complementary base pairing, which offers several advantages, including good adhesion, biocompatibility, and flow properties, making it a good material for wound dressings. Loaded GSNO and bArg can steadily release NO and L-arginine through the degradation of the gel. Then, the released L-arginine not only possesses antioxidant properties but can also continue to generate a small amount of NO under the action of NOS. This design achieves a sustained and stable supply of NO at the wound site, maximizing the angiogenesis-promoting and antibacterial effects of NO. More neovascularization and abundant collagen were observed in the regenerated tissues. This study provides an effective repair hydrogel material for diabetic wound.
研究领域:
生物医学工程
·
材料科学
·
药剂学
·
伤口愈合
·
组织工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF LIPID RESEARCH
·
2022
·Vol. 63
·期 10
·
IF 6.676
Yue Li,Ran Yao,Miao Ren,Ke Yuan,Yuwei Du,Yuan He,Haiquan Kang,Shengnan Yuan,Wen Ju,Jianlin Qiao,Kailin Xu,Lingyu Zeng
Liposomes are the most widely used nanocarrier platform for the delivery of therapeutic and diagnostic agents, and a number of liposomes have been approved for use in clinical practice. After systemic administration, most liposomes are cleared by macrophages in the mononuclear phagocyte system, such as the liver and bone marrow (BM). However, the majority of studies have focused on investigating the therapeutic results of liposomal drugs, and too few studies have evaluated the potential side effects of empty nanocarriers on the functions of macrophages in the mononuclear phagocyte system. Here, we evaluate the potential effects of empty liposomes on the functions of BM niche macrophages. Following liposome administration, we observed lipid droplet (LD) accumulation in cultured primary macrophages and BM niche macrophages. We found that these LD-accumulating macrophages, similar to foam cells, exhibited increased expression of inflammatory cytokines, such as IL-1β and IL-6. We further provided evidence that liposome deposition and degradation induced LD biogenesis on the endoplasmic reticulum membrane and subsequently disturbed endoplasmic reticulum homeostasis and activated the inositol-requiring transmembrane kinase/endoribonuclease 1α/NF-κB signaling pathway, which is responsible for the inflammatory activation of macrophages after liposome engulfment. Finally, we also showed the side effects of dysfunctional BM niche macrophages on hematopoiesis in mice, such as the promotion of myeloid-biased output and impairment of erythropoiesis. This study not only draws attention to the safety of liposomal drugs in clinical practice but also provides new directions for the design of lipid-based drug carriers in preclinical studies.
研究领域:
药理学
·
免疫学
·
血液学
·
纳米医学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6.8
Yan Chen,Ming Zhang,Yanqin He,Suying Li,Shuaiqi Feng,Zhifang Liu,Ning Zhang,Meifeng Liu,Qingpeng Wang
Epithelial–mesenchymal transition (EMT) is a critical process for cancer progression, which is crucial in inhibiting the immunity in tumors and further boosting tumor metastasis. The suppression of EMT represents a promising strategy for inhibiting metastatic tumors. Herein, a series of new canadine platinum(IV) conjugates with potent antiproliferative and antimetastatic activities were developed, which activated by suppressing EMT and provoking immune response in tumors besides causing DNA injury. The complexes could covalently conjugate to DNA and induce mitochondria-mediated apoptosis via Bcl-2/Bax/caspase3 signaling. The EMT process was remarkably inhibited by suppressing the Wnt/β-catenin pathway, reversing the inflammatory tumor microenvironment, and inhibiting the HIF-1α pathway, which further resulted in the inhibited angiogenesis in tumors. Moreover, the antitumor immunity was elevated by blocking immune checkpoints PD-L1 and CD47 accompanied by the improvement of CD3+ and CD8+ T lymphocytes and the macrophage polarization from M2- toward M1-type simultaneously in tumors.
研究领域:
癌症生物学
·
药理学
·
免疫学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2024
·
IF 18.5
Huitong Luo,Zetao Wang,Fanglei Yu,Zhiyu Zhou,Jianmin Wang,Dafu Chen,Qi Feng,Xiaodong Cao
Harnessing endogenous stem/progenitor cells to enhance extracellular matrix (ECM) deposition in the nucleus pulposus (NP) is considered as a potential treatment for intervertebral disc degeneration (IVDD), but is limited by the lack of suitable scaffolds for cell infiltration and growth, as well as the tailored release of bioactive factors. Herein, an injectable cell-free microgel assembly (MA-TNS) with interconnected microporous structure is developed to recruit stem/progenitor cells and induce the differentiation of the recruited cells by releasing stromal cell-derived factor-1 α (SDF-1 α ) and transforming growth factor- β 1 (TGF- β 1) sequentially. TGF- β 1 is initially loaded by the chondroitin sulfate/gelatin nanoparticles. Together with SDF-1 α , these nanoparticles are co-encapsulated into the photo-cross-linked microgels, which are then assembled into a microporous scaffold via dynamic boronate ester bonds. An initial rapid release of SDF-1 α followed by a sustained release of TGF- β 1 lasting over 28 days is achieved. MA-TNS significantly promotes the recruitment, infiltration, and chondrocyte-like differentiation of marrow mesenchymal stem cells in vitro. Furthermore, in vivo experiments on rats and cynomolgus monkeys prove that MA-TNS can inhibit IVDD and recover ECM deposition markedly, thereby enabling long-term NP reconstruction. The resulting efficacy in rats and nonhuman primates supports that MA-TNS is a promising scaffold for intervertebral disc repair and regeneration.
研究领域:
生物医学工程
·
组织工程
·
再生医学
✓ 已验证
DOI
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Zhuojun Yu,Yi Li,Liping Bai,Yanbo Zheng,Xiujun Liu,Yongsu Zhen
Cytokine storm is a life-threatening disorder, and therapeutic treatments are urgently needed. Here, we investigated the anti-cytokine storm efficacy of DBDx, a triple drug combination composed of dipyridamole, ubenimex and dexamethasone. Evaluated by lipopolysaccharide (LPS)-induced cytokine storm murine model, DBDx significantly improved survival rate and prolonged survival time of the model mice. Notably, the efficacy of DBDx was higher than that of dipyridamole, ubenimex and dexamethasone. Determined by ELISA, DBDx significantly reduced the LPS-stimulated serum levels of TNF-α, IL-6 and IL-1β in mice. Luminex assay showed that DBDx suppressed the serum levels of a wide variety of inflammatory cytokines and chemokines, which was more potent than dexamethasone alone. Otherwise, DBDx exerted similar inhibitory effects on cytokine profiles in bronchoalveolar lavage fluid. Histopathological observation showed that DBDx significantly reduced the LPS-induced thickening of alveolar septum, indicating its suppression of capillary congestion, edema and neutrophil infiltration in the lung. Ultra-structure analysis showed that DBDx suppressed the LPS-induced morphological changes of microvilli in type II pneumocytes. In vitro experiment showed that DBDx inhibited IL-6 and TNF-α secretion in THP-1 cells, and downregulated TLR4/NF-κB/HIF-1α signaling pathway. All of these results demonstrate that DBDx, a triple combination of clinical orally-administered drugs, can alleviate cytokine storm and related lung injury. DBDx is beneficial for treating cytokine storm disorders.
研究领域:
免疫学
·
药理学
·
炎症
·
呼吸医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）