JOURNAL OF DRUG TARGETING
·
2024
·
IF 4.3
Mingli Sui,Chaoqun Wang,Yingmei Tian,Huijuan Zhang
Phototherapy can cause autophagy while killing tumour cells, leading to tumour recurrence and metastasis. Here, we constructed a laser and enzyme dual responsive nanodrug delivery system Tf-Te@CTSL-HCQ (TT@CH) to precisely regulate autophagy in synergy with phototherapy to inhibit the proliferation and metastasis of melanoma. Firstly, transferrin (Tf) was used as a nanoreactor to synthesise phototherapy agent Tf-Te by the biological template mineralisation method. Then, the thermosensitive liposome modified with FAP-α-responsive peptide (CAP) was used as a carrier to encapsulate autophagy inhibitor hydroxychloroquine (HCQ) and Tf-Te, to obtain an intelligent TT@CH delivery system. Once arriving at the tumour site, TT@CH can be cleaved by FAP-α overexpressed on cancer-associated fibroblasts (CAFs), and release Tf-Te and HCQ. Then Tf-Te can target melanoma cells and exert PTT/PDT anti-tumour effect. What’s more, hyperpyrexia induced by PTT can further promote drugs release from TT@CH. Meanwhile, HCQ simultaneously inhibited autophagy of CAFs and melanoma cells, and down-regulated IL-6 and HMGB1 secretion, thus effectively inhibiting melanoma metastasis. Pharmacodynamic results exhibited the best anti-tumour effect of TT@CH with the highest tumour inhibition rate of 91.3%. Meanwhile, lung metastatic nodules of TT@CH treated mice reduced by 124.33 compared with that of mice in control group. Overall, TT@CH provided an effective therapy strategy for melanoma.
研究领域:
肿瘤学
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药学
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纳米技术
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
Mucosal Immunology
·
2019
·Vol. 12
·期 4
·945-957
·
IF 7.352
Qiu Miao,Huang Keqing,Liu Yanzhuo,Yang Yuqing,Tang Honglin,Liu Xiaoxiao,Wang Chenlong,Chen Honglei,Xiong Yu,Zhang Jing,Yang Jing
High-fat diet (HFD) promotes lung pre-metastatic niche formation and metastasis. Thus, there is an urgent need to identify the underlying mechanisms and develop strategies to overcome them. Here we demonstrate that glycyrrhizic acid (GA) prevents HFD-enhanced pre-metastatic niche formation and metastasis through gut microbiota. GA reduced HFD-enhanced myeloid-derived suppressor cell recruitment, pro-metastatic protein S100A8/A9 expression and metastasis burden of 4T1 breast cancer and B16F10 melanoma, accompanied by gut microbiota alteration and colonic macrophage polarization far away the M1-like phenotype. These parameters were greatly decreased by treatment with antibiotics, recolonization of Desulfovibrio vulgaris and Clostridium sordellii , and administration of lipopolysaccharide or deoxycholic acid. Macrophage depletion attenuated HFD-enhanced pre-metastatic niche formation and metastasis, but failed to further affect the effects of GA. Mechanistically, counteraction of HFD-enhanced gut microbiota dysbiosis by GA inhibited Gr-1 + myeloid cell migration and S100A8/A9 expression through decreasing the proportion of M1-like macrophages and their production of CCL2 and TNF-α in the colons via LPS/HMGB1/NF-κB signaling inactivation. Together, targeting the gut microbiota by GA to modulate colonic macrophages could be a novel strategy for the prevention of HFD-enhanced pre-metastatic niche formation and metastasis.
研究领域:
肿瘤学
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微生物学
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免疫学
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营养学
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产品关联
DOI
PubMed
高影响因子
Current Pharmaceutical Analysis
·
2026
·
IF 3.6
Renjun Gao,Yu Cai,Xue Jiang,Xue Li,Jingrui Li,Yu Kang
Background Safflower yellow injection (SYI) has demonstrated cardioprotective effects on myocardial ischemia/reperfusion (MI/R) injury. This study aimed to explore its mechanistic basis. Methods H9c2 cells were pre-treated with 80 μg/mL SYI for 24 h before exposure to oxygen-glucose deprivation/reoxygenation (OGD/R). Protein levels related to endoplasmic reticulum (ER) stress and apoptosis were detected by western blot (WB). IL‑6 and TNF‑α protein and mRNA levels were determined by ELISA and qPCR. CCK-8 test and flow cytometry were used to measure cell viability and apoptosis, respectively. Moreover, the expression of proteins implicated in HMGB1/TLR4/NF-κB pathway was measured by WB assay. Finally, rescue validation was performed using recombinant HMGB1 (rHMGB1). Results SYI treatment alleviated OGD/R-induced ER stress and reduced IL-6 and TNF-α levels in H9c2 cells. These changes were accompanied by increased cell viability and reduced OGD/R‑induced apoptosis. Mechanistically, SYI significantly restrained activation of the HMGB1/TLR4/NF-κB signaling cascade in H9c2 cells triggered by OGD/R. Further rescue experiments with recombinant HMGB1 (rHMGB1) reversed the protective effects of SYI against OGD/R damage. Conclusion These findings indicate that the HMGB1/TLR4/NF‑κB axis mediates the protective effects of SYI against myocardial OGD/R injury, potentially through modulating ER stress and inflammatory responses. This study provides a mechanistic basis for the cardioprotective action of SYI in vitro and informs future investigations into its therapeutic potential. However, these results are derived from cell-based experiments alone, and further validation in animal models is needed to confirm the in vivo relevance of this mechanism.
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DOI
高影响因子
EXPERIMENTAL EYE RESEARCH
·
2020
·
IF 3.011
Yuzhen Hou,Jie Lan,Fan Zhang,Xianggen Wu
As a damage-associated molecular pattern molecule, high-mobility group box 1 protein (HMGB1) is involved in diabetes and its complications. However, the role of HMGB1 in diabetic keratopathy is not yet understood. The purpose of this study was to investigate the potential roles of HMGB1 in the development of diabetic keratopathy as well as potential strategies to block HMGB1 in order to prompt epithelial wound healing and nerve regeneration in diabetic corneas. The results demonstrated that diabetic keratopathy developed in mice over the duration of the diabetic condition with typical symptoms, including damaged ocular surfaces and corneal nerves . The diabetic corneas had significantly increased protein expression levels of HMGB1 and its receptors—the receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4)—compared to the age-matched normal corneas ( P < 0.05). Corneal HMGB1 levels significantly increased during the corneal wound healing process of the diabetic mice, peaking on the first day after the wound was created and then decreasing to the unwounded level on the seventh day. Exogenous HMGB1 peptide significantly retarded wound and nerve healing, while glycyrrhizin (an HMGB1 inhibitor) significantly prompted wound and nerve healing. Further, the western blot results confirmed that RAGE and TLR4 were also involved in corneal wound and nerve healing. In conclusion, these data showed that HMGB1 and its related receptors are highly involved in the development of diabetic keratopathy. This finding indicates that the blockage of HMGB1 might serve as a strategy to prompt diabetic corneal and nerve wound healing.
研究领域:
眼科学
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糖尿病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2022
·
IF 11.467
Jing-E Zhou,Lei Sun,Li Liu,Yujie Jia,Yuqiao Han,Jiaqi Shao,Jing Wang,Yiting Wang,Lei Yu,Zhiqiang Yan
HMGB1 is an inflammatory factor produced by macrophages after liver injury, which plays a key role in promoting NASH progression and further developing into liver fibrosis and cirrhosis. In this study, a mannose-modified HMGB1-siRNA loaded stable nucleic acid lipid particle delivery system (mLNP-siHMGB1) was constructed to target liver macrophages with mannose receptor mediation, thereby silencing HMGB1 protein expression and treating NASH. We also examined the effect of co-administration with docosahexaenoic acid (DHA), a kind of unsaturated fatty acid , on NASH. The results showed that mLNP-siHMGB1 could target macrophages through mannose receptors, effectively silence HMGB1 gene, reduce the release of HMGB1 protein in the liver, regulate liver macrophages to be an anti-inflammatory M2 phenotype, effectively reduce hepatic lobular inflammation and bullous steatosis in the liver, and restore the liver function of NASH model mice to a normal level. After 8 weeks of combined treatment with mLNP-siHMGB1 and DHA, the liver function of NASH model mice recovered rapidly and the hepatic steatosis returned to normal level. In view of inflammation, a key factor in the progression of NASH, we provided an actively targeted siRNA delivery system in this study, and clarified the important role of the delivery system in phenotypic regulation of liver macrophages in NASH. In addition, we also demonstrated the effectiveness of DHA co-administration in NASH treatment. This study provided a useful idea and scientific basis for the development of therapeutic strategies for NASH in the future.
研究领域:
药理学
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分子生物学
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治疗学
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肝病学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
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2022
·
IF 5.589
Qiangwei Liang,Yang Lan,Yifan Li,Yongjin Cao,Juan Li,Yanhua Liu
Chemotherapeutic agents can trigger the immune response via inducing immunogenic cell death (ICD), but the weak ICD effect induced by chemotherapy alone limits its lasting antitumor immunotherapy effect. A Cro polymerized prodrug carriers (POEG- b -PCro) with immunostimulatory by ICD induction was developed and co-delivered DOX to generate synergistic ICD induction for chemo-immunotherapy on breast cancer. DOX/POEG- b -PCro micelles displayed prolonged circulation in blood, efficient accumulation in tumors, internalization and then co-released DOX&Cro in tumor cells. Moreover, the DOX/POEG- b -PCro micelles synergistically triggered ICD induction by releasing the nuclear high mobility group box 1 (HMGB1) and down-regulation of c-Met level for generating chemo-immune anti-tumor actions. Importantly, the DOX/POEG- b -PCro micelles synergistically enhanced the tumor cytotoxic T lymphocytes infiltration , concomitant decreasing the immunosuppressive regulatory T (Treg) cells, accompanied with the increased cytokines secretion of IFN-γ and TNF-α, consequently displaying an improved anti-tumor activity in 4 T1 breast cancer mice. Overall, POEG- b -PCro prodrug micelles co-delivered DOX could be served as a promising nano drug delivery system for synergistic ICD induction on breast cancer chemo-immunotherapy.
研究领域:
药学
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肿瘤学
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免疫治疗
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2023
·
IF 15.1
Wenjie Xu,Yu Xiao,Minzhi Zhao,Jiahui Zhu,Yu Wang,Wenbin Wang,Peng Wang,Huan Meng
A nano-enabled drug delivery acupuncture technology ( nd -Acu) is developed that is based on traditional acupuncture needles where the stainless-steel surface is designed to deliver various payload molecules. To create the nd -Acu platform, an electrochemistry procedure is used to attach methyl salicylate-modified cyclodextrin in which the sugar rings allow the encapsulation of structurally defined single or multiple payload molecules via an inclusion complexation process. Drug loading and release profile are first studied using fluorescent dyes abiotically and at intact animal level. nd -Acu allows more efficient dye loading and time-dependent release compared to pristine needles without cyclodextrin modification. Subsequently, a proof-of-principle efficacy study is conducted using the platform to load a local anesthetic, lidocaine, for the treatment of knee osteoarthritis (KOA) in mice. It is demonstrated that lidocaine-laden nd -Acu can effectively alleviate pain, reduce inflammation, and slow down KOA development biochemically and histologically. Hypothesis-driven and proteomic approaches are utilized to investigate the working mechanisms of lidocaine nd -Acu, indicating that the therapeutic outcome is attributed to the in vivo modulation of the HMGB1/TLR4 signaling pathway. The study also obtained preliminary evidence suggesting the involvement of mitochondria as well as small GTPase such as cdc42 during the treatment by lidocaine nd -Acu.
研究领域:
纳米技术
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药学
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生物医学工程
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骨科
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疼痛管理
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炎症研究
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2021
·
IF 9.776
Jiao Zheng,Jiangchuan Sun,Jia Chen,Shenyin Zhu,Shuning Chen,Yujiao Liu,Lan Hao,Zhigang Wang,Shufang Chang
Immunotherapy by stimulating the host immune system has been a promising therapeutic strategy for advanced ovarian cancer . Here we describe a treatment strategy that combines chemotherapy and photo-sonodynamic therapy (PSDT) to induce systemic antitumor immunity. We have successfully fabricated phase-changeable core-shell nanoparticles (OIX_NPs), which carry oxygen in the core and the photosensitizer indocyanine green (ICG)/oxaliplatin (OXP) in the shell for our combination therapy. In the present study, we demonstrated that OIX_NPs have great potential as contrast agents to enhance photoacoustic (PA) imaging. Furthermore, our combined strategy could induce immunogenic cell death (ICD) by promoting surface exposure of calreticulin (CRT) and passive release of high-mobility group box 1 (HMGB1). Importantly, it could inhibit the growth not only primary tumors but also distant tumors in a bilateral syngeneic mouse model by increasing intratumor infiltration of cytotoxic T lymphocytes . In conclusion, the combination of chemotherapy and PSDT has the potential to enhance antitumor immunity significantly and achieve the integration of diagnosis and treatment for ovarian cancer.
研究领域:
癌症研究
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免疫学
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纳米医学
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化疗
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诊疗一体化
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产品关联
DOI
PubMed
高影响因子
PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY
·
2024
·
IF 2.6
Zijian Wang,Xixi Song,Yanjun Wei,Xianggen Wu,Ying Jie
This experiment aimed to investigate the feasibility of cytisine (CYT) in treating eye diseases with ocular topical application. An in vitro cytotoxicity test, a hen’s egg test-chorioallantoic membrane (HET-CAM), and a mouse eye tolerance test were used to fully reveal the ocular safety profiles of CYT. For the efficacy evaluations, CYT’s effects on cell wound healing, against H2O2-induced oxidative stress damages on cells, and on benzalkonium chloride (BAC)–induced dry eye disease (DED) in mice were evaluated. Results showed that CYT did not show any cytotoxicities at concentrations no higher than 250 μg/ml, while lipoic acid (α-LA) at 250 μg/ml and BAC at 1.25 μg/ml showed significant cytotoxicities within 48 h incubation. The HET-CAM and mouse eye tolerance test confirmed that 0.5% CYT eye drops demonstrated good safety characteristics. Efficacy evaluations showed that CTY significantly promoted cell migration and wound healing. CYT significantly improved cell survival against H2O2-induced oxidative stress damage by reversing the imbalance between the reactive oxygen species (ROS) and antioxidant defense mechanisms. The animal evaluation of the BAC-induced dry eye model revealed that CYT demonstrated a strong treatment effect, including reversing ocular surface damages, recovering corneal sensitivity, and inhibiting neovascularization; HMGB1/NF-κB signaling was involved in this DED treatment by CTY. In conclusion, CYT had strong experimental treatment efficacy against DED with good ocular safety profiles, and it might be a novel and promising drug for DED.
研究领域:
眼科学
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药理学
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细胞生物学
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实验医学
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产品关联
DOI
PubMed
高影响因子
Journal of Orthopaedic Surgery and Research
·
2022
·Vol. 17
·期 1
·1-8
·
IF 2.677
Zhang Bin-Fei,Song Wei,Wang Jun,Wen Peng-Fei,Zhang Yu-Min
Objectives The lung injury is often secondary to severe trauma. In the model of crush syndrome, there may be secondary lung injury. We hypothesize that high-mobility group box 1 (HMGB1), released from muscle tissue, mediates the apoptosis of alveolar epithelial cells (AEC) via HMGB1/Receptor of advanced glycation end-products (RAGE)/c-Jun N-terminal kinase (JNK) pathway. The study aimed to investigate how HMGB1 mediated the apoptosis of AEC in the rat model. Methods Seventy-five SD male rats were randomly divided into five groups: CS, CS + vehicle, CS + Ethyl pyruvate (EP), CS + FPS-ZM1 group, and CS + SP600125 groups. When the rats CS model were completed after 24 h, the rats were sacrificed. We collected the serum and the whole lung tissues. Inflammatory cytokines were measured in serum samples. Western blot and RT-qPCR were used to quantify the protein and mRNA. Lastly, apoptotic cells were detected by TUNEL. We used SPSS 25.0 for statistical analyses. Results Nine rats died during the experiments. Dead rats were excluded from further analysis. Compared to the CS group, levels of HMGB1 and inflammatory cytokines in serum were downregulated in CS + EP, CS + FPS-ZM1, and CS + SP600125 groups. Western blot and RT-qPCR analysis revealed a significant downregulation of HMGB1, RAGE, and phosphorylated-JNK in CS + EP, CS + FPS-ZM1, and CS + SP600125 groups, compared with the CS groups, excluding total-JNK mRNA. Apoptosis of AEC was used TUNEL to assess. We found the TUNEL-positive cells were downregulated in CS + EP, CS + FPS-ZM1, and CS + SP600125 groups. Conclusion The remote lung injury begins early after crush injuries. The HMGB1/RAGE/JNK signaling axis is an attractive target to abrogate the apoptosis of AEC after crush injuries.
研究领域:
病理生理学
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肺医学
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创伤外科
·
分子生物学
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DOI
PubMed
高影响因子
Journal of Advanced Research
·
2024
·
IF 11.4
Dongwei Guan,Pengju Huang,Xinlei Liu,Qing Li,Xiaoxun Zhang,Nan Liu,Yong Wang,Ying Wan,Jin Chai,Shiying Cai,Rui Chen,Zhijia Ye
Introduction Niemann-Pick C1 (NPC1), a lysosomal cholesterol transport protein, is required for efficient efferocytosis. Patients with Npc1 mutation are frequently accompanied with hepatic symptoms, including hepatomegaly, elevated liver transaminases, or even acute liver failure, but the pathogenic mechanism remains unknown. Objectives Our work aims to characterize the functional role of myeloid NPC1 in liver injury and elucidate its underlying mechanism. Methods Analyses of injured livers from patients with liver diseases and mouse models were conducted to examine NPC1 expression. Myeloid cell-specific Npc1 knockout mice were constructed to determine the functional role of macrophage NPC1 in liver injury. Isolated macrophages were subjected to in vitro mechanistical assays. Results We found that NPC1 is mainly expressed in hepatic macrophages. Its mRNA and protein expression are significantly elevated in injured livers from both patients and mouse models. Tissue-specific deletion of myeloid Npc1 increased liver inflammation, levels of serum liver function enzymes, and liver fibrosis in mouse models of liver injury induced by carbon tetrachloride (CCl 4 ) injection and methionine-and-choline-deficient (MCD) diets. Further analyses indicate that Npc1 deficiency in mouse models of liver injury resulted in increased levels of serum HMGB1 and mitochondrial DNA, promoted hepatic macrophage proinflammatory activation, M1 polarization, led to overproduction of hepatic inflammatory cytokines/chemokines, e.g. CCL2 and STING/NFκB pathway activation. In vitro mechanistical studies reveal that Npc1 -deficient macrophages exhibited inefficient efferocytosis, partly due to impaired cargo degradation. Conclusions These findings indicate that elevated expression of myeloid NPC1 in liver diseases protects liver from injury by promoting macrophage efferocytosis of damaged cells. Dysfunction of NPC1 aggravates liver injury, suggesting that NPC1 may be a potential therapeutic target for treating liver diseases.
研究领域:
肝病学
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免疫学
·
细胞生物学
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病理学
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产品关联
DOI
PubMed
高影响因子
DALTON TRANSACTIONS
·
2024
·Vol. 53
·期 20
·8772-8780
·
IF 3.5
Kai Xie,Xing-Yun Lu,Hou Zhu,Lin-Yuan Zhu,Rong-Tao Li,Rui-Rong Ye
A series of Ir(III)–naproxen (NPX) conjugates with the molecular formula [Ir(C^N)2bpy(4-CH2ONPX-4′-CH2ONPX)](PF6) (Ir-NPX-1–3) were designed and synthesized, including C^N = 2-phenylpyridine (ppy, Ir-NPX-1), 2-(2-thienyl)pyridine (thpy, Ir-NPX-2) and 2-(2,4-difluorophenyl)pyridine (dfppy, Ir-NPX-3). Cytotoxicity tests showed that Ir-NPX-1–3 exhibited excellent antitumor activity, especially in A549R cells. The cellular uptake experiment showed that the complexes were mainly localized in mitochondria, and induced apoptosis in A549R cells by damaging the structure and function of mitochondria. The main manifestations are a decrease in the mitochondrial membrane potential (MMP), an increase in reactive oxygen species (ROS) levels, and cell cycle arrest. Furthermore, Ir-NPX-1–3 could inhibit the migration and colony formation of cancer cells, demonstrating potential anti-metastatic ability. Finally, the anti-inflammatory and immunological applications of Ir-NPX-1–3 were verified. The downregulation of cyclooxygenase-2 (COX-2) and programmed death-ligand 1 (PD-L1) expression levels and the release of immunogenic cell death (ICD) related signaling molecules such as damage-associated molecular patterns (DAMPs) (cell surface calreticulin (CRT), high mobility group box 1 (HMGB1), and adenosine triphosphate (ATP)) indicate that these Ir(III) –NPX conjugates are novel ICD inducers with synergistic effects in multiple anti-tumor pathways.
研究领域:
肿瘤学
·
药物化学
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细胞生物学
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免疫学
✓ 已验证
DOI
高影响因子
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