查找使用阿拉丁产品的科研文献

Combination of 3-methyladenine therapy and Asn-Gly-Arg (NGR)-modified mesoporous silica nanoparticles loaded with temozolomide for glioma therapy in vitro

Peng Zhang,Menghuan Tang,Qin Huang,Guanjian Zhao,Ning Huang,Xiang Zhang,Ying Tan,Yuan Cheng

Mesoporous silica nanoparticles (MSNPs) of a small diameter were loaded with the anticancer drug temozolomide (TMZ), coated with polydopamine (PDA), and conjugated with Asn-Gly-Arg (NGR) for use in the treatment of glioma. The accumulation of NGR-MSNPs in C6 cells was shown to be higher than that of unmodified MSNPs. Anticancer drugs can cause autophagy in tumor cells, whereas autophagy inhibitors can block this reaction and enhance the therapeutic effect of the drugs. In this study, we demonstrated that MSNP-TMZ-PDA-NGR had stronger autophagy- and apoptosis-inducing effects in C6 cells than TMZ alone, and its anticancer effect was further enhanced when combined with autophagy inhibition. These results demonstrate that the combination of targeting vehicles and autophagy inhibitors may have research value in the treatment of gliomas.

Intranasal delivery of temozolomide and disulfiram in situ gel combined with copper for enhanced glioblastoma therapy

Ying Qu,Jingjing Zhao,Long Ma,Xue Wang,Feifei Sun,Yizhe Li,Yihua Wu,Guozhi Zhao,Shijia Liu,Wenqing Ma,Tao Li,Zhongxi Zhao

Combination therapies show promise for glioblastoma (GBM) treatment, however, insufficient drug accumulation in the brain and significant toxic side effects continue to pose critical challenges to therapeutic efficacy. Here, we report an intranasal ion-sensitive hydrogel (IHG) platform for efficient co-delivery of TMZ and disulfiram (DSF) to GBM via the nose-to-brain pathway. The optimized IHG formulation demonstrates superior gelation properties, sustained drug release, and enhanced brain accumulation, achieving remarkable drug targeting efficiency (468.9%) and direct transport percentage (80.3%). Within the tumor microenvironment, in situ-generated TMZ and the chelation product of DSF and copper ions (CuET) synergistically induce DNA damage and apoptosis, thereby enhancing tumor cell sensitivity to TMZ. Furthermore, tdIHG+Cu induces robust immunogenic cell death, stimulates CXCL10 release, mediates dendritic cell maturation, and promotes CD8 + T cell infiltration, thereby establishing a potent antitumor immune response. This approach not only demonstrates superior therapeutic efficy against GBM progression through enhanced intracranial drug accumulation and optimized drug ratios, but also minimizes systemic toxicity via localized delivery. Our findings offer a potentially clinical translatable strategy worth further investigation.

Immuno-Initiator Rectifies Immunodeficiency to Restore Immune Function and Potentiate Immunotherapy against IDH Mutant Glioma

Songlei Zhou,Fenfen Ma,Jianing Gong,Yukun Huang,Yu Chen,Shiqiang Tong,Zheng Cheng,Yinzhe Sun,Xiaoying Xie,Tongtong Zhang,Xin Luan,Huiping Lu,Hongzhuan Chen,Jun Chen

Glioma induces distinctive immunodeficiency, impeding functional tumor-infiltrating T cells and resisting immunotherapy. Both systemic and local immunosuppression contribute to attenuating T-cell-mediated antitumor immunity, posing a challenge to developing effective counterstrategies. Herein, we introduce “Immuno-initiator” coated with glioma cell membrane and glucose derivative, for delivering immune modulator α-Mangostin (α-M) and photosensitizer indocyanine green (ICG) to restore immune function and evoke potent immune responses against isocitrate dehydrogenase mutant (IDH-mt) glioma. Our investigation reveals that immuno-initiator employs α-M to mitigate systemic immunosuppression and increase systemic T cells, and synergize with ICG to enhance reactive oxygen species production upon laser exposure, thereby inducing immunogenic glioma cell death to overcome local immunosuppression and facilitate functional T-cell infiltration. Crucially, when coupled with immune checkpoint inhibitor therapy, Immuno-initiator demonstrates synergistic efficacy, yielding long-term survival in 33.3% of mice by inhibiting IDH-mt glioma growth post laser irradiation. These findings underscore the potential of concurrently addressing systemic and local immunosuppression to rectify immunodeficiency, offering a clinically feasible therapeutic platform for combating brain malignancies.

Targeting VCP with V8 suppresses glioblastoma development via formation of aggregates and disruption of mitophagy flux

Cao Xuejun,Li Yishen,Guo Bin,Liu Yan,Wang Baoshuai,Wang Hao,Lu Jingbo,Wei Libin,Gao Yuan,Guo Yongjian,Wu Tao

Background Glioblastoma (GBM) is a highly lethal malignancy with limited therapeutic options. Identifying effective therapeutic targets and developing corresponding drugs remain unmet clinical needs. Purpose This study aimed to investigate the expression and role of VCP in GBM, as well as the anti-GBM activity and underlying mechanisms of V8, a wogonin-derived small molecule. Methods The expression of VCP in GBM cells and its correlation with glioma malignancy were analyzed. The binding of V8 to VCP was verified, and the effects of V8 on VCP function, cellular proteostasis, mitochondrial status, mitophagy process, and lysosomal integrity were evaluated to clarify its anti-GBM mechanisms. Results VCP is highly expressed in GBM cells and correlates with glioma malignancy. V8 exerts anti-GBM activity by binding to the D1 domain of VCP, with dual mechanisms of action: (1) Aggresome-mediated proteostatic crisis: V8 immobilizes VCP, triggers protein aggregates in the cytoplasm and mitochondria, and induces mitochondrial injury; (2) Disruption of mitophagy flux: VCP inhibition-induced damaged mitochondria recruit mitophagy receptors (BNIP3/P62/TAX1BP1) to initiate mitophagy, and VCP directly interacts with PRKN to promote mitophagy initiation. However, V8 concurrently impairs lysosomal integrity, thereby obstructing mitophagy flux and ultimately leading to GBM cell death. Additionally, VCP was found to not only maintain mitochondrial proteostasis but also preserve lysosomal integrity to facilitate the clearance of damaged mitochondria via mitophagy. Conclusion Targeting VCP with inhibitors such as V8 induces mitochondrial dysfunction, effectively suppresses GBM cell viability, and holds potential for GBM therapy. VCP may serve as a promising therapeutic target for GBM.

Monacolin K Induces Apoptosis of Human Glioma U251 Cells by Triggering ROS-Mediated Oxidative Damage and Regulating MAPKs and NF-κB Pathways

Xiaoyi Shi,Meng Li,Qiming Huang,Liuming Xie,Zhibing Huang

Monacolin K (MK), a polyketo secondary metabolic compound of the mold genus Monascus, can promote the apoptosis of malignant cancer cells, possessing potential antitumor properties. However, its mechanism of action on gliomas remains unclear. Here, we explored and investigated the potential of the monacolin K’s antitumor effect on human glioma U251 cells and its possible molecular mechanism. Results showed that the application of 10 μM monacolin K inhibited the proliferation of U251 cells, with an inhibitory rate of up to 53.4%. Additionally, monacolin K induced the generation of reactive oxygen species and activated mitochondria-mediated pathways, including decreased MMP, activation of caspase3/caspase9, decreased Na+/K+-ATPase and Ca2+-ATPase activities, and disruption of the antioxidant system, resulting in the disruption of intracellular reduction–oxidation homeostasis. Monacolin K also activated MAPK and NF-κB pathways, upregulating P38 activity and downregulating JNK/ERK/P65/IκBα expression, ultimately leading to apoptosis of U251 cells. Importantly, monacolin K was not cytotoxic to normal human cells, hUC-MSCs. We concluded that monacolin K can induce apoptosis in U251 cells by triggering ROS-mediated oxidative damage and regulating MAPKs and NF-κB pathways.

Gut microbiota mediated the individualized efficacy of Temozolomide via immunomodulation in glioma

Hou Xiaoying,Du Hongzhi,Deng Yufei,Wang Haiping,Liu Jinmi,Qiao Jialu,Liu Wei,Shu Xiji,Sun Binlian,Liu Yuchen

Background Temozolomide (TMZ) is the preferred chemotherapy strategy for glioma therapy. As a second-generation alkylating agent, TMZ provides superior oral bio-availability. However, limited response rate (less than 50%) and high incidence of drug resistance seriously restricts TMZ’s application, there still lack of strategies to increase the chemotherapy sensitivity. Methods Luci-GL261 glioma orthotopic xenograft model combined bioluminescence imaging was utilized to evaluate the anti-tumor effect of TMZ and differentiate TMZ sensitive (S)/non-sensitive (NS) individuals. Integrated microbiomics and metabolomics analysis was applied to disentangle the involvement of gut bacteria in TMZ sensitivity. Spearman’s correlation analysis was applied to test the association between fecal bacteria levels and pharmacodynamics indices. Antibiotics treatment combined TMZ treatment was used to confirm the involvement of gut microbiota in TMZ response. Flow cytometry analysis, ELISA and histopathology were used to explore the potential role of immunoregulation in gut microbiota mediated TMZ response. Results Firstly, gut bacteria composition was significantly altered during glioma development and TMZ treatment. Meanwhile, in vivo anti-cancer evaluation suggested a remarkable difference in chemotherapy efficacy after TMZ administration. Moreover, 16s rRNA gene sequencing and non-targeted metabolomics analysis revealed distinct different gut microbiota and immune infiltrating state between TMZ sensitive and non-sensitive mice, while abundance of differential gut bacteria and related metabolites was significantly correlated with TMZ pharmacodynamics indices. Further verification suggested that gut microbiota deletion by antibiotics treatment could accelerate glioma development, attenuate TMZ efficacy and inhibit immune cells (macrophage and CD8α + T cell) recruitment. Conclusions The current study confirmed the involvement of gut microbiota in glioma development and individualized TMZ efficacy via immunomodulation, hence gut bacteria may serve as a predictive biomarker as well as a therapeutic target for clinical TMZ application.

Development of tLyP-1 functionalized nanoliposomes with tunable internal water phase for glioma targeting

Yajing Wang,Ziwei Ding,Shiqun Lv,Jie Liu,Jie Pan,Yingcong Yu,Jun Gao,Xianfeng Huang

Reprogramming systemic and local immune function to empower immunotherapy against glioblastoma

Zhou Songlei,Huang Yukun,Chen Yu,Liu Yipu,Xie Laozhi,You Yang,Tong Shiqiang,Xu Jianpei,Jiang Gan,Song Qingxiang,Mei Ni,Ma Fenfen,Gao Xiaoling,Chen Hongzhuan,Chen Jun

The limited benefits of immunotherapy against glioblastoma (GBM) is closely related to the paucity of T cells in brain tumor bed. Both systemic and local immunosuppression contribute to the deficiency of tumor-infiltrating T cells. However, the current studies focus heavily on the local immunosuppressive tumor microenvironment but not on the co-existence of systemic immunosuppression. Here, we develop a nanostructure named Nano-reshaper to co-encapsulate lymphopenia alleviating agent cannabidiol and lymphocyte recruiting cytokine LIGHT. The results show that Nano-reshaper increases the number of systemic T cells and improves local T-cell recruitment condition, thus greatly increasing T-cell infiltration. When combined with immune checkpoint inhibitor, this therapeutic modality achieves 83.3% long-term survivors without recurrence in GBM models in male mice. Collectively, this work unveils that simultaneous reprogramming of systemic and local immune function is critical for T-cell based immunotherapy and provides a clinically translatable option for combating brain tumors.

Induction of apoptosis in glioma cells by lycorine via reactive oxygen species generation and regulation of NF-κB pathways

Su Jie,Yin Wei,Huo Mengmeng,Yao Qing,Ding Liqiong

Glioma is an extremely aggressive primary brain tumor, which is highly resistant to chemotherapy, presenting a therapeutic challenge. Here, we explored the anti-glioma effects and the underlying mechanism of lycorine, an isoquinoline alkaloid isolated from lycoris on glioma cells. We found that lycorine could dose dependently inhibit C6 glioma cell growth and induce cell apoptosis and intracellular reactive oxygen species (ROS) production. The half-maximal inhibitory concentration (IC 50 ) values of lycorine on C6 glioma cells at 48 h was 2.85 μM. Meanwhile, lycorine treatment caused dysfunction of the NF-κB signal, as demonstrated by the up-regulation of NF-κB inhibitor protein IκB and the downregulation of the NF-κB phosphorylation protein p-p65. The addition of NF-κB inhibitor SC75741 further confirmed the importance of the NF-κB pathway in lycorine-induced cell-growth inhibition. Moreover, lycorine might act synergically with temozolomide (TMZ) to reduce drug resistance by blocking the NF-κB pathway. Our study suggested that lycorine exerts an anti-glioma effect by inducing ROS production and inhibiting NF-κB, which validated that lycorine may be a potential candidate for glioma treatment alone or in combination with TMZ.

Lysine methylation promotes NFAT5 activation and determines temozolomide efficacy in glioblastoma

Li Yatian,Gao Zhenyue,Wang Yuhong,Pang Bo,Zhang Binbin,Hu Ruxin,Wang Yuqing,Liu Chao,Zhang Xuebin,Yang Jingxuan,Mei Mei,Wang Yongzhi,Zhou Xuan,Li Min,Ren Yu

Temozolomide (TMZ) therapy offers minimal clinical benefits in patients with glioblastoma multiforme (GBM) with high EGFR activity, underscoring the need for effective combination therapy. Here, we show that tonicity-responsive enhancer binding protein (NFAT5) lysine methylation, is a determinant of TMZ response. Mechanistically, EGFR activation induces phosphorylated EZH2 (Ser21) binding and triggers NFAT5 methylation at K668. Methylation prevents NFAT5 cytoplasm interaction with E3 ligase TRAF6, thus blocks NFAT5 lysosomal degradation and cytosol localization restriction, which was mediated by TRAF6 induced K63-linked ubiquitination, resulting in NFAT5 protein stabilization, nuclear accumulation and activation. Methylated NFAT5 leads to the upregulation of MGMT, a transcriptional target of NFAT5, which is responsible for unfavorable TMZ response. Inhibition of NFAT5 K668 methylation improved TMZ efficacy in orthotopic xenografts and patient-derived xenografts (PDX) models. Notably, NFAT5 K668 methylation levels are elevated in TMZ-refractory specimens and confer poor prognosis. Our findings suggest targeting NFAT5 methylation is a promising therapeutic strategy to improve TMZ response in tumors with EGFR activation.

Quercetin Suppresses Human Glioblastoma Migration and Invasion via GSK3β/β-catenin/ZEB1 Signaling Pathway

Chen Bo,Li Xiaoli,Wu Lihong,Zhou Duanfang,Song Yi,Zhang Limei,Wu Qiuya,He Qichen,Wang Gang,Liu Xu,Hu Hui,Zhou Weiying

High invasiveness is a biological and clinical characteristic of glioblastoma and predicts poor prognosis of patients. Quercetin, a natural flavonoid compound, exhibits anticancer activity. However, we have a limited understanding of the possible underlying mechanism of quercetin in glioblastoma. In this study, we investigated the anticancer effect of quercetin in human glioblastoma cells. Our results showed that quercetin markedly suppressed the viability of glioblastoma cells in vitro and in vivo, and significantly inhibited glioblastoma cell migration and invasion. Moreover, quercetin reversed EMT-like mesenchymal phenotype and reduced the expression levels of EMT-related markers. Furthermore, we found that quercetin suppressed GSK-3β/β-catenin/ZEB1 signaling in glioblastoma. Taken together, our results demonstrate that quercetin inhibited migration and invasion of human glioma cells by suppressing GSK3β/β-catenin/ZEB1 signaling. Our study provides evidence that quercetin is a promising therapeutic natural compound to treat glioblastoma.

Dietary Antioxidant-Constructed Nanodrugs Can High-Efficiently Kill Cancer Cells while Protecting Noncancer Cells

Chunyan Liao,Xiang Wang,Xueying Zhou,Dequan Wang,Ziyin Zhang,Yan Liu,Xiao Wu,Ying Chen,Yifeng Tan,Xin Dai,Pei Jing,Jie Pang,Xiao Xiao,Jie Liu,Xiaoming Liao,Shiyong Zhang

Despite great advances, the development of cancer drugs that can efficiently kill cancer cells while protecting noncancer cells has not been achieved. By using only dietary antioxidants vitamin C (VC) and (R)-(+)-lipoic acid (LA), we herein develop a nanodrug VC@cLAV featuring the above function. After entering cells, cLAV dissociates into LA and DHLA (dihydrolipoic acid, reduced form of LA) and releases VC and DHA (dehydroascorbate, oxidized form of VC). In cancer cells, the two redox pairs recycle each other and dramatically promote the intracellular reactive oxygen species production to kill cancer cells at low doses comparable to cytotoxic drugs. Oppositely in noncancer cells, the LA/DHLA and VC/DHA pairs exert anti-oxidant action to actively protect the organism by preventing the normal cells from oxidative stress and repairing cells suffering from oxidative stress. When compared with the first-line cytotoxic drug, VC@cLAV displayed superior therapeutic outcomes yet without side effects in diverse tumor models including patient-derived xenograft (PDX). This drug with efficient cancer cell killing and noncancer cell protection represents a new cancer therapy.