BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2018
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IF 2.559
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.
研究领域:
纳米技术
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药学
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肿瘤学
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细胞生物学
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BMC Pharmacology & Toxicology
·
2025
·Vol. 26
·期 1
·1-13
·
IF 2.7
Fu Wenying,Lu Hui,Yan Ying,Shu Chongchong,Xu Chenxin,Chen Yinghua,Xia Yiqun,Chen Jundixia,Chen Yunzhi,Zou Peng,Cui Ri,Ni Daoyong
Section
Background
Lung cancer continues to rank as a leading cause of cancer-related mortality worldwide. Despite notable advances in medical research, therapeutic options for advanced-stage lung cancer remain inadequate. Heat shock protein 90 (HSP90) has been identified as a potential therapeutic target in multiple malignancies, such as lung and colon cancers, owing to its pivotal role in stabilizing numerous oncoproteins. Nonetheless, the clinical application of HSP90 inhibitors has faced challenges, including suboptimal efficacy and the development of resistance mechanisms. B-AP15 is a promising small molecule in cancer therapy that functions by inhibiting deubiquitinating enzymes, which regulate protein degradation through the proteasome pathway. In this study, we aim to investigate its combinatorial activity with the HSP90 inhibitor tanespimycin (TAU) in lung cancer cells.
Section
Methods
The levels of the specified molecules were measured by Western blot analysis. Reactive oxygen species (ROS) levels were determined using the 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) probe. 53BP1 foci formation and C/EBP homologous protein (CHOP) expression were assessed by immunofluorescence. Autophagic flux was monitored using mRFP-GFP-tagged microtubule-associated protein 1 light chain 3 (LC3) lentivirus.
Section
Results
Our findings reveal that the combination of TAU and B-AP15 induces significant synergistic antitumor effects, characterized by substantial accumulation of ROS. This ROS accumulation serves as a crucial mediator of the enhanced therapeutic response elicited by the combination treatment. Mechanistic analyses further demonstrated that the combined treatment induces cell death via activation of endoplasmic reticulum (ER) stress and the c-Jun N-terminal kinase (JNK) pathway.
Section
Conclusion
In summary, our study provides robust evidence supporting the potential of combining TAU with B-AP15 as a viable therapeutic option for lung cancer treatment.
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EUROPEAN JOURNAL OF PHARMACOLOGY
·
2026
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IF 4.7
Wenying Fu,Ying Yan,Chongchong Shu,Chenxin Xu,Yinghua Chen,Yiqun Xia,Jundixia Chen,Yunzhi Chen,Ri Cui,Peng Zou,Daoyong Ni
6-Methoxydihydrosanguinarine is a natural alkaloid derived from medicinal plants that exhibits significant antitumor activity, making it a promising candidate for cancer therapy. However, the exact molecular mechanisms underlying its effects require further investigation. In this study, we investigated the cytotoxicity and underlying mechanisms of 6-Methoxydihydrosanguinarine in human non-small cell lung cancer (NSCLC) cells. Our findings reveal that reactive oxygen species (ROS) accumulation is the key driver of its antitumor activity. Mechanistically, 6-Methoxydihydrosanguinarine activates the JNK signaling pathway and induces endoplasmic reticulum (ER) stress, both of which can be reversed by the ROS scavenger N-acetylcysteine (NAC). Interestingly, 6-Methoxydihydrosanguinarine also activates autophagy, and inhibition of autophagy reverses the JNK and ER stress pathway activation induced by 6-Methoxydihydrosanguinarine. Notably, 6-Methoxydihydrosanguinarine synergistically enhances cisplatin-induced NSCLC cell death, and this synergistic effect is abolished by NAC, highlighting the critical role of ROS accumulation in their combined efficacy. This study systematically elucidates the molecular mechanisms of 6-Methoxydihydrosanguinarine against NSCLC, revealing that, in addition to the JNK and autophagy pathways, ER stress also mediates its antitumor effects. Moreover, our data establish a rationale for exploring 6-Methoxydihydrosanguinarine in NSCLC therapy and highlight its combination with cisplatin as a potentially effective strategy.
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CHEMICO-BIOLOGICAL INTERACTIONS
·
2026
·
IF 5.2
Jiaqi Li,Zhengxin Lu,Nan Zhang,Xiaowei Zhou,Yuanbiao Ma,Jia-qi Li,Yimu Zhang,Zhewen Deng,Na Lin,Peng Yue,Yilin Yang,Qi Zhang,Bo Ma
Andrographolide (Andro), the primary bioactive compound of Andrographis paniculata , has known bioactivities but also male reproductive toxicity with unclear mechanisms. This study investigated its testicular injury effects and mechanism, focusing on Sertoli cells (SCs) ferroptosis. Toxicity was evaluated in mice and SCs. Mechanisms were probed using RT-qPCR, Western blot, co-immunoprecipitation, and ubiquitination assays. LC-MS/MS assessed tissue distribution. Molecular docking and dynamics simulations characterized the Andro-β-TrCP interaction. The results demonstrated that Andro exposure caused significant testicular atrophy, blood-testis barrier (BTB) disruption, and spermatogenic impairment in mice. Meanwhile, pharmacokinetic analysis revealed SCs as the primary target of Andro-induced testicular damage, showing rapid Andro accumulation that was subsequently detected in sperm and the epididymis. Furthermore, Andro triggered ferroptosis in testicular injury and SCs, marked by increased ROS, MDA, iron overload, and lipid peroxidation. These effects were rescued by the ferroptosis inhibitor deferoxamine. Mechanistically, Andro directly bound to β-TrCP, downregulating its expression and subsequently stabilizing ATF4 by impairing its ubiquitin-mediated degradation. Silencing ATF4 inhibited ferroptosis and restored cell viability upon Andro challenge. The direct Andro-β-TrCP interaction was consistently confirmed by molecular docking, dynamics simulations, and CETSA. This study reveals that Andro triggers SCs ferroptosis by inhibiting β-TrCP-mediated ATF4 ubiquitination and degradation, leading to BTB disruption and spermatogenic impairment. These findings provide a theoretical basis for optimizing clinical application of Andro in the future.
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ACS Omega
·
2026
·Vol. 11
·期 28
·42728-42741
·
IF 5.2
Kong Wenbin,Su Baoqiang,Gu Han,Huang Weiqiang,Wang Jing,Zhu Yaqi,Xu Rongrong,Tong Dali,Xu Weiping
Cancer
remains a major global health challenge, and conventional
therapies are still limited by poor tumor specificity, therapeutic
resistance, and systemic side effects. Herein, we developed a glutathione
(GSH)-responsive FFSSFF coacervate system for the codelivery of chrysin
(CH) and the autophagy inhibitor 3-methyladenine (3-MA) to induce
tumor-selective autophagic stress. CH activated endoplasmic reticulum
stress and promoted autophagy through the GRP78/PERK and Akt/mTOR
signaling pathways, while 3-MA simultaneously disrupted autophagic
flux, leading to intracellular homeostasis imbalance, mitochondrial
dysfunction, excessive reactive oxygen species accumulation, and tumor
cell death. The resulting CH/3-MA@FFSSFF coacervates exhibited favorable
physicochemical properties, GSH-responsive behavior, efficient intracellular
uptake, and selective accumulation in tumor cells. Both in vitro and
in vivo experiments demonstrated potent antitumor activity of the
CH/3-MA@FFSSFF system. In particular, in an orthotopic lung cancer
model, CH/3-MA@FFSSFF effectively suppressed tumor growth, prolonged
median survival time, and inhibited tumor cell migration and invasion.
Collectively, this study presents a promising liquid–liquid
phase separation-derived coacervate platform for targeted combinational
cancer therapy through the induction of autophagic stress, with enhanced
therapeutic efficacy and reduced off-target toxicity.
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Journal of Traditional and Complementary Medicine
·
2025
·
IF 3
Huan Hou,Yaping Yang,Minyan Zhu,Meilin Xie,Yan Zhang,Rong Chen
Background and aim Trastuzumab (TRZ)-induced cardiotoxicity impairs breast cancer patients' quality of life, with no effective prevention currently. Osthole (OST) has been reported to exert cardioprotective effects in certain cardiovascular diseases. The purpose of this study was to investigate the probable mechanisms behind the protective effect of OST against TRZ-induced cardiotoxicity. Experimental procedure Mice were pretreated with OST (50 or 100 mg/kg) for 5 days, followed by TRZ (10 mg/kg, 10 days) to establish a cardiotoxicity model. The protective effects of OST on TRZ-induced cardiotoxicity was assessed via echocardiography, cardiac weight index (CWI), serum myocardial injury markers, H&E, and Masson staining. To explore the mechanisms, SOD/MDA levels, DHE staining (ROS), Nick-End-Labeling (TUNEL) staining (apoptosis), and Western blot were performed with/without 3-methyladenine (autophagy inhibitor) or SB203580 (p38MAPK inhibitor). Results and Conclusion OST pretreatment significantly improved cardiac function, alleviated myocardial damage and fibrosis, and enhanced autophagy (increased LC3II/I, Beclin-1 and decreased p62). Oxidative stress damage was ameliorated by OST, as demonstrated by higher activity of SOD, lower level of MDA and reactive oxygen species (ROS). In addition, OST decreased the ratio of Bax/Bcl-2 and Caspase-3 expression, and reduced apoptosis rate. OST activated p38MAPK (increased p-p38MAPK level) while inhibiting mTOR (decreased p-mTOR level). While these effects were blocked by the autophagy inhibitor 3-MA or p38MAPK inhibitor SB203580. These results indicated that OST has a protective effect on TRZ-induced cardiotoxicity, and its underlying mechanism may be related to enhancing autophagy via the p38MAPK/mTOR signaling pathway, thus reducing oxidative stress and apoptosis.
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Autophagy
·
2022
·
IF 13.391
Haitao Wang,Jianhua Zhang,Haoqiu Liu,Man Wang,Yan Dong,Yijun Zhou,Sek-Man Wong,Kai Xu,Qiufang Xu
Hosts can initiate macroautophagy/autophagy as an antiviral defense response, while viruses have developed multiple ways to evade the host autophagic degradation. However, little is known as to whether viruses can target lipids to subvert autophagic degradation. Here, we show that a low abundant signaling lipid, phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2), is required for rice black-streaked dwarf virus (RBSDV) to evade the autophagic degradation in the insect vector Laodelphax striatellus. RBSDV binds to PtdIns(3,5)P2 and elevates its level through its main capsid protein P10, leading to inhibited autophagy and promoted virus propagation. Furthermore, we show that PtdIns(3,5)P2 inhibits the autophagy pathway by preventing the fusion of autophagosomes and lysosomes through activation of Trpml (transient receptor potential cation channel, mucolipin), an effector of PtdIns(3,5)P2. These findings uncover a strategy whereby a plant virus hijacks PtdIns(3,5)P2 via its viral capsid protein to evade autophagic degradation and promote its survival in insects.
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PLoS One
·
2023
·Vol. 18
·期 2
·e0281845
·
IF 3.7
Hao Tang,Shida Zhu,Kai Chen,Shujie Yuan,Junzu Hu,Hongkai Wang
Bone is a frequent target of tumor metastasis, with high incidence rate and poor prognosis. Osteoclasts play a key role in the process of tumor bone metastasis. Interleukin-17A (IL-17A) is an inflammatory cytokine, highly expressed in a variety of tumor cells, that can alter the autophagic activity of other cells, thereby causing corresponding lesions. Previous studies have shown that low concentration IL-17A can promote osteoclastogenesis. The aim of this study was to clarify the mechanism of low concentration IL-17A promoting osteoclastogenesis by regulating autophagic activity. The results of our study showed that IL-17A could promote the differentiation of osteoclast precursors (OCPs) into osteoclasts in the presence of RANKL, and increase the mRNA levels of osteoclast-specific genes. Moreover, IL-17A increased the expression of Beclin1 by inhibiting the phosphorylation of ERK and mTOR, leading to enhanced autophagy of OCPs, accompanied by decreased OCP apoptosis. Furthermore, knockdown of Beclin1 and suppression of autophagy by 3-methyladenine (3-MA) significantly attenuated the enhanced osteoclastogenesis induced by IL-17A. In summary, these results indicate that low concentration IL-17A enhances the autophagic activity of OCPs through the ERK/mTOR/Beclin1 pathway during osteoclastogenesis, and further promotes osteoclast differentiation, suggesting that IL-17A may serve as a potential therapeutic target for cancer-related bone resorption in cancer patients.
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ARCHIVES OF TOXICOLOGY
·
2022
·Vol. 97
·期 2
·441-456
·
IF 6.168
Xu Chi,Jiang Shuyun,Ma Xingyu,Jiang Zeyong,Pan Youguang,Li Xiang,Zhang Liying,Zhou Hao,Chen Shen,Xing Xiumei,Chen Liping,Fu Wenfan,Wang Qing,Chen Wen,Li Daochuan
Cisplatin is recommended as a first-line chemotherapeutic agent against advanced non-small cell lung cancer (NSCLC), but acquired resistance substantially limits its clinical efficacy. Recently, DNA methylation has been identified as an essential contributor to chemoresistance. However, the precise DNA methylation regulatory mechanism of cisplatin resistance remains unclear. Here, we found that nicotinamide nucleotide transhydrogenase ( NNT ) was silenced by DNA hypermethylation in cisplatin resistance A549 (A549/DDP) cells. Also, the DNA hypermethylation of NNT was positively correlated to poor prognosis in NSCLC patients. Overexpression of NNT in A549/DDP cells could reduce their cisplatin resistance, and also suppressed their tumor malignancy such as cell proliferation and clone formation. However, NNT enhanced sensitivity of A549/DDP cells to cisplatin had little to do with its function in mediating NADPH and ROS level, but was mainly because NNT could inhibit protective autophagy in A549/DDP cells. Further investigation revealed that NNT could decrease NAD + level, thereby inactivate SIRT1 and block the autophagy pathway, while re-activation of SIRT1 through NAD + precursor supplementation could antagonize this effect. In addition, targeted demethylation of NNT CpG island via CRISPR/dCas9-Tet1 system significantly reduced its DNA methylation level and inhibited the autophagy and cisplatin resistance in A549/DDP cells. Thus, our study found a novel chemoresistance target gene NNT , which played important roles in cisplatin resistance of lung cancer cells. Our findings also suggested that CRISPR-based DNA methylation editing of NNT could be a potential therapeutics method in cisplatin resistance of lung cancer.
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PHYTOMEDICINE
·
2021
·
IF 5.34
Shangmin Yu,Shan Liu,Ning Wang,Di Yu,Meng Qin,Ji Wu,Qingxiang Guan
Background Kai Xin San (KXS) was widely applied for the treatment of depression for thousands of years. However, the underlying antidepressant mechanism of KXS remains not clear. Purpose This study aimed to investigate whether NLRP3 inflammasome and autophagy are involved in inflammation-induced depression and antidepressant mechanism of KXS. Methods Wistar rats were exposed to chronic unpredictable mild stress (CUMS) for 6 weeks, and KXS (3, 5, and 10 g/kg/d) was administrated during the last 2 weeks of CUMS procedure. The effects of KXS on depressive-like behaviors, neuroinflammation , NLRP3 inflammasome activation, and autophagy were investigated in CUMS rats . Rat astrocytes were employed to further explore the potential mechanism of KXS in regulating NLRP3 inflammasome and autophagy. Autophagy inhibitor 3-methyladenine (3-MA, 5 mM) was used in vitro to elucidate the role of autophagy in the antidepressant mechanism of KXS. Results In vivo , KXS improved depressive-like behaviors of CUMS rats in sucrose preference test , open field test and forced swimming test . Moreover, KXS inhibited the neuroinflammation induced by CUMS and promoted autophagy in prefrontal cortex of rats. The results in vitro further validated the anti-inflammatory and proautohapgic effects of KXS. More importantly, autophagy inhibitor 3-MA diminished the inhibitory effect of KXS on NLRP3 inflammasome activation in rat astrocytes. Conclusion KXS ameliorated CUMS-induced depressive behaviors in rats and inhibited the NLRP3 inflammasome-mediated inflammation in vivo and in vitro . These effects might be regulated by KXS-induced autophagy.
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International Journal of Nanomedicine
·
2021
·
IF 6.4
Xiaodi Gong,Xin Pu,Jing Wang,Linlin Yang,Yunxia Cui,Lijuan Li,Xiao Sun,Jichang Liu,Jingfeng Bai,Yudong Wang
Purpose Iron-based nanomaterials have recently been developed as excellent and potent Fenton reagents to reactive oxygen species (ROS) during chemodynamic therapy (CDT). The performance of the materials, however, can be impaired by the intrinsic antioxidant defense mechanism in organisms, such as autophagy. Methods The nanoscale metal-organic frameworks (nMOFs), nMIL-100 (Fe), were exploited and characterized. Also, the Fenton-like catalytic characteristics, anti-endometrial cancer (EC) effects and potential mechanisms of nMIL-100 (Fe) nanoparticles were investigated in vitro. Results The synthesized nMIL-100 (Fe) nanocatalyst catalyzed hydroxyl radicals (·OH) production in the presence of hydrogen peroxide (H 2 O 2 ) and simultaneously depleted intracellular glutathione (GSH). Combining with H 2 O 2 , nMIL-100 (Fe) nanoparticles exhibited enhanced cytotoxicity for EC cells, especially for progesterone treatment-insensitive KLE cells, probably due to relatively lower expression of the catalase gene. The accumulated ·OH initiated PTEN induced putative kinase 1 (PINK1)/E3 ubiquitin-protein ligase Parkin-mediated cytoprotective mitophagy in turn to partially rescue ·OH-induced cell apoptosis. Furthermore, both pretreatments of EC cells with siRNA-mediated Parkin knockdown and Mdivi-1 (a mitophagy inhibitor) addition were sufficient to ensure nMIL-100 (Fe) synergizing with H 2 O 2 -induced oxidative damages. Conclusion These results suggest that the degree of mitophagy should be taken into consideration to optimize therapeutic efficiency when developing ROS based-CDT for EC cancer therapies. Therefore, a nMIL-100 (Fe)-guided, elevated ROS and overwhelmed mitophagy-mediated therapeutic strategy may have greater promise for EC therapy compared with current treatment modalities.
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ACS Chemical Neuroscience
·
2021
·
IF 4.418
Bei Sun,Hao Ou,Fei Ren,Yujiao Guan,Ye Huan,Hongwei Cai
Cerebral ischemia-reperfusion (CI/R) injury is a serious central nervous system disease. Propofol (PPF) exerts a neuroprotective effect in CI/R injury; the underlying cause is still unclear. Here, we cultured mouse hippocampal neuron (HT22 cells) in oxygen-glucose deprivation/reoxygenation (OGD/R) conditions to mimic CI/R injury in vitro. PPF treatment promoted cell viability and reduced apoptotic cells in the OGD/R-treated HT22 cells, which was effectively abrogated by SNHG14 overexpression. Moreover, we constructed a CI/R injury mouse model on C57BL/6J mice by middle cerebral artery occlusion/reperfusion (MCAO/R), followed by administration of PPF. PPF reduced neuronal damage and loss, enhanced glial cell hyperplasia, and ameliorated cerebral cortex tissue damage and brain infarct in MCAO/R-induced mice. SNHG14 overexpression aggravated MCAO/R-induced CI/R injury in mice. Furthermore, SNHG14 promoted the expression of Atg5 and Beclin 1 via competitively binding miR-30b-5p, which contributed to activate autophagy and apoptosis in HT22 cells. In addition, the levels of p-p38 and p-SP1 were reduced in the OGD/R-treated HT22 cells in the presence of PPF. SP1 interacted with the promoter of SNHG14 and elevated the expression of SNHG14. PPF treatment inhibited the SP1-mediated up-regulation of SNHG14. In conclusion, this work demonstrates that PPF inhibits SNHG14 expression though the p38 MAPK signaling pathway. SNHG14 promotes Atg5 and Beclin 1 expression by sponging miR-30b-5p and thus activates autophagy and aggravates CI/R injury.
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