PHYTOMEDICINE
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2024
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IF 6.7
Lujuan Han,Xiaohan Xiang,Yuhui Fu,Sisi Wei,Cong Zhang,Lei Li,Yueping Liu,Huilai Lv,Lianmei Zhao,Baoen Shan
Background Esophageal squamous cell carcinoma (ESCC) is the predominant histological subtype of esophageal cancer (EC) in China, and demonstrates varying levels of resistance to multiple chemotherapeutic agents. Our previous studies have proved that periplocin (CPP), derived from the extract of cortex periplocae, exhibiting the capacity to hinder proliferation and induce apoptosis in ESCC cells. Several studies have identified additional anti-cancer constituents in the extract of cortex periplocae, named periplcymarin (PPM), sharing similar compound structure with CPP. Nevertheless, the inhibitory effects of PPM on ESCC and their underlying mechanisms remain to be further elucidated. Purpose The aim of this study was to investigate function of PPM inhibiting the growth of ESCC in vivo and in vitro and to explore its underlying mechanism, providing the potential anti-tumor drug for ESCC. Methods Initially, a comparative analysis was conducted on the inhibitory activity of three naturally compounds obtained from the extract of cortex periplocae on ESCC cells. Among these compounds, PPM was chosen for subsequent investigation owing to its comparatively structure and anti-tumor activity simultaneously. Subsequently, a series of biological functional experiments were carried out to assess the impact of PPM on the proliferation, apoptosis and cell cycle arrest of ESCC cells in vitro . In order to elucidate the molecular mechanism of PPM, various methodologies were employed, including bioinformatics analyses and mechanistic experiments such as high-performance liquid chromatography combined with mass spectrometry (HPLC-MS), cell glycolysis pressure and mitochondrial pressure test. Additionally, the anti-tumor effects of PPM on ESCC cells and potential toxic side effects were evaluated in vivo using the nude mice xenograft assay. Results Our study revealed that PPM possesses the ability to impede the proliferation of ESCC cells, induce apoptosis, and arrest the cell cycle of ESCC cells in the G2/M phase in vitro . Mechanistically, PPM exerted its effects by modulating glycolysis and mitochondrial oxidative phosphorylation (OXPHOS), as confirmed by glycolysis pressure and mitochondrial pressure tests. Moreover, rescue assays demonstrated that PPM inhibits glycolysis and OXPHOS in ESCC cells through the PI3K/AKT and MAPK/ERK signaling pathways. Additionally, we substantiated that PPM effectively suppresses the growth of ESCC cells in vivo , with only modest potential toxic side effects. Conclusion Our study provides novel evidence that PPM has the potential to simultaneously target glycolysis and mitochondrial OXPHOS in ESCC cells. This finding highlights the need for further investigation into PPM as a promising therapeutic agent that targets the tumor glucose metabolism pathway in ESCC.
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JOURNAL OF CONTROLLED RELEASE
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2024
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IF 10.5
Borui Zhao,Xuan Qin,Rui Fu,Maosen Yang,Xin Hu,Shaorong Zhao,Yange Cui,Qingxiang Guo,Wei Zhou
Chemoresistance to cisplatin remains a significant challenge affecting the prognosis of advanced oral squamous cell carcinoma (OSCC). However, the specific biomarkers and underlying mechanisms responsible for cisplatin resistance remain elusive. Through comprehensive bioinformatic analyses, we identified a potential biomarker, BCL2 associated athanogene-1 (BAG1), showing elevated expression in head and neck squamous cell carcinoma (HNSCC). Since OSCC represents the primary pathological type of HNSCC, we investigated BAG1 expression in human tumor tissues and cisplatin resistant OSCC cell lines, revealing that silencing BAG1 induced apoptosis in cisplatin-resistant cells both in vitro and in vivo . This effect led to impaired cell viability of cisplatin resistant OSCC cells and indicated a positive correlation between BAG1 expression and the G1/S transition during cell proliferation. Based on these insights, the administration of a CDK4/6 inhibitor in combination with cisplatin effectively overcame cisplatin resistance in OSCC through the CDK4/6-BAG1 axis. Additionally, to enable simultaneous drug delivery and enhance synergistic antitumor efficacy, we developed a novel supramolecular nanodrug LEE011-FFERGD/CDDP, which was validated in an OSCC orthotopic mouse model. In summary, our study highlights the potential of a combined administration of CDK4/6 inhibitor and cisplatin as a promising therapeutic regimen for treating advanced or cisplatin resistant OSCC.
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Journal for ImmunoTherapy of Cancer
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2025
·Vol. 13
·期 8
·e011799
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IF 10.6
Ziqi Chen,Yaohua Ke,Junmeng Zhu,Lanqi Cen,Wenmei Rao,Sen Hong,Yan Wang,Jie Shao,Yanhong Chu,Xiaoping Qian,Baorui Liu,Rutian Li,Qin Liu
Background Combining chemotherapy with immunotherapy is a promising strategy to enhance in situ immunity by increasing antigen exposure and inflammation in the tumor microenvironment (TME). However, the inconvenience of separate administration and the randomness of delivery can diminish the synergistic effect of these treatments. An efficient co-delivery system to optimize chemo-immunotherapy is urgently needed. Methods We have previously developed an engineered Lactococcus lactis (FOLactis) expressing Flt3L and OX40L to activate immune cells. Here, we biomineralized FOLactis by magnesium (Mg 2+ )-based frameworks (Mg-metal-organic frameworks (MOFs)) loaded with cisplatin and vincristine (D&V@FOLactis) to achieve sequential activation of in situ antitumor efficacy. The biomineralized D&V@FOLactis was characterized by scanning electron microscope. Confocal laser scanning microscopy, flow cytometry analysis, and immunofluorescence were employed to assess the biodistribution and the synergistic antitumor mechanisms of D&V@FOLactis in TME. Results On intratumoral administration, D&V@FOLactis exhibited pH-responsive drug release, primarily inducing immunogenic cell death and enhancing antigen exposure. Subsequently, FOLactis acted as immunopotentiators to recruit immune cells and maintain long-lasting effect. D&V@FOLactis was instrumental in thoroughly improving TME, activating T-cell responses, suppressing both “cold” and “hot” tumors with abscopal effect, and prolonging survival. In the clinical trial involving three patients, the combination of D&V@FOLactis with radiotherapy suggested potential improvements in systemic immunity and a possible reduction in multiple types of tumors. Conclusions We achieved the sequential activation of synergistic chemo-immunotherapy using an all-in-one biomineralized strategy. This study marked the first instance of biomineralizing probiotics with Mg-MOFs, creating a biosafe and versatile platform for combined in situ vaccination treatment.
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npj Precision Oncology
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2025
·Vol. 9
·期 1
·1-21
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IF 8
Li Xiaoli,Wang Jiashuo,Guo Jiaxing,Zhang Ming
Cisplatin resistance is a major challenge in laryngeal cancer treatment. Tumor necrosis factor-alpha-induced protein 2 (TNFAIP2) has been implicated in chemoresistance, though its role in laryngeal cancer remains unclear. We identified TNFAIP2 as a key gene associated with cisplatin resistance and developed a second near-infrared (NIR-II) light-responsive CRISPR-Cas9 nanosystem (APC@RBCs) to target it. In cisplatin-resistant Tu177/CDDP cells, light-activated knockout of TNFAIP2 significantly increased cisplatin sensitivity (IC50 reduced from 12.55 to 4.37 µg/mL). Mechanistic studies revealed that TNFAIP2 modulates cisplatin resistance via the NRF2 pathway, affecting oxidative stress response and epithelial-mesenchymal transition. TNFAIP2 deletion also suppressed cancer cell migration and invasion. Our results establish TNFAIP2 as a critical mediator of chemoresistance and demonstrate the potential of APC@RBCs as a precise, non-invasive gene therapy platform. This strategy offers a promising approach to overcoming cisplatin resistance and improving treatment outcomes in laryngeal cancer patients.
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INTERNATIONAL IMMUNOPHARMACOLOGY
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2025
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IF 4.7
Wei Zhu,Sai Zhu,Shan Jiang,Jiuyu Yin,Yonggui Wu,Xiaomei Luo
Background Cisplatin (CIS), a widely administered chemotherapeutic agent, is associated with acute kidney injury (AKI). Lansoprazole (LPZ), commonly prescribed to mitigate chemotherapy-induced gastrointestinal complications, may further elevate AKI risk. Paeoniflorin (Pae), a bioactive compound derived from traditional Chinese medicine, demonstrates renal protective properties in AKI, yet its mechanism against CIS and LPZ induced AKI remains undefined. Methods A composite AKI model was established in vivo and in vitro using CIS and LPZ. The protective effect of Pae on the injury of renal tissue or renal tubular cells in mice was observed, followed by Pae pretreatment. The target of Pae was found through network pharmacology, and the binding ability of the target was verified by CETSA experiment and molecular docking. Finally, the target gene was knocked out or over expressed to verified whether Pae regulates necroptosis through this target. Results It was found that renal injury could be exacerbated by LPZ in the CIS induced AKI. Pae could alleviate CIS and LPZ induced AKI. The target gene of Pae was TNFAIP3, which played an important role in necroptosis. The TNFAIP3 could bind well to Pae in molecular docking and CETSA experiment. The necroptosis and inflammatory responses in AKI induced by CIS and LPZ could be also inhibited by Pae in vivo and in vitro. Overexpression of TNFAIP3 played the same cellular protective role as Pae preconditioning. In contrast, Pae could not continue to play a protective role after TNFAIP3 was knocked down. Conclusion The traditional Chinese medicine Pae holds promise as a potential therapeutic agent for AKI, with TNFAIP3 representing an effective therapeutic target in this pathology.
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Food Science & Nutrition
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2025
·Vol. 13
·期 9
·e70862
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IF 3.8
Lu Jin,Yuanquan Ran,Nian Yang,Lanlan Yang,Xiaoyan Jia,Huan Zhao,Qiong Hu,Bing Yang,Dongxin Tang,Minyi Tian
α-Caryophyllene is a natural condiment and flavoring additive. Herein, we first study the in vivo and in vitro anti-lung cancer efficacy of α-caryophyllene and its potential mechanism. In antitumor activity in vitro, α-caryophyllene exhibited obvious selective cytotoxicity, and its cytotoxicity against lung cancer A549 cells (IC 50 = 22.94 ± 0.56) was superior to the elemene injection (EI, positive control), while its toxicity against normal cell lines was lower (MRC-5: IC 50 = 76.66 ± 2.60 μg/mL, L929: IC 50 = 44.04 ± 0.72 μg/mL). α-Caryophyllene blocked the cell cycle in the G1 phase via reducing cyclin E2-CDK2 and cyclin D3-CDK 4/6 complexes and increasing p21, thereby suppressing A549 cell proliferation. Simultaneously, α-caryophyllene activated the mitochondrial apoptotic pathway through elevating the Bax/Bcl-2 ratio, lowering ΔΨm, releasing Cyt c, activating caspase 9 and caspase 3, and triggering PARP fragmentation. In addition, α-caryophyllene downregulated N-cadherin and MMP-2 levels, thereby preventing the metastasis of A549 cells. In antitumor activity in vivo, α-caryophyllene effectively suppressed transplanted tumor growth by inducing apoptosis of transplanted tumor cells and was superior to the positive control EI. Therefore, α-caryophyllene has outstanding anticancer properties in vitro and in vivo, showing great potential to become a new anticancer drug in the pharmaceutical field.
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NEW JOURNAL OF CHEMISTRY
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2025
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IF 2.5
Xiong-Li Liu,Jing Lou,Xian-Qiao Zhu,Di-Cheng Pan,De-Wu Liu,Hui-Xian Jing,Wenjing Zhang,Hong-Xing Cen,Guo-Deng Guo-Deng Dong
The development of single chiral source-derived ligands to fine-switch enantioselectivity has continuously attracted the attention in asymmetric catalysis. Herein, we use the same chiral source L-prolinamide as the starting material, synthesizing chiral bidentate pyridine-type N-oxide ligands (denoted as Py-NO) and chiral monodentate phenyl N-oxide ligands (denoted as Ph-NO); their effectiveness was demonstrated in the switch of enantioselectivity in palladium(II)-catalysed Friedel-Crafts (FC) alkylation of indoles and 2,3-dioxopyrrolidines, and both enantiomers of structurally important indole derivatives can be prepared in good yields (up to 91% yield) and high enantioselectivities (up to 99% ee). Key to the success of switch of enantioselectivity is the existence of two different activation patterns in this palladium(II) catalytic system. Experiments demonstrated that a counteranion would plausibly coordinate to the palladium(II) center in the stereoselectivity-determining step. Preliminary mechanistic studies provide a rational explanation for the above observations. This study was the first example of monodentate ligand in asymmetric catalytic Friedel-Crafts alkylation.
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Frontiers in Pharmacology
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2025
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IF 4.8
Yuru Pang,Qiqi Meng,Yangchen Cui,Shiyi Liu,Huihui Jiang,Chenlan Xu,Yan An,Yang Jiao,Qi Zhang,Jihua Nie
Background: Lung cancer is the leading cause of cancer-related death in the worldwide. Although cisplatin and other platinum-based drugs are widely used as radiosensitizers in radiotherapy and considered the first-line treatment for advanced lung cancer, their clinical utility is often limited by drug resistance and severe cytotoxic side effects. In recent years, iridium-based complexes and other transition metal cation complexes with similar structural properties have garnered increasing research interest due to their potential anticancer properties.Methods: Recently, we synthesized a novel iridium (III) complex (Ir-1) and evaluated its safety and stability. The present study aimed to identify Ir-1 with potent anticancer activity by assessing its cytotoxic effects on lung cancer cells in vitro. Additionally, it investigated Ir-1's radiosensitizing efficacy and the underlying mechanisms.Results: The results demonstrated that Ir-1 exhibited significant radiosensitizing effects on lung cancer cells. Ir-1 effectively reduced cell viability and colony formation, arrested the cell cycle at the G2/M phase, inhibited cell migration and invasion, decreased mitochondrial membrane potential, and increased reactive oxygen species (ROS) generation in lung cancer cells. Importantly, these cytotoxic effects were selective, with minimal impact on normal cells. Mechanistic studies showed that Ir-1 enhanced radiation-induced cancer cell death by disrupting mitochondrial function and activating the mitochondrial apoptotic pathway. This was evidenced by upregulated expression levels of Bax, Cytochrome c (Cyt-C), and Caspase9 proteins, along with reduced level of Bcl-2 protein. Notably, the addition of a Cyt-C inhibitor significantly reduced the expression of Cyt-C and Caspase9 proteins. Similarly, treatment with the Caspase9 inhibitor Z-LEHD-FMK also reduced Caspase9 protein level.Conclusion: This study provides robust evidence that Ir-1 is a promising and safe radiosensitizer for lung cancer therapy. Its ability to enhance radiation-induced cytotoxicity through mitochondrial dysfunction and activation of apoptotic pathways highlights its potential for clinical application.
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Journal of Ovarian Research
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2024
·Vol. 17
·期 1
·1-17
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IF 3.8
Sui Xue,Gao Bingqing,Zhang Liu,Wang Yanmin,Ma Junnan,Wu Xingchen,Zhou Chenyu,Liu Min,Zhang Lin
Background Cisplatin (DDP) is one of the most effective anticancer drugs, commonly used to treat advanced ovarian cancer (OC). However, DDP has significant limitations of platinum-based drugs, including chemical resistance and high-dose toxic side effects. Traditional Chinese medicines (TCMs) often presented in the form of formula, in which the herb pair was the basic unit. Scutellaria barbata D.Don and Hedyotis diffusa Willd (SB-HD) are famous TCMs herb pair that have been shown to help treat multiple types of cancers. However, the synergistic effects and mechanism of combination of SB-HD and DDP to enhance DDP chemosensitivity in OC are still unknown.Results In vitro, we found that the optimal proportion of SB-HD to inhibit the proliferation of OC cells was 2:1, SB-HD and DDP were shown to synergistically reduce the viability of OC cells, inhibit the colony formation, promote cell cycle arrest and apoptosis, as well as inhibit cell migration and invasion. In vivo, combination treatment significantly inhibited the growth of subcutaneous tumors in BALB/c nude mice and reduced the toxic side effects of DDP. Mechanistically, SB-HD and DDP combination treatment significantly promoted oxidative stress response, decreased MMP, inhibited ATP production, decreased ROS levels and increased SOD activity, increased the expression of NRF2, HO-1, ATG5 and LC3, decreased the expression of p62 and FTH1 both in OC cells and tumor tissue of mice. Inhibitor 3-MA (Methyladenine, autophagy inhibitor) and Fer-1 (Ferrostatin-1, iron ion inhibitor) can effectively reverse the expression changes of the key target proteins, but not ZnPP (Zinc protoporphyrin, HO-1 inhibitor). Through bioinformatics analysis, it was found that the abnormal expression level of NRF2 and FTH1 mRNA has a high prognostic value, at the same time, the other four key proteins respectively or interacting with NRF2 and FTH1, also play important roles in the occurrence and development of OC.Conclusion Our findings uncover a synergistic effect of SB-HD and DDP against OC through modulating oxidative stress via NRF2-FTH1 autophagic degradation pathway, which may provide an important theoretical foundation for the use of SB-HD and a new strategy for enhancing DDP chemosensitivity as well as reducing toxic side effects.
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JOURNAL OF PHARMACY AND PHARMACOLOGY
·
2024
·
IF 2.8
Song Zeyu,Li Zhenyuan,Pan Tao,Liu Teng,Gong Baifang,Wang Zhixia,Liu Ke,Fan Huaying
ObjectivesAcute kidney injury (AKI) caused by cisplatin (CDDP) is a complex, critical illness with no effective or specific treatment. The purpose of the study was to assess the protective effect of protopanaxadiol (PPD) on the kidneys in CDDP-induced AKI models and its possible mechanisms.MethodsIn vitro, the protection of PPD was assessed in HK-2. KM mice were injected with CDDP to induce AKI models in vivo. The determination of blood urea nitrogen and serum creatinine (SCr) was performed, and pathological changes were examined by histopathological examination. Immunostaining and western blot analyses were used to analyze the expression levels of proteins.ResultsPPD can increase the viability of HK-2 cells damaged by CDDP, improve cell morphology, and alleviate the symptoms of AKI in mice. In addition, PPD can down-regulate the protein expression of TRF and up-regulate the protein expression of Ferritin heavy chain, Glutathione peroxidase 4, and ferroptosis suppressor protein 1 reduce the iron content in cells and kidney tissues, and restore the antioxidant defense system.ConclusionPPD has an inhibitory effect on cisplatin-induced nephrotoxicity, which may be related to the inhibition of ferroptosis by regulating iron metabolism and lipid peroxidation.
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Biomaterials Science
·
2025
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IF 5.7
Peinan Yin,Anamaria Brozovic,Wei Zhang,Chengwei Wu
Ovarian cancer (OC) is one of the most fatal malignant tumors of the female reproductive system, and its high recurrence rate in advanced stages and drug resistance severely limit the efficacy of current treatment methods. The molecular mechanisms of drug resistance are complex and remain incompletely understood. Previous studies have attempted to enhance treatment sensitivity by co-delivering antitumor drugs with inhibitors of drug resistance-associated factors. However, these approaches often suffer from inadequate therapeutic efficacy and poor precision due to the inability to precisely control the sequential release of the two agents. To address this, this study designed and constructed a core–shell hydrogel microsphere (MSs) system with both sequential release and magnetothermal synergy functions to effectively intervene in drug-resistant OC. In this system, the shell layer is loaded with the DYRK1B inhibitor AZ191, which is released preferentially to disrupt drug-resistant signaling pathways and sensitize tumor cells. Subsequently, the core layer releases cisplatin to achieve sustained killing of tumor cells. In addition, magnetic nanoparticles embedded in the core can be heated to 42–46 °C under an alternating magnetic field, inducing thermosensitive apoptosis and enhancing cisplatin efficacy. This approach holds promise as a non-invasive alternative to traditional hyperthermic intraperitoneal chemotherapy (HIPEC). In vitro drug release experiments demonstrated that AZ191 exhibited rapid release within the first three hours with a cumulative release of approximately 26%, whereas cisplatin showed minimal early release (∼5%) followed by a markedly accelerated release. In vitro antitumor studies confirmed that the combined chemo-hyperthermia treatment using the core–shell MSs produced the most effective inhibitory effect on drug-resistant OC cells, reducing cell viability to 21% after 48 h, significantly outperforming either chemotherapy or hyperthermia alone. This strategy enables a “resistance-reversal first, precision-killing later” treatment model, offering a novel and effective solution for the treatment of drug-resistant OC.
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BIOELECTROCHEMISTRY
·
2025
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IF 4.5
Cheng Huang,Haowen Liu,Bao Jiang,Guoli Li,Xinlu Qin,Yinan Hua,Yongming Deng,Yicheng Wang,Lin Zhou
Acute kidney injury (AKI), a critical clinical syndrome marked by high incidence and mortality, is currently diagnosed mainly by serum creatinine (SCr) and blood urea nitrogen (BUN), which have high miss rates. This study innovatively proposes using urinary hydrogen peroxide (H 2 O 2 ) concentration changes, caused by renal oxidative stress in AKI, as a new indicator for AKI risk assessment and treatment monitoring. Results from in vitro and AKI animal models show this indicator can quickly monitor AKI onset and drug effects in mice via electrochemical sensing technology based on Bi 2 S 3 @Cu 0.1 , offering a novel approach for AKI diagnosis and rehabilitation monitoring.
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