BIOMEDICINE & PHARMACOTHERAPY
·
2022
·
IF 7.419
Tianqiao Yong,Danling Liang,Chun Xiao,Longhua Huang,Shaodan Chen,Yizhen Xie,Xiong Gao,Qingping Wu,Huiping Hu,Xiangmin Li,Yuancao Liu,Manjun Cai
In this paper, we reported the hypouricemic effect of 2,4-dihydroxybenzoic acid methyl ester (DAE), a component of Ganoderma applanatum , in hyperuricemic mice through inhibiting XOD and down-regulating URAT1. Computationally, DAE showed a high similarity to allopurinol and depicted a high affinity in docking to XOD. In vitro , DAE exhibited an inhibitory effect against XOD. Importantly, DAE demonstrated a remarkable hypouricemic effect, decreasing serum uric acids (SUAs) of hyperuricemic mice (407 ± 31 μmol/L) to 195 ± 23, 145 ± 33 and 134 ± 16 μmol/L ( P < 0.01) at the doses of 20, 40, and 80 mg/kg with a dose-dependent manner and showing efficacies at 54–68 %, which were close to the efficacies of allopurinol (61 %) and benzbromarone (57 %). DAE depicted higher and negatively dose-independent urinary uric acids in comparison with that of the hyperuricemic control, implying DAE exerted an uricosuric effect and also a reduction effect on uric acid production. Unlike toxic allopurinol and benzbromarone, no general toxicity on body weights and no negative influence on liver, kidney, spleen and thymus were observed for DAE. Mechanistically, DAE inhibited XOD activities in vivo . Moreover, DAE up-regulated OAT1 and down-regulated GLUT9, URAT1 and CNT2. Overall, DAE may present a hypouricemic effect through inhibiting XOD and up-regulating OAT1 and down-regulating GLUT9, URAT1 and CNT2. This work provided novel insights into the hypouricemic effect of DAE and G. applanatum.
研究领域:
药理学
·
生物化学
·
分子生物学
·
医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2024
·
IF 5.3
Renjiang Kong,Jiaqi Huang,Yeyang Wu,Ni Yan,Xin Chen,Hong Cheng
The unsatisfactory immunotherapeutic responses are primarily attributed to the insufficient immune recognition and the presence of an immunosuppressive tumor microenvironment (ITM). This study focuses on the development of a tricomponent immunoactivating nanomedicine called TIN that combines a photosensitizer, an inhibitor of epidermal growth factor receptor (EGFR) and a CSF-1R inhibitor to enable photodynamic immunotherapy by downregulating PD-L1 expression and repolarizing tumor-associated macrophages (TAMs). TIN is designed to facilitate the drug delivery and target specific pathways involved in tumor progression. By inhibiting the activity of EGFR and CSF-1R, TIN reduces PD-L1 expression on tumor cells and induces the TAMs polarization to M1 phenotype, restoring the immune recognition of T cells and the phagocytosis of macrophage to reshape the immunosuppressive microenvironment. Additionally, the photodynamic therapy (PDT) of TIN can greatly destroy the primary tumor and trigger immunogenic cell death (ICD). Importantly, the immune checkpoint blockade effect of TIN can enhance the immune response of PDT-induced ICD for metastatic tumor treatment. This study presents a self-assembling strategy for the development of an all-in-one nanomedicine, effectively integrating multiple therapeutic modalities to provide a comprehensive and systemic approach for tumor suppression.
研究领域:
肿瘤学
·
免疫学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Neuroinflammation
·
2024
·Vol. 21
·期 1
·1-25
·
IF 9.3
Cheng Shimei,Lu Qiying,Liu Qiuli,Ma Yuanchen,Chen Jinshuo,Lu Di,Huang Mudan,Huang Yinong,Zhao Erming,Luo Jing,Zheng Haiqing
Background Neuronal death is the primary cause of poor outcomes in cerebral ischemia. The inflammatory infiltration in the early phase of ischemic stroke plays a vital role in triggering neuronal death. Either transplantation of mesenchymal stem cells (MSCs) derived from humans or repetitive transcranial magnetic stimulation (rTMS) have respectively proved to be neuroprotective and anti-inflammatory in cerebral ischemia. However, either treatment above has its limitations. Whether these two therapies have synergistic effects on improving neurological function and the underlying mechanisms remains unclear. This investigation aims to elucidate the synergistic effects and underlying mechanisms of MSCs combined with rTMS treatment on the neurological function recovery post-ischemia.Methods A Sprague-Dawley rat model of cerebral infarction was induced via transient middle cerebral artery occlusion (tMCAO). The rats were divided into five groups (n = 50): sham, tMCAO, rTMS, MSCs, and MSCs + rTMS groups. Transplantation of human umbilical cord MSCs and rTMS intervention were performed 24 h post-stroke. Neurological function was further assessed via several behavioral tests and the 2,3,5-triphenyltetrazolium chloride (TTC) staining companied with Nissl staining were used to assess neuronal survival. TUNEL staining, western blotting, immunofluorescence, immunohistochemistry, ELISA, and flow cytometry were employed to measure the levels of neuroinflammation and PANoptosis. The molecular mechanisms underlying the special role of rTMS in the combined therapy were distinguished with transcriptome sequencing via PC12 cells in oxygen-glucose deprivation/reoxygenation (OGD/R) conditions.Results The combined therapy efficiently reduced lesion volume and improved neuronal survival (P < 0.05), subsequently improving functional recovery after ischemic stroke. MSCs + rTMS treatment ameliorated the PANoptosis in neurons (P < 0.05), accompanied by decreased levels of inflammatory factors in the cerebral tissue and serum during the subacute phase of cerebral infarction. To further explore the roles of either therapy on synergistic effect, we found that the transplanted MSCs primarily localized in the spleen and reduced cerebral inflammatory infiltration after ischemia via suppressed splenic inflammation. Meanwhile, rTMS significantly protects neurons from PANoptosis in MSCs-inhibited inflammatory conditions by downregulating REST unveiled by transcriptome sequencing.Conclusion sOur study elucidates an unidentified mechanism by which the combination of MSCs and rTMS could synergistically promote neuronal survival and suppress neuroinflammation during the subacute phase of cerebral infarction, thus improving neurological outcomes. The downregulating REST induced by rTMS may potentially contribute to the neuroprotective effect against PANoptosis in MSCs-inhibited inflammatory conditions. These results are expected to provide novel insights into the mechanisms of MSCs and rTMS combination therapy in synergistically protecting against cerebral ischemia injury and potential targets underlying neuronal PANoptosis in the early phase of stroke.
研究领域:
神经科学
·
干细胞生物学
·
神经病学
·
免疫学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHARMACEUTICAL BIOLOGY
·
2022
·
IF 3.889
Feng-guo Zhai,Qi-chao Liang,Yi-yan Wu,Jia-qi Liu,Jia-wei Liu
Context Red ginseng polysaccharide (RGP) is an active component of the widely used medicinal plant Panax ginseng C. A. Meyer (Araliaceae), which has displayed promising activities against cancer cells. However, the detailed molecular mechanism of RGP in ferroptosis is still unknown.Objective This study evaluates the effects of RGP in cancer cells.Materials and methods A549 and MDA-MB-231 cells were used. Cell proliferation was measured by CCK-8 assay after being treated with RGP at concentrations of 0, 50, 100, 200, 400, 800 and 1600 μg/mL at 0, 12, 24 and 48 h. Lipid reactive oxygen species (ROS) levels were assessed by C11-BODIPY assay. The control group was treated with PBS.Results RGP inhibited human A549 (IC50: 376.2 μg/mL) or MDA-MB-231(IC50: 311.3 μg/mL) proliferation and induced lactate dehydrogenase (LDH) release, promoted ferroptosis and suppressed the expression of GPX4. Moreover, the effects of RGP were enhanced by the ferroptosis inducer erastin, while abolished by ferroptosis inhibitor ferrostatin-1.Discussion and conclusions Our study is the first to demonstrate (1) the anticancer activity of RGP in human lung cancer and breast cancer. (2) RGP presented the anti-ferroptosis effects in lung and breast cancer cells via targeting GPX4.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2023
·
IF 8
Lijuan Lin,Xizhen Zhuang,Ruiqi Huang,Simin Song,Zhaojie Wang,Shilong Wang,Liming Cheng,Rongrong Zhu
Purpose In this study, we aim to explore the effects of graphene oxide (GO), a derivative of graphene, nanoparticles of four different sizes on the cellular fate of mouse neural stem cells (mNSCs).Methods GO NPs were characterized with transmission electron microscopy (TEM), scanning electron micrography (SEM), atomic force microscopy (AFM) and Raman Spectra analysis. The cytotoxic effects of the GO NPs of different sizes on the mNSCs were determined using CCK-8 assay, Annexin V-APC/ 7-AAD staining and EdU staining assays. We investigated the biological and the mechanisms of GO NPs on cells using immunofluorescence analysis and quantitative real-time PCR (qPCR).Results The average hydrodynamic sizes of the GO NPs were 417 nm, 663 nm, 1047 nm, and 4651 nm, with a thickness of approximately 22.5 nm, 17.7 nm, 22.4 nm, and 13.4 nm, respectively. GO NPs of all sizes showed low cytotoxicity at a concentration of 20 μg/mL on the mNSCs. Immunostaining demonstrated that treatment with GO NPs, especially the 663 nm ones, enhanced the self-renewal ability of mNSCs in the absence of EGF and bFGF. Under differentiation medium conditions that are free of mitogenic factors, all the GO NPs, particularly the 4651 nm ones, increased the expression level of Tuj1 and GFAP. With regards to the migration ability, we found that 417 nm GO-NP-treated mNSCs migrated over a longer distance than the control group obviously. In addition, higher expression of Rap1, Vinculin and Paxillin was observed in the GO NP-treated groups compared to the control group. mRNA-Sequence analysis and Western blotting results suggested that the 4651 nm GO NPs triggered positive neuronal differentiation through phosphorylation of ERK1/2 by the downregulating of TRPC2.Conclusion GO NPs play an important role in the applications of inducing self-renewal and differentiation of mNSC, and are promising in the future for further studies.
研究领域:
材料科学
·
神经科学
·
细胞生物学
·
生物医学工程
✓ 已验证
DOI
PubMed
高影响因子
INDUSTRIAL CROPS AND PRODUCTS
·
2024
·
IF 5.6
Chenggang Song,Wuliang Shi,Jian Yang,Gang Ding,Wei Chen,Chengguo Jia,Mingzhe Zhang,Jianchun Qin
The presence of aflatoxins resulting from Aspergillus flavus infection in food poses a significant threat to human health due to their potent carcinogenicity or hepatotoxicity. Monarda didyma essential oil, with 92.3% thymol as the active ingredient, is effective in inhibiting A. flavus infestation during peanut storage. Thymol was found to inhibit the growth of A. flavus with an IC 50 value of 14.5 µg mL −1 . When exposed to thymol stress, A. flavus experiences disruption of its glycolysis and tricarboxylic acid cycle, leading to the accumulation of reactive oxygen species and resulting in cell membrane damage and apoptosis. Furthermore, thymol leads to the downregulation of multiple genes, including aflA , involved in the aflatoxin biosynthesis, resulting in a reduction in the production of aflatoxins. This demonstrates the potential of M. didyma essential oil and thymol as effective inhibitors of mycotoxins, thereby contributing to the resolution of food safety issues.
研究领域:
食品科学
·
微生物学
·
药理学
·
真菌学
·
植物化学
✓ 已验证
产品关联
DOI
高影响因子
ACS Nano
·
2024
·
IF 15.8
Weiran Cao,Xue Zhang,Yaxuan Feng,Rui Li,An Lu,Zijie Li,Fei Yu,Lu Sun,Jiancheng Wang,Zhiyu Wang,Huining He
Intrinsic or acquired resistance to chemical drugs severely limits their therapeutic efficacy in cancer treatment. Various intracellular antioxidant molecules, particularly glutathione (GSH), play a crucial role in maintaining intracellular redox homeostasis by mitigating the overproduced reactive oxygen species (ROS) due to rapid cell proliferation. Notably, these antioxidants also eliminate chemical-drug-induced ROS, eventually diminishing their cytotoxicity and rendering them less effective. In this study, we combined erastin, a GSH biosynthesis inhibitor, with 2′-deoxy-5-fluorouridine 5′-monophosphate sodium salt (FdUMP), an ROS-based drug, to effectively disrupt intracellular redox homeostasis and reverse chemotherapy resistance. Therefore, efficient ferroptosis and apoptosis were simultaneously induced for enhanced antitumor effects. Additionally, we employed small interfering RNA targeting PD-L1 (siPD-L1) as a third agent to block immune-checkpoint recognition by CD8+ T cells. The highly immunogenic cell peroxidates or damage-associated molecular patterns (DAMPs) induced by erastin acted synergistically with downregulated PD-L1 to enhance the antitumor effects. To codeliver these three drugs simultaneously and efficiently, we designed GE11 peptide-modified lipid nanoparticles (LNPs) containing calcium phosphate cores to achieve high encapsulation efficiencies. In vitro studies verified its enhanced cytotoxicity, efficient intracellular ROS induction and GSH/GPX4 downregulation, substantial lipid peroxidation product accumulation, and mitochondrial depolarization. In vivo, this formulation effectively accumulated at tumor sites and achieved significant tumor inhibition in subcutaneous colon cancer (CRC) mouse models with a maximum tumor inhibition rate of 83.89% at a relatively low dose. Overall, a strategy to overcome clinical drug resistance was verified in this study by depleting GSH and activating adaptive immunity.
研究领域:
癌症生物学
·
药学
·
纳米技术
·
免疫学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
APOPTOSIS
·
2018
·Vol. 23
·期 2
·132-142
·
IF 3.967
Hu Cuihua,Chen Xiaolong,Huang Yibing,Chen Yuxin
In this study, a peptide–peptide co-administration therapy between hybrid peptide kla-TAT and cationic anticancer peptide HPRP-A1 was designed to increase the anticancer activity of the combination peptides through synergistic effect. kla is a pro-apoptotic peptide which could induce rapid cancer cell apoptosis by disruption the mitochondrial membrane when internalized the cells. To enhance more kla peptides pass through cell membrane, a double improvement strategy was designed by chemically conjugation with cell penetration peptide TAT as well as co-administration with cationic membrane active peptide HPRP-A1, and the double anticancer mechanism of the kla-TAT peptide and HPRP-A1 including membrane disruption and apoptosis induction was verified through in vitro experiments. The CompuSyn synergism/antagonism analysis showed that kla-TAT acted synergistically with HPRP-A1 against a non-small cell lung cancer (NSCLC) A549 cell line. The anticancer activities of the two peptides were dramatically increased by co-administration, under the mechanism of cell membrane disruption, caspase-dependent apoptosis induction, as well as cyclin-D1 down-regulation based G1 phase arrest. We believe that the synergic therapeutic strategy would be a meaningful method for the anticancer peptides used in cancer treatment.
研究领域:
肿瘤学
·
药学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nano Research
·
2020
·Vol. 14
·期 1
·222-231
·
IF 8.183
Zhu Huimin,Cao Guodong,Fu Yike,Fang Chao,Chu Qiang,Li Xiang,Wu Yulian,Han Gaorong
Multidrug resistance (MDR) restricts chemotherapy efficacy due to P-glycoprotein (P-gp) mediated drug efflux, whereas current approaches to suppressing P-gp expression suffer from intrinsic challenges, such as low transfection, high toxicity and poor specificity. Here, hollow ferric-tannic acid complex nanocapsules (HFe-TA), which can be effectively degraded by the reaction with adenosine triphosphate (ATP), are synthesized for the delivery of glucose oxidase (GOx) and doxorubicin (DOX) for tumor treatment. The findings indicate that the intracellular ATP is significantly decreased due to the combined effect of HFe-TA degradation and GOx-mediated glucose consumption. Along with this ATP down-regulation, P-gp expression of tumor cells is suppressed remarkably, which in turn promotes the intracellular accumulation and anticancer efficacy of DOX. In addition, the production of OH by Fe ions released from HFe-TA is promoted by the by-products of the oxidation of glucose process by GOx. In consequence, HFe-TA nanocapsules loaded with DOX and GOx enable significant inhibition effect to tumors both in vitro and in vivo due to the synergistic effect of cascade reactions. This study has therefore provided an alternative therapeutic platform for effective tumor inhibition with the potential in overcoming intrinsic MDR.
研究领域:
纳米技术
·
药学
·
癌症研究
·
生物医学工程
✓ 已验证
DOI
高影响因子
CELLULAR SIGNALLING
·
2024
·
IF 4.4
Jingyi Li,Ziyu Chen,Mingming Jin,Xuefeng Gu,Yuhan Wang,Gang Huang,Weiming Zhao,Changlian Lu
Lactylation, a newly identified post-translational modification, is uncertain in its implication in triple-negative breast cancer (TNBC). In this study, we analyzed 60 TNBC samples using immunohistochemical staining and revealed elevated levels of pan-lactylated proteins and specific histone H4K12 lactylation in tumor tissues, correlating with TNBC progression. Lactate exposure in TNBC cell lines significantly induced lysine lactylation at the H4K12 site, leading to alterations in gene profiles and reduced apoptosis. These effects were attenuated by DCA or sodium Oxamate, inhibitors of endogenous lactate production. Gene sequencing showed an increase in Schlafen 5 (SLFN5) expression in TNBC cells treated with Oxamate, contrasting with the effects of lactate exposure. Analysis of TNBC tissues showed a negative correlation between H4K12 lactylation and SLFN5 protein levels. Overexpression of SLFN5 countered the effects of lactate on apoptosis and tumor growth, highlighting its pivotal role in TNBC malignancy. CUT&Tag sequencing indicated that lactylated H4K12 potentially binds to the SLFN5 promoter region. Luciferase reporter assays further verified that lactate-induced suppression of SLFN5 promoter activity is mediated by wild-type H4K12, but not by its R or A mutants, verified by both in vitro and in vivo apoptosis detection in response to lactate and Oxamate stimulation. These results establish that H4K12 lactylation, induced by lactate in TNBC cells, specifically suppresses SLFN5 expression, contributing to TNBC malignancy. Our findings illuminate a critical histone lactylation-dependent carcinogenic pathway in TNBC.
研究领域:
肿瘤学
·
分子生物学
·
癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6.8
Zekun Li,Mochen Guo,Mingxiao Gu,Zhongtian Cai,Qiuyu Wu,Jia Yu,Meilun Tang,Chenxi He,Yuxuan Wang,Piaoyang Sun,Qidong You,Lei Wang
The serine/threonine phosphatase family is important in tumor progression and survival. Due to the high conserved catalytic domain, designing selective inhibitors is challenging. Herein, we obtained compound 28a with 38-fold enhanced PP5 selectivity (PP2A/5 IC50 = 33.8/0.9 μM) and improved drug-like properties (favorable stability and safety, F = 82.0%) by rational drug design based on a phase II PP2A/5 dual target inhibitor LB-100. Importantly, we found the spatial conformational restriction of the 28a indole fragment was responsible for the selectivity of PP5. Thus, 28a activated p53 and downregulated cyclin D1 and MGMT, which showed potency in cell cycle arrest and reverse temozolomide (TMZ) resistance in the U87 MG cell line. Furthermore, oral administration of 28a and TMZ was well tolerated to effectively inhibit tumor growth (TGI = 87.7%) in the xenograft model. Collectively, these results implicate 28a could be a drug candidate by reversing TMZ resistance with a selective PP5 inhibition manner.
研究领域:
药理学
·
肿瘤学
·
药物化学
·
癌症生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2025
·
IF 19
Shuai Wu,Ya Wang,Yunfan Li,Minyao Qiu,Yuan Zhong,Maolan Zhang,Haifeng Yang,Jianshu Li,Wei Wu
Clinical treatment of temozolomide (TMZ)-resistant glioblastoma (GBM) remains a significant challenge. This study aims to develop a multifunctional biomimetic Nano-AUTAC (BM@pPPD/TMZ) that can selectively degrade β-catenin via autophagy, thereby overcoming TMZ resistance in GBM. BM@pPPD/TMZ is capable of penetrating the blood-brain barrier (BBB), targeting GBM lesions via microglia-derived membrane camouflage, and inducing degradation of β-catenin through the autophagy-lysosomal pathway. For improving the selective and efficient degradation of β-catenin, BM@pPPD/TMZ is functionalized with a tri-functional peptide comprising a β-catenin-binding domain, a cathepsin B (CTSB)-cleavable GLFG linker, and a phosphatidylserine (PS)-targeting motif. In the GBM microenvironment, the elevated CTSB triggers linker cleavage, promoting membrane shedding and enhancing the cellular uptake. Meanwhile, the incorporation of the cationic lipid DOTAP promotes autophagosome formation, further facilitating degradation of β-catenin. Both in vitro and in vivo studies demonstrate that BM@pPPD/TMZ is able to effectively penetrate the BBB and accumulate within tumor lesion, concurrently promoting β-catenin degradation and MGMT downregulation. This finding provides a promising nanotherapeutic strategy for overcoming TMZ resistance and improving GBM therapeutic efficacy.
研究领域:
纳米医学
·
癌症治疗
·
分子生物学
·
神经肿瘤学
·
自噬研究
·
药物递送
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）