Nanofactory for Metabolic and Chemodynamic Therapy: Pro-Tumor Lactate Trapping and Anti-Tumor ROS Transition

2021 ◽  
Author(s):  
Ruiqing He ◽  
Jie Zang ◽  
Yuge Zhao ◽  
Ying Liu ◽  
Shuangrong Ruan ◽  
...  
Keyword(s):  
Copper Ions ◽  
Critical Role ◽  
Treatment Plant ◽  
Tumor Model ◽  
Great Promise ◽  
Lactate Oxidase ◽  
Metabolic Therapy ◽  
Immunosuppressive Tumor Microenvironment ◽  
Lactate Degradation ◽  
Novel Strategy

Abstract Lactate plays a critical role in tumorigenesis, invasion and metastasis. Exhausting lactate in tumors holds great promise for the reversal of the immunosuppressive tumor microenvironment (TME). Herein, we report on a “lactate treatment plant” (i.e., nanofactory) that can dynamically trap pro-tumor lactate and in situ transformation into anti-tumor cytotoxic reactive oxygen species (ROS) for a synergistic chemodynamic and metabolic therapy. To this end, lactate oxidase (LOX) was nano-packaged by cationic polyethyleneimine (PEI), assisted by a necessary amount of copper ions (PLNPCu). As a reservoir of LOX, the tailored system can actively trap lactate through the cationic PEI component to promote lactate degradation by two-fold efficiency. More importantly, the byproducts of lactate degradation, hydrogen peroxide (H2O2), can be transformed into anti-tumor ROS catalyzing by copper ions, mediating an immunogenic cell death (ICD). With the remission of immunosuppressive TME, ICD process effectively initiated the positive immune response in 4T1 tumor model (88% tumor inhibition). This work provides a novel strategy that rationally integrates metabolic therapy and chemodynamic therapy (CDT) for combating tumors.

scholarly journals Nanofactory for metabolic and chemodynamic therapy: pro-tumor lactate trapping and anti-tumor ROS transition

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Ruiqing He ◽  
Jie Zang ◽  
Yuge Zhao ◽  
Ying Liu ◽  
Shuangrong Ruan ◽  
...  
Keyword(s):  
Copper Ions ◽  
Critical Role ◽  
Treatment Plant ◽  
Tumor Model ◽  
Great Promise ◽  
Lactate Oxidase ◽  
Metabolic Therapy ◽  
Immunosuppressive Tumor Microenvironment ◽  
Lactate Degradation ◽  
Novel Strategy

AbstractLactate plays a critical role in tumorigenesis, invasion and metastasis. Exhausting lactate in tumors holds great promise for the reversal of the immunosuppressive tumor microenvironment (TME). Herein, we report on a “lactate treatment plant” (i.e., nanofactory) that can dynamically trap pro-tumor lactate and in situ transformation into anti-tumor cytotoxic reactive oxygen species (ROS) for a synergistic chemodynamic and metabolic therapy. To this end, lactate oxidase (LOX) was nano-packaged by cationic polyethyleneimine (PEI), assisted by a necessary amount of copper ions (PLNPCu). As a reservoir of LOX, the tailored system can actively trap lactate through the cationic PEI component to promote lactate degradation by two-fold efficiency. More importantly, the byproducts of lactate degradation, hydrogen peroxide (H2O2), can be transformed into anti-tumor ROS catalyzing by copper ions, mediating an immunogenic cell death (ICD). With the remission of immunosuppressive TME, ICD process effectively initiated the positive immune response in 4T1 tumor model (88% tumor inhibition). This work provides a novel strategy that rationally integrates metabolic therapy and chemodynamic therapy (CDT) for combating tumors. Graphical Abstract

scholarly journals Deciphering the Mounting Complexity of the p53 Regulatory Network in Correlation to Long Non-Coding RNAs (lncRNAs) in Ovarian Cancer

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 527 ◽  
Author(s):  
Sonali Pal ◽  
Manoj Garg ◽  
Amit Kumar Pandey
Keyword(s):  
Ovarian Cancer ◽  
Molecular Mechanisms ◽  
Human Cancer ◽  
Critical Role ◽  
Functional Characterization ◽  
Great Promise ◽  
Altered Expression ◽  
Disease Biology ◽  
Non Coding Rnas ◽  
Post Transcriptional Regulation

Amongst the various gynecological malignancies affecting female health globally, ovarian cancer is one of the predominant and lethal among all. The identification and functional characterization of long non-coding RNAs (lncRNAs) are made possible with the advent of RNA-seq and the advancement of computational logarithm in understanding human disease biology. LncRNAs can interact with deoxyribonucleic acid (DNA), ribonucleic acid (RNA), proteins and their combinations. Moreover, lncRNAs regulate orchestra of diverse functions including chromatin organization and transcriptional and post-transcriptional regulation. LncRNAs have conferred their critical role in key biological processes in human cancer including tumor initiation, proliferation, cell cycle, apoptosis, necroptosis, autophagy, and metastasis. The interwoven function of tumor-suppressor protein p53-linked lncRNAs in the ovarian cancer paradigm is of paramount importance. Several lncRNAs operate as p53 regulators or effectors and modulates a diverse array of functions either by participating in various signaling cascades or via interaction with different proteins. This review highlights the recent progress made in the identification of p53 associated lncRNAs while elucidating their molecular mechanisms behind the altered expression in ovarian cancer tumorigenesis. Moreover, the development of novel clinical and therapeutic strategies for targeting lncRNAs in human cancers harbors great promise.

scholarly journals Murine hepatoma treatment with mature dendritic cells stimulated by Trichinella spiralis excretory/secretory products

Parasite ◽  
2020 ◽  
Vol 27 ◽  
pp. 47
Author(s):  
Jing Ding ◽  
Xiaolei Liu ◽  
Bin Tang ◽  
Xue Bai ◽  
Yang Wang ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Tumor Growth ◽  
Antitumor Effect ◽  
Trichinella Spiralis ◽  
Critical Role ◽  
Tumor Model ◽  
Control Group ◽  
Tumor Inhibition ◽  
Significant Difference ◽  
Secretory Products

Excretory/Secretory Products (ESPs) of the nematode Trichinella spiralis contain antitumor-active substances that inhibit tumor growth. Mature dendritic cells (DCs) play a critical role in the antitumor immunity of the organism. As pathogen-derived products, it ought to be discussed whether T. spiralis ESPs will reduce the antitumor effect of mature DCs from the host before it is applied to patients’ tumors. Therefore, the aim of this work was to evaluate the immunological effect of DCs stimulated by T. spiralis ESPs in H22 tumor-bearing mice. H22 tumor model mice in this study were randomly divided into four groups according to the treatment: PBS control group, ESP group, DCs group, and DCs stimulated with T. spiralis ESP (ESP+DCs group). The antitumor effect was evaluated by tumor inhibition rate and cytokine detection using ELISA. The results showed significant inhibition in tumor growth in the ESP+DCs, DCs and ESP groups when compared with the PBS control group (p < 0.01, p < 0.01, and p < 0.05, respectively). However, no significant difference was observed on tumor inhibition rates between the ESP+DCs and DCs groups. The decrease in IL-4, IL-6, and IL-10, and the increase in IFN-γ between the DCs and ESP+DCs groups were also not significant. Therefore, DCs stimulated by ESP did not reduce the antitumor effect of mature DCs, which demonstrated that the T. spiralis ESP would not affect the antitumor effect of mature DCs by modulating the immune response of the host, and that ESPs are safe in antitumor immunology when applied in a tumor model mice.

scholarly journals Highly efficient and tumor-selective nanoparticles for dual-targeted immunogene therapy against cancer

2020 ◽  
Vol 6 (3) ◽  
pp. eaax5032 ◽  
Author(s):  
Kuan-Wei Huang ◽  
Fu-Fei Hsu ◽  
Jiantai Timothy Qiu ◽  
Guann-Jen Chern ◽  
Yi-An Lee ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Immunotherapy ◽  
Plasmid Dna ◽  
Systemic Toxicity ◽  
Great Promise ◽  
Anticancer Efficacy ◽  
Highly Efficient ◽  
Immunogene Therapy ◽  
Immunosuppressive Tumor Microenvironment ◽  
Tumor Selective

While immunotherapy holds great promise for combating cancer, the limited efficacy due to an immunosuppressive tumor microenvironment and systemic toxicity hinder the broader application of cancer immunotherapy. Here, we report a combinatorial immunotherapy approach that uses a highly efficient and tumor-selective gene carrier to improve anticancer efficacy and circumvent the systemic toxicity. In this study, we engineered tumor-targeted lipid-dendrimer-calcium-phosphate (TT-LDCP) nanoparticles (NPs) with thymine-functionalized dendrimers that exhibit not only enhanced gene delivery capacity but also immune adjuvant properties by activating the stimulator of interferon genes (STING)–cGAS pathway. TT-LDCP NPs delivered siRNA against immune checkpoint ligand PD-L1 and immunostimulatory IL-2–encoding plasmid DNA to hepatocellular carcinoma (HCC), increased tumoral infiltration and activation of CD8+ T cells, augmented the efficacy of cancer vaccine immunotherapy, and suppressed HCC progression. Our work presents nanotechnology-enabled dual delivery of siRNA and plasmid DNA that selectively targets and reprograms the immunosuppressive tumor microenvironment to improve cancer immunotherapy.

scholarly journals PD-L1 lncRNA splice promotes lung adenocarcinoma progression via enhancing c-Myc activity

2020 ◽  
Author(s):  
Shuang Qu ◽  
Zichen Jiao ◽  
Geng Lu ◽  
Bing Yao ◽  
Ting Wang ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Great Promise ◽  
Non Coding Rna ◽  
Adenocarcinoma Cells ◽  
T Cell Immune Responses ◽  
Lung Adenocarcinoma Cells ◽  
Novel Strategy ◽  
L1 Protein

ABSTRACTAlthough blockade of programmed death-ligand 1 (PD-L1) to enhance T cell immune responses shows great promise in tumor immunotherapy, the efficacy of such immune-checkpoint inhibition strategy is limited for patients with solid tumors. The mechanism underlying the limited efficacy of PD-L1 inhibitors remains unclear. Here, we show that human lung adenocarcinoma, regardless of PD-L1 protein positive or negative, all produce a long non-coding RNA isoform of PD-L1 (PD-L1-lnc) via alternative splicing, which promotes lung adenocarcinoma proliferation and metastasis. PD-L1-lnc in various lung adenocarcinoma cells is significantly upregulated by IFNγ in a manner similar to PD-L1 mRNA. Both in vitro and in vivo studies demonstrate that PD-L1-lnc increases proliferation and invasion but decreases apoptosis of lung adenocarcinoma cells. Mechanistically, PD-L1-lnc directly binds to c-Myc and enhances c-Myc transcriptional activity downstream in lung adenocarcinoma cells. Our results provide targeting PD-L1-lnc−c-Myc axis as a novel strategy for lung cancer therapy.

scholarly journals Increasing Full Child Immunization Rates by Government Using an Innovative Computerized Immunization Due List in Rural India

2018 ◽  
Vol 55 ◽  
pp. 004695801775129
Author(s):  
Enakshi Ganguly ◽  
Rahul Gupta ◽  
Alik Widge ◽  
R. Purushotham Reddy ◽  
K. Balasubramanian ◽  
...  
Keyword(s):  
Vaccination Coverage ◽  
Andhra Pradesh ◽  
Health Workers ◽  
Immunization Coverage ◽  
Rural India ◽  
Great Promise ◽  
Immunization Rates ◽  
Comprehensive Health ◽  
Charitable Trust ◽  
Novel Strategy

Increasing child vaccination coverage to 85% or more in rural India from the current level of 50% holds great promise for reducing infant and child mortality and improving health of children. We have tested a novel strategy called Rural Effective Affordable Comprehensive Health Care (REACH) in a rural population of more than 300 000 in Rajasthan and succeeded in achieving full immunization coverage of 88.7% among children aged 12 to 23 months in a short span of less than 2 years. The REACH strategy was first developed and successfully implemented in a demonstration project by SHARE INDIA in Medchal region of Andhra Pradesh, and was then replicated in Rajgarh block of Rajasthan in cooperation with Bhoruka Charitable Trust (private partners of Integrated Child Development Services and National Rural Health Mission health workers in Rajgarh). The success of the REACH strategy in both Andhra Pradesh and Rajasthan suggests that it could be successfully adopted as a model to enhance vaccination coverage dramatically in other areas of rural India.

scholarly journals A Facile Colorimetric Method For Ultra-Rapid And Sensitive Detection of Copper Ions In Water

2021 ◽  
Author(s):  
Lei Chen ◽  
Yan Li ◽  
Ping Sun ◽  
Hualin Chen ◽  
He Li ◽  
...  
Keyword(s):  
Color Change ◽  
Copper Ions ◽  
Colorimetric Method ◽  
Ethanol Solution ◽  
Sensitive Detection ◽  
World Health ◽  
Great Promise ◽  
Experimental Conditions ◽  
Interesting Phenomenon ◽  
Health Organization

Abstract It is of great meaning to develop a facile, reliable and sensitive method to detect copper ions in water. In the study, a facile method has been developed for rapid and sensitive detection of Cu2+. An interesting phenomenon has been observed that 3,3',5,5'-tetramethylbenzidine (TMB) ethanol solution can be extremely fast passed from colorless to yellow once Cu2+ ions are added. It easily occurs to us that Cu2+ can be quantitatively determined via the absorbance at 904 nm of the color changed TMB solution. More importantly, some specific anions (Cl- , Br- ) can significantly enhance the absorption intensity. Under the optimized experimental conditions, this method exhibits a good linear response range for Cu2+ from 0.5 to 100 μM, with the detection limit of 93 nM. Moreover, the possible detection principle has been explored. It is worth mentioning that the color change can be clearly observed by naked eyes for the detection of 1 μM Cu2+, which is far below the threshold limit of Cu2+ in drinking water suggested by World Health Organization. It means that this method possess great promise for on-site Cu2+ detection.

Liposomal ET-18-OCH3 Induces Cytochrome c-Mediated Apoptosis Independently of CD95 (APO-1/Fas) Signaling

Blood ◽  
1999 ◽  
Vol 94 (10) ◽  
pp. 3583-3592 ◽  
Author(s):  
Olivier Cuvillier ◽  
Eric Mayhew ◽  
Andrew S. Janoff ◽  
Sarah Spiegel
Keyword(s):  
Cytochrome C ◽  
Critical Role ◽  
Ether Lipid ◽  
Tumor Model ◽  
Model Systems ◽  
Triggered Release ◽  
Receptor System ◽  
Cd95 Ligand ◽  
Fas Signaling ◽  
Induced Apoptosis

ELL-12, a liposome formulation of the ether-lipid 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine (ET-18-OCH3), is a nonmyelosuppressive antiproliferative agent that is more effective and less toxic than the ether lipid itself in tumor model systems. We found that ELL-12 induced apoptosis in Jurkat, H9, and U-937 cells that was preceded by activation of executioner caspases. In addition, ELL-12 triggered release of cytochrome c from mitochondria to the cytoplasm before caspase-9 activation. Apoptosis, activation of caspases, and cytochromec release were blocked by Bcl-xL overexpression in Jurkat T cells, suggesting a critical role for mitochondria in ELL-12–triggered cell death. Furthermore, ELL-12 had no effect on expression of CD95 ligand, and inhibition of the Fas signaling pathway with antagonistic anti-CD95 antibody did not affect apoptosis induced by ELL-12. Hence, ELL-12 could be a promising adjunct for the treatment of tumors in addition to myelosuppressive chemotherapeutic drugs and/or those that use the CD95-ligand/receptor system to trigger apoptosis.

scholarly journals Nanoparticle-enhanced chemo-immunotherapy to trigger robust antitumor immunity

2020 ◽  
Vol 6 (35) ◽  
pp. eabc3646 ◽  
Author(s):  
Jingjing Liang ◽  
Huifang Wang ◽  
Wenxiu Ding ◽  
Jianxiang Huang ◽  
Xuefei Zhou ◽  
...  
Keyword(s):  
Triblock Copolymer ◽  
Rational Design ◽  
Antitumor Immunity ◽  
Chemotherapeutic Agent ◽  
Therapeutic Benefit ◽  
Combination Regimen ◽  
Cross Presentation ◽  
New Class ◽  
Immunosuppressive Tumor Microenvironment ◽  
Novel Strategy

Mounting evidence suggests that immunotherapies are a promising new class of anticancer therapies. However, the immunosuppressive tumor microenvironment (TME), poor immunogenicity, and off-target toxicity hinder the broader implementation of immunotherapies. Here, we describe a novel strategy combining chemotherapy and immunotherapy to modulate the TME by systemically and concurrently delivering the chemotherapeutic agent SN38 (7-ethyl-10-hydroxycamptothecin) and the STING agonist DMXAA (5,6-dimethylxanthenone-4-acetic acid) into tumors using triblock copolymer nanoparticles, named PS3D1@DMXAA, which enhances antigen cross-presentation and induces the conversion of the immunosuppressive TME to immunogenic TME through the newly found synergistic function between SN38 and STING activation. PS3D1@DMXAA thus shows potent therapeutic efficacy in three mice tumor models and elicits remarkable therapeutic benefit when combined with anti–PD-1 therapy. Our engineered nanosystem offers a rational design of an effective immunotherapy combination regimen to convert uninflamed “cold” tumors into “hot” tumors, addressing the major challenges immunotherapies faced.

scholarly journals KIF15 Promotes Proliferation and Growth of Hepatocellular Carcinoma

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Yue-Feng Sun ◽  
Hong-Li Wu ◽  
Rui-Fang Shi ◽  
Lin Chen ◽  
Chao Meng
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Critical Role ◽  
Great Promise ◽  
Cell Processes ◽  
Multiple Cell ◽  
Molecular Therapeutic ◽  
Molecular Therapeutic Targets

Liver cancer is thought as the most common human malignancy worldwide, and hepatocellular carcinoma (HCC) accounts for nearly 90% liver cancer. Due to its poor early diagnosis and limited treatment, HCC has therefore become the most lethal malignant cancers in the world. Recently, molecular targeted therapies showed great promise in the treatment of HCC, and novel molecular therapeutic targets is urgently needed. KIF15 is a microtubule-dependent motor protein involved in multiple cell processes, such as cell division. Additionally, KIF15 has been reported to participate in the growth of various types of tumors; however, the relation between KIF15 and HCC is unclear. Herein, our study investigated the possible role of KIF15 on the progression of HCC and found that KIF15 has high expression in tumor samples from HCC patients. KIF15 could play a critical role in the regulation of cell proliferation of HCC, which was proved by in vitro and in vivo assays. In conclusion, this study confirmed that KIF15 could be a novel therapeutic target for the treatment of HCC.

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