scholarly journals Erythrocyte Membrane-Enveloped Molybdenum Disulfide Nanodots for Biofilm Elimination on Implants Via Toxin Neutralization and Immune Modulation

2021 ◽  
Author(s):  
Tingwang Shi ◽  
Zesong Ruan ◽  
Jianrong Wu ◽  
Weijuan Zou ◽  
Xiaojun Cai ◽  
...  
Keyword(s):  
Molybdenum Disulfide ◽  
Erythrocyte Membrane ◽  
Tissue Damage ◽  
Immune Modulation ◽  
Near Infrared ◽  
Erythrocyte Membranes ◽  
Clinical Issue ◽  
Immunosuppressive Microenvironment

Abstract Backgrounds: Implant-related infections (IRIs) caused by bacterial biofilms remain a prevalent but tricky clinical issue, which are characterized by drug resistance, toxin impairment and immunity suppression. Recently, antimicrobial therapies based on reactive oxygen species (ROS) or hyperthermia have been developed to effectively destroy biofilms. However, all of them have failed to simultaneously focus on the immunosuppressive microenvironment of biofilms and tissue damage caused by bacterial toxins. Results Herein, we proposed a one-arrow-three-hawks strategy to orchestrate hyperthermia/ROS antibiofilm therapy, toxin neutralization and immunomodulatory therapies through engineering a bioinspired erythrocyte membrane-enveloped molybdenum disulfide nanodots (EM@MoS2) nanoplatform. In biofilm microenvironment, pore-forming toxins actively attack the erythrocyte membranes on the nanodots and be detained, thus keeping toxins away from their targets and mitigating tissue damage. Under near-infrared laser irradiation, MoS2 nanodots, with superb photothermal and peroxidase-like properties, exert a powerful synergistic antibiofilm effect. More intriguingly, we initially identified that they possess the ability to reverse the immunosuppressive microenvironment through skewing the macrophages from an anti-inflammatory phenotype to a proinflammatory phenotype, which would promote the elimination of biofilm debris and prevention of infection relapse. Systematic in vitro and in vivo evaluations have demonstrated that EM@MoS2 achieves remarkable antibiofilm effect. Conclusion The current study integrated the functions of hyperthermia/ROS therapy, virulence clearance and immune regulation, which could provide an effective paradigm for IRIs therapy.

scholarly journals The Response of Prostate Cancer to Androgen Deprivation and Irradiation Due to Immune Modulation

Cancers ◽  
2018 ◽  
Vol 11 (1) ◽  
pp. 20 ◽  
Author(s):  
Chun-Te Wu ◽  
Wen-Cheng Chen ◽  
Miao-Fen Chen
Keyword(s):  
Prostate Cancer ◽  
Immune Modulation ◽  
Treatment Resistance ◽  
Suppressor Cell ◽  
Androgen Deprivation ◽  
High Dose ◽  
Castration Resistant Prostate Cancer ◽  
Immunosuppressive Microenvironment

This study investigated changes in the immune system and the biological consequences of androgen deprivation therapy (ADT) and radiotherapy (RT) for augmenting the treatment response in prostate cancer, particularly for castration-resistant prostate cancer (CRPC). Human and murine prostate cancer cell lines were used to examine the response to ADT and RT in vitro and in vivo. Biological changes following treatment and related immune modulation in the tumor microenvironment were examined. Our results showed that CRPC cells were demonstrated to be more resistant to the RT and ADT treatments. ADT increased tumor inhibition following irradiation. The underlying changes included increased cell death, attenuated myeloid-derived suppressor cell recruitment, and an increase in the number of tumor-infiltrating T cells (TILs). Furthermore, when high-dose fractionated RT was given to the primary CRPC tumor, a smaller size of secondary non-irradiated tumor associated with increased TILs was noted in ADT-treated mice. In conclusion, treatment resistance in CRPC was associated with a more immunosuppressive microenvironment. Enhanced antitumor immunity was responsible for the augmented RT-induced tumoricidal effect induced by ADT. Immune modulation could be a promising strategy for prostate cancer, especially for metastatic CRPC.

scholarly journals Encapsulation of Photothermal Nanoparticles in Stealth and pH-Responsive Micelles for Eradication of Infectious Biofilms In Vitro and In Vivo

Nanomaterials ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 3180
Author(s):  
Ruifang Gao ◽  
Linzhu Su ◽  
Tianrong Yu ◽  
Jian Liu ◽  
Henny C. van der Mei ◽  
...  
Keyword(s):  
Tissue Damage ◽  
Near Infrared ◽  
Polymeric Micelles ◽  
Surrounding Tissue ◽  
Infection Site ◽  
Ph Responsive ◽  
Photothermal Conversion ◽  
Good Penetration

Photothermal nanoparticles can be used for non-antibiotic-based eradication of infectious biofilms, but this may cause collateral damage to tissue surrounding an infection site. In order to prevent collateral tissue damage, we encapsulated photothermal polydopamine-nanoparticles (PDA-NPs) in mixed shell polymeric micelles, composed of stealth polyethylene glycol (PEG) and pH-sensitive poly(β-amino ester) (PAE). To achieve encapsulation, PDA-NPs were made hydrophobic by electrostatic binding of indocyanine green (ICG). Coupling of ICG enhanced the photothermal conversion efficacy of PDA-NPs from 33% to 47%. Photothermal conversion was not affected by micellar encapsulation. No cytotoxicity or hemolytic effects of PEG-PAE encapsulated PDA-ICG-NPs were observed. PEG-PAE encapsulated PDA-ICG-NPs showed good penetration and accumulation in a Staphylococcus aureus biofilm. Penetration and accumulation were absent when nanoparticles were encapsulated in PEG-micelles without a pH-responsive moiety. PDA-ICG-NPs encapsulated in PEG-PAE-micelles found their way through the blood circulation to a sub-cutaneous infection site after tail-vein injection in mice, yielding faster eradication of infections upon near-infrared (NIR) irradiation than could be achieved after encapsulation in PEG-micelles. Moreover, staphylococcal counts in surrounding tissue were reduced facilitating faster wound healing. Thus, the combined effect of targeting and localized NIR irradiation prevented collateral tissue damage while eradicating an infectious biofilm.

scholarly journals Hypoxic glioma-derived exosomes promote M2-like macrophage polarization by enhancing autophagy induction

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Jianye Xu ◽  
Jian Zhang ◽  
Zongpu Zhang ◽  
Zijie Gao ◽  
Yanhua Qi ◽  
...  
Keyword(s):  
Macrophage Polarization ◽  
Autophagy Induction ◽  
Antitumor Immunotherapy ◽  
Novel Biomarkers ◽  
And Migration ◽  
Immunosuppressive Microenvironment ◽  
Proliferation And Migration ◽  
Glioma Progression

AbstractExosomes participate in intercellular communication and glioma microenvironment modulation, but the exact mechanisms by which glioma-derived exosomes (GDEs) promote the generation of the immunosuppressive microenvironment are still unclear. Here, we investigated the effects of GDEs on autophagy, the polarization of tumor-associated macrophages (TAMs), and glioma progression. Compared with normoxic glioma-derived exosomes (N-GDEs), hypoxic glioma-derived exosomes (H-GDEs) markedly facilitated autophagy and M2-like macrophage polarization, which subsequently promoted glioma proliferation and migration in vitro and in vivo. Western blot and qRT-PCR analyses indicated that interleukin 6 (IL-6) and miR-155-3p were highly expressed in H-GDEs. Further experiments showed that IL-6 and miR-155-3p induced M2-like macrophage polarization via the IL-6-pSTAT3-miR-155-3p-autophagy-pSTAT3 positive feedback loop, which promotes glioma progression. Our study clarifies a mechanism by which hypoxia and glioma influence autophagy and M2-like macrophage polarization via exosomes, which could advance the formation of the immunosuppressive microenvironment. Our findings suggest that IL-6 and miR-155-3p may be novel biomarkers for diagnosing glioma and that treatments targeting autophagy and the STAT3 pathway may contribute to antitumor immunotherapy.

scholarly journals Pharmacoinformatics and UPLC-QTOF/ESI-MS-Based Phytochemical Screening of Combretum indicum against Oxidative Stress and Alloxan-Induced Diabetes in Long–Evans Rats

Molecules ◽  
2021 ◽  
Vol 26 (15) ◽  
pp. 4634
Author(s):  
Md. Shaekh Forid ◽  
Md. Atiar Rahman ◽  
Mohd Fadhlizil Fasihi Mohd Aluwi ◽  
Md. Nazim Uddin ◽  
Tapashi Ghosh Roy ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Immune Modulation ◽  
Computational Study ◽  
Density Lipoprotein ◽  
Control Group ◽  
Esi Ms ◽  
Long Evans ◽  
Antidiabetic Effects

This research investigated a UPLC-QTOF/ESI-MS-based phytochemical profiling of Combretum indicum leaf extract (CILEx), and explored its in vitro antioxidant and in vivo antidiabetic effects in a Long–Evans rat model. After a one-week intervention, the animals’ blood glucose, lipid profile, and pancreatic architectures were evaluated. UPLC-QTOF/ESI-MS fragmentation of CILEx and its eight docking-guided compounds were further dissected to evaluate their roles using bioinformatics-based network pharmacological tools. Results showed a very promising antioxidative effect of CILEx. Both doses of CILEx were found to significantly (p < 0.05) reduce blood glucose, low-density lipoprotein (LDL), and total cholesterol (TC), and increase high-density lipoprotein (HDL). Pancreatic tissue architectures were much improved compared to the diabetic control group. A computational approach revealed that schizonepetoside E, melianol, leucodelphinidin, and arbutin were highly suitable for further therapeutic assessment. Arbutin, in a Gene Ontology and PPI network study, evolved as the most prospective constituent for 203 target proteins of 48 KEGG pathways regulating immune modulation and insulin secretion to control diabetes. The fragmentation mechanisms of the compounds are consistent with the obtained effects for CILEx. Results show that the natural compounds from CILEx could exert potential antidiabetic effects through in vivo and computational study.

scholarly journals Fibroblast activation protein targeted near infrared photoimmunotherapy (NIR PIT) overcomes therapeutic resistance in human esophageal cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ryoichi Katsube ◽  
Kazuhiro Noma ◽  
Toshiaki Ohara ◽  
Noriyuki Nishiwaki ◽  
Teruki Kobayashi ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Near Infrared ◽  
Fibroblast Activation Protein ◽  
Therapeutic Resistance ◽  
Fibroblast Activation ◽  
Human Esophageal Cancer

AbstractCancer-associated fibroblasts (CAFs) have an important role in the tumor microenvironment. CAFs have the multifunctionality which strongly support cancer progression and the acquisition of therapeutic resistance by cancer cells. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer treatment that uses a highly selective monoclonal antibody (mAb)-photosensitizer conjugate. We developed fibroblast activation protein (FAP)-targeted NIR-PIT, in which IR700 was conjugated to a FAP-specific antibody to target CAFs (CAFs-targeted NIR-PIT: CAFs-PIT). Thus, we hypothesized that the control of CAFs could overcome the resistance to conventional chemotherapy in esophageal cancer (EC). In this study, we evaluated whether EC cell acquisition of stronger malignant characteristics and refractoriness to chemoradiotherapy are mediated by CAFs. Next, we assessed whether the resistance could be rescued by eliminating CAF stimulation by CAFs-PIT in vitro and in vivo. Cancer cells acquired chemoradiotherapy resistance via CAF stimulation in vitro and 5-fluorouracil (FU) resistance in CAF-coinoculated tumor models in vivo. CAF stimulation promoted the migration/invasion of cancer cells and a stem-like phenotype in vitro, which were rescued by elimination of CAF stimulation. CAFs-PIT had a highly selective effect on CAFs in vitro. Finally, CAF elimination by CAFs-PIT in vivo demonstrated that the combination of 5-FU and NIR-PIT succeeded in producing 70.9% tumor reduction, while 5-FU alone achieved only 13.3% reduction, suggesting the recovery of 5-FU sensitivity in CAF-rich tumors. In conclusion, CAFs-PIT could overcome therapeutic resistance via CAF elimination. The combined use of novel targeted CAFs-PIT with conventional anticancer treatments can be expected to provide a more effective and sensible treatment strategy.

scholarly journals Time-Programmed Delivery of Sorafenib and Anti-CD47 Antibody via a Double-Layer-Gel Matrix for Postsurgical Treatment of Breast Cancer

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Liping Huang ◽  
Yiyi Zhang ◽  
Yanan Li ◽  
Fanling Meng ◽  
Hongyu Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Near Infrared ◽  
Immune Escape ◽  
Regulatory Protein ◽  
In Vivo Studies ◽  
Breast Cancer Patients ◽  
Thermally Responsive ◽  
Immunosuppressive Microenvironment

AbstractThe highly immunosuppressive microenvironment after surgery has a crucial impact on the recurrence and metastasis in breast cancer patients. Programmable delivery of immunotherapy-involving combinations through a single drug delivery system is highly promising, yet greatly challenging, to reverse postoperative immunosuppression. Here, an injectable hierarchical gel matrix, composed of dual lipid gel (DLG) layers with different soybean phosphatidylcholine/glycerol dioleate mass ratios, was developed to achieve the time-programmed sequential delivery of combined cancer immunotherapy. The outer layer of the DLG matrix was thermally responsive and loaded with sorafenib-adsorbed graphene oxide (GO) nanoparticles. GO under manually controlled near-infrared irradiation generated mild heat and provoked the release of sorafenib first to reeducate tumor-associated macrophages (TAMs) and promote an immunogenic tumor microenvironment. The inner layer, loaded with anti-CD47 antibody (aCD47), could maintain the gel state for a much longer time, enabling the sustained release of aCD47 afterward to block the CD47-signal regulatory protein α (SIRPα) pathway for a long-term antitumor effect. In vivo studies on 4T1 tumor-bearing mouse model demonstrated that the DLG-based strategy efficiently prevented tumor recurrence and metastasis by locally reversing the immunosuppression and synergistically blocking the CD47-dependent immune escape, thereby boosting the systemic immune responses.

scholarly journals Lactate secreted by PKM2 upregulation promotes Galectin-9-mediated immunosuppression via inhibiting NF-κB pathway in HNSCC

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Hanyue Chang ◽  
Qiaoshi Xu ◽  
Jiayi Li ◽  
Mingyu Li ◽  
Zhiyuan Zhang ◽  
...  
Keyword(s):  
Critical Role ◽  
Lactate Production ◽  
Metabolic Reprogramming ◽  
Migration And Invasion ◽  
Histone Deacetylase 3 ◽  
Proliferation And Metastasis ◽  
Immunosuppressive Microenvironment ◽  
Transcriptional Complex

AbstractPyruvate kinase M2 as a key rate-limiting enzyme in glycolysis, it plays a critical role in metabolic reprogramming and carcinogenesis. However, whether PKM2 can promote immunosuppressive microenvironment formation remains unknown in head and neck squamous cell carcinoma (HNSCC). PKM2 expression was detected using immunohistochemical staining. The biological functions of PKM2 were investigated in vitro and in vivo. Lactate production and the expression of Galectin-9, a critical immunosuppression molecule, were detected after PKM2 knockdown and overexpression in HNSCC cells. The mechanism of lactate regulating Galectin-9 expression through NF-κB signaling was explored in vitro. Overexpression of PKM2 correlates with poor prognosis in HNSCC patients. Silencing PKM2 markedly inhibits proliferation and metastasis capacity in vivo and in vitro, and vice versa. The glycolysis and glycolytic capacity are significantly decreased after PKM2 silencing. Lactate secretion induced by PKM2 significantly promotes migration and invasion capacity. Furthermore, a positive correlation between PKM2 and Galectin-9 expression is observed in HNSCC tissues. The induction of Galectin-9 expression by PKM2 can be affected by a lactate transporter inhibitor. Mechanically, lactate impeded the suppressive transcriptional complex formation of NF-κB and histone deacetylase 3 (HDAC3), which released the transcription of Galectin-9 mediated by NF-κB signaling. Our findings demonstrate that lactate produced by PKM2 upregulation promotes tumor progression and Galectin-9-mediated immunosuppression via NF-κB signaling inhibition in HNSCC, which bridges metabolism and immunosuppression. The novel PKM2-lactate-Galectin-9 axis might be a potential therapeutic target in HNSCC.

scholarly journals Molecular imaging and deep learning analysis of uMUC1 expression in response to chemotherapy in an orthotopic model of ovarian cancer

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Hongwei Zhao ◽  
Hasaan Hayat ◽  
Xiaohong Ma ◽  
Daguang Fan ◽  
Ping Wang ◽  
...  
Keyword(s):  
Neural Networks ◽  
Ovarian Cancer ◽  
Deep Learning ◽  
Cancer Progression ◽  
In Vivo Imaging ◽  
Near Infrared ◽  
Response To Therapy ◽  
Response To Chemotherapy

Abstract Artificial Intelligence (AI) algorithms including deep learning have recently demonstrated remarkable progress in image-recognition tasks. Here, we utilized AI for monitoring the expression of underglycosylated mucin 1 (uMUC1) tumor antigen, a biomarker for ovarian cancer progression and response to therapy, using contrast-enhanced in vivo imaging. This was done using a dual-modal (magnetic resonance and near infrared optical imaging) uMUC1-specific probe (termed MN-EPPT) consisted of iron-oxide magnetic nanoparticles (MN) conjugated to a uMUC1-specific peptide (EPPT) and labeled with a near-infrared fluorescent dye, Cy5.5. In vitro studies performed in uMUC1-expressing human ovarian cancer cell line SKOV3/Luc and control uMUC1low ES-2 cells showed preferential uptake on the probe by the high expressor (n = 3, p < .05). A decrease in MN-EPPT uptake by SKOV3/Luc cells in vitro due to uMUC1 downregulation after docetaxel therapy was paralleled by in vivo imaging studies that showed a reduction in probe accumulation in the docetaxel treated group (n = 5, p < .05). The imaging data were analyzed using deep learning-enabled segmentation and quantification of the tumor region of interest (ROI) from raw input MRI sequences by applying AI algorithms including a blend of Convolutional Neural Networks (CNN) and Fully Connected Neural Networks. We believe that the algorithms used in this study have the potential to improve studying and monitoring cancer progression, amongst other diseases.

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