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1.
ACS Biomater Sci Eng ; 10(1): 442-454, 2024 Jan 08.
Article in English | MEDLINE | ID: mdl-38047725

ABSTRACT

Combinations of different therapeutic strategies, including chemotherapy (CT), chemodynamic therapy (CDT), and photothermal therapy (PTT), are needed to effectively address evolving drug resistance and the adverse effects of traditional cancer treatment. Herein, a camouflage composite nanoformulation (TCBG@PR), an antitumor agent (tubercidin, Tub) loaded into Cu-doped bioactive glasses (CBGs) and subsequently camouflaged by polydopamine (PDA), and red blood cell membranes (RBCm), was successfully constructed for targeted and synergetic antitumor therapies by combining CT of Tub, CDT of doped copper ions, and PTT of PDA. In addition, the TCBG@PRs composite nanoformulation was camouflaged with a red blood cell membrane (RBCm) to improve biocompatibility, longer blood retention times, and excellent cellular uptake properties. It integrated with long circulation and multimodal synergistic treatment (CT, CDT, and PTT) with the benefit of RBCms to avoid immune clearance for efficient targeted delivery to tumor locations, producing an "all-in-one" nanoplatform. In vivo results showed that the TCBG@PRs composite nanoformulation prolonged blood circulation and improved tumor accumulation. The combination of CT, CDT, and PTT therapies enhanced the antitumor therapeutic activity, and light-triggered drug release reduced systematic toxicity and increased synergistic antitumor effects.


Subject(s)
Nanoparticles , Neoplasms , Humans , Phototherapy/methods , Photothermal Therapy , Nanoparticles/therapeutic use , Neoplasms/drug therapy , Cell Membrane/metabolism , Cell Membrane/pathology
2.
ACS Appl Mater Interfaces ; 15(50): 58260-58273, 2023 Dec 20.
Article in English | MEDLINE | ID: mdl-38051559

ABSTRACT

Microglial cells play a critical role in glioblastoma multiforme (GBM) progression, which is considered a highly malignant brain cancer. The activation of microglia can either promote or inhibit GBM growth depending on the stage of the tumor development and on the microenvironment conditions. The current treatments for GBM have limited efficacy; therefore, there is an urgent need to develop novel and efficient strategies for drug delivery and targeting: in this context, a promising strategy consists of using nanoplatforms. This study investigates the microglial response and the therapeutic efficacy of dual-cell membrane-coated and doxorubicin-loaded hexagonal boron nitride nanoflakes tested on human microglia and GBM cells. Obtained results show promising therapeutic effects on glioma cells and an M2 microglia polarization, which refers to a specific phenotype or activation state that is associated with anti-inflammatory and tissue repair functions, highlighted through proteomic analysis.


Subject(s)
Brain Neoplasms , Glioblastoma , Humans , Microglia , Proteomics , Glioblastoma/pathology , Doxorubicin/pharmacology , Doxorubicin/therapeutic use , Brain Neoplasms/pathology , Cell Membrane/pathology , Tumor Microenvironment/physiology , Cell Line, Tumor
3.
Int J Nanomedicine ; 18: 7729-7744, 2023.
Article in English | MEDLINE | ID: mdl-38115989

ABSTRACT

Aim: To produce pH-responsive bionic high photothermal conversion nanoparticles actively targeting tumors for sensitizing photothermal therapy (PTT). Materials and Methods: The bionic nanoparticles (ICG-PEI@HM NPs) were prepared by electrostatic adsorption of indocyanine green (ICG) coupled to polyethyleneimine (PEI) and modified with tumor cell membranes. In vitro and in vivo experiments were conducted to investigate the efficacy of ICG-PEI@HM-mediated PTT. Results: The intelligent responsiveness of ICG-PEI@HM to pH promoted the accumulation of ICG and enhanced the PTT performance of ICG-PEI@HM NPs. Compared with free ICG, NPs exhibited great photothermal stability, cellular uptake, and active tumor targeting for PTT. Conclusion: ICG-PEI@HM NPs can enhance the efficacy of PTT and can be used as a new strategy for the construction of photothermal agents.


Subject(s)
Nanoparticles , Neoplasms , Humans , Photothermal Therapy , Bionics , Neoplasms/pathology , Indocyanine Green/pharmacology , Cell Membrane/pathology , Hydrogen-Ion Concentration , Cell Line, Tumor , Phototherapy
4.
ACS Biomater Sci Eng ; 9(10): 5709-5723, 2023 10 09.
Article in English | MEDLINE | ID: mdl-37713674

ABSTRACT

Spinal cord injury is an impact-induced disabling condition. A series of pathological changes after spinal cord injury (SCI) are usually associated with oxidative stress, inflammation, and apoptosis. These pathological changes eventually lead to paralysis. The short half-life and low bioavailability of many drugs also limit the use of many drugs in SCI. In this study, we designed nanovesicles derived from macrophages encapsulating selenium nanoparticles (SeNPs) and metformin (SeNPs-Met-MVs) to be used in the treatment of SCI. These nanovesicles can cross the blood-spinal cord barrier (BSCB) and deliver SeNPs and Met to the site of injury to exert anti-inflammatory and reactive oxygen species scavenging effects. Transmission electron microscopy (TEM) images showed that the SeNPs-Met-MVs particle size was approximately 125 ± 5 nm. Drug release assays showed that Met exhibited sustained release after encapsulation by the macrophage cell membrane. The cumulative release was approximately 80% over 36 h. In vitro cellular experiments and in vivo animal experiments demonstrated that SeNPs-Met-MVs decreased reactive oxygen species (ROS) and malondialdehyde (MDA) levels, increased superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities, and reduced the expression of inflammatory (TNF-α, IL-1ß, and IL-6) and apoptotic (cleaved caspase-3) cytokines in spinal cord tissue after SCI. In addition, motor function in mice was significantly improved after SeNPs-Met-MVs treatment. Therefore, SeNPs-Met-MVs have a promising future in the treatment of SCI.


Subject(s)
Metformin , Nanoparticles , Selenium , Spinal Cord Injuries , Mice , Animals , Selenium/pharmacology , Selenium/therapeutic use , Reactive Oxygen Species/metabolism , Metformin/pharmacology , Metformin/therapeutic use , Spinal Cord Injuries/drug therapy , Spinal Cord Injuries/metabolism , Spinal Cord Injuries/pathology , Antioxidants/pharmacology , Antioxidants/therapeutic use , Antioxidants/metabolism , Macrophages/metabolism , Macrophages/pathology , Cell Membrane/metabolism , Cell Membrane/pathology
5.
Int J Mol Sci ; 24(14)2023 Jul 17.
Article in English | MEDLINE | ID: mdl-37511311

ABSTRACT

Ninjurin 1 (NINJ1) is a double-transmembrane cell-surface protein that might mediate plasma membrane rupture (PMR) and the diffusion of inflammatory factors. PMR is a characteristic of acinar cell injury in severe acute pancreatitis (SAP). However, the involvement of NINJ1 in mediating the PMR of acinar cells in SAP is currently unclear. Our study has shown that NINJ1 is expressed in acinar cells, and the expression is significantly upregulated in sodium-taurocholate-induced SAP. The knockout of NINJ1 delays PMR in acinar cells and alleviates SAP. Moreover, we observed that NINJ1 expression is mediated by Ca2+ concentration in acinar cells. Importantly, we found that Ca2+ overload drives mitochondrial stress to upregulate the P53/NINJ1 pathway, inducing PMR in acinar cells, and amlodipine, a Ca2+ channel inhibitor, can reduce the occurrence of PMR by decreasing the concentration of Ca2+. Our results demonstrate the mechanism by which NINJ1 induces PMR in SAP acinar cells and provide a potential new target for treatment of SAP.


Subject(s)
Acinar Cells , Calcium , Cell Membrane , Pancreatitis , Tumor Suppressor Protein p53 , Humans , Acinar Cells/metabolism , Acinar Cells/pathology , Acute Disease , Calcium/metabolism , Calcium, Dietary/metabolism , Cell Adhesion Molecules, Neuronal/metabolism , Cell Membrane/metabolism , Cell Membrane/pathology , Nerve Growth Factors/metabolism , Pancreatitis/metabolism , Pancreatitis/pathology , Pancreatitis/physiopathology , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism
6.
Med ; 4(7): 398-400, 2023 Jul 14.
Article in English | MEDLINE | ID: mdl-37453414

ABSTRACT

Chimeric antigen receptor (CAR)-based cellular therapies have achieved remarkable success against hematologic malignancies, but their application against solid tumors remains challenging. In this issue, Goulding et al.1 describe a unique CAR natural killer (NK) cell platform with pan-cancer activity via preservation and recognition of stress ligands on tumor cell membranes.


Subject(s)
Neoplasms , Humans , Ligands , Neoplasms/therapy , Killer Cells, Natural/metabolism , Killer Cells, Natural/pathology , Immunotherapy, Adoptive , Cell Membrane/pathology
7.
Nature ; 618(7967): 1072-1077, 2023 Jun.
Article in English | MEDLINE | ID: mdl-37196676

ABSTRACT

Plasma membrane rupture (PMR) in dying cells undergoing pyroptosis or apoptosis requires the cell-surface protein NINJ11. PMR releases pro-inflammatory cytoplasmic molecules, collectively called damage-associated molecular patterns (DAMPs), that activate immune cells. Therefore, inhibiting NINJ1 and PMR may limit the inflammation that is associated with excessive cell death. Here we describe an anti-NINJ1 monoclonal antibody that specifically targets mouse NINJ1 and blocks oligomerization of NINJ1, preventing PMR. Electron microscopy studies showed that this antibody prevents NINJ1 from forming oligomeric filaments. In mice, inhibition of NINJ1 or Ninj1 deficiency ameliorated hepatocellular PMR induced with TNF plus D-galactosamine, concanavalin A, Jo2 anti-Fas agonist antibody or ischaemia-reperfusion injury. Accordingly, serum levels of lactate dehydrogenase, the liver enzymes alanine aminotransaminase and aspartate aminotransferase, and the DAMPs interleukin 18 and HMGB1 were reduced. Moreover, in the liver ischaemia-reperfusion injury model, there was an attendant reduction in neutrophil infiltration. These data indicate that NINJ1 mediates PMR and inflammation in diseases driven by aberrant hepatocellular death.


Subject(s)
Antibodies, Monoclonal , Cell Membrane , Inflammation , Liver , Nerve Growth Factors , Reperfusion Injury , Animals , Mice , Alanine Transaminase , Alarmins , Antibodies, Monoclonal/immunology , Aspartate Aminotransferases , Cell Adhesion Molecules, Neuronal/antagonists & inhibitors , Cell Adhesion Molecules, Neuronal/deficiency , Cell Adhesion Molecules, Neuronal/immunology , Cell Adhesion Molecules, Neuronal/ultrastructure , Cell Death , Cell Membrane/pathology , Cell Membrane/ultrastructure , Concanavalin A , Galactosamine , Hepatocytes/pathology , Hepatocytes/ultrastructure , Inflammation/pathology , Lactate Dehydrogenases , Liver/pathology , Microscopy, Electron , Nerve Growth Factors/antagonists & inhibitors , Nerve Growth Factors/deficiency , Nerve Growth Factors/immunology , Nerve Growth Factors/ultrastructure , Neutrophil Infiltration , Reperfusion Injury/pathology
8.
Nature ; 618(7967): 1065-1071, 2023 Jun.
Article in English | MEDLINE | ID: mdl-37198476

ABSTRACT

Eukaryotic cells can undergo different forms of programmed cell death, many of which culminate in plasma membrane rupture as the defining terminal event1-7. Plasma membrane rupture was long thought to be driven by osmotic pressure, but it has recently been shown to be in many cases an active process, mediated by the protein ninjurin-18 (NINJ1). Here we resolve the structure of NINJ1 and the mechanism by which it ruptures membranes. Super-resolution microscopy reveals that NINJ1 clusters into structurally diverse assemblies in the membranes of dying cells, in particular large, filamentous assemblies with branched morphology. A cryo-electron microscopy structure of NINJ1 filaments shows a tightly packed fence-like array of transmembrane α-helices. Filament directionality and stability is defined by two amphipathic α-helices that interlink adjacent filament subunits. The NINJ1 filament features a hydrophilic side and a hydrophobic side, and molecular dynamics simulations show that it can stably cap membrane edges. The function of the resulting supramolecular arrangement was validated by site-directed mutagenesis. Our data thus suggest that, during lytic cell death, the extracellular α-helices of NINJ1 insert into the plasma membrane to polymerize NINJ1 monomers into amphipathic filaments that rupture the plasma membrane. The membrane protein NINJ1 is therefore an interactive component of the eukaryotic cell membrane that functions as an in-built breaking point in response to activation of cell death.


Subject(s)
Cell Adhesion Molecules, Neuronal , Cell Death , Cell Membrane , Nerve Growth Factors , Animals , Humans , Mice , Cell Adhesion Molecules, Neuronal/chemistry , Cell Adhesion Molecules, Neuronal/genetics , Cell Adhesion Molecules, Neuronal/metabolism , Cell Adhesion Molecules, Neuronal/ultrastructure , Cell Membrane/metabolism , Cell Membrane/pathology , Cell Membrane/ultrastructure , Cryoelectron Microscopy , Nerve Growth Factors/chemistry , Nerve Growth Factors/genetics , Nerve Growth Factors/metabolism , Nerve Growth Factors/ultrastructure , Mutagenesis, Site-Directed , Biopolymers/chemistry , Biopolymers/genetics , Biopolymers/metabolism
9.
Mini Rev Med Chem ; 23(15): 1535-1559, 2023.
Article in English | MEDLINE | ID: mdl-36740792

ABSTRACT

Tumors are a major cause of human mortality worldwide, and the rapid development of nanomaterials (NMs) for tumor therapy and drug delivery has provided new treatment methods. However, NMs' high immunogenicity, short circulation time, and low specificity limit their application in tumor therapy. In recent years, bionanomaterials using cell membranes have emerged to overcome the shortcomings of monomeric NMs. Cell membrane-encapsulated NMs extracted from multiple cells not only retain the physicochemical properties of NMs but also inherit the biological functions of the source cells, aiding in drug delivery. The combination of the cell membrane and drug-loading NMs offers an efficient and targeted drug delivery system tailored to the tumor microenvironment. The research and application of this method have been widely carried out in the academic field of tumor diagnosis and treatment. This review presents the recent research progress of cell membrane-coated NMs as drug carriers in tumor therapy, including cell membrane extraction methods, encapsulation strategies, and the applications of cell membrane-encapsulated NMs in tumor therapy. We believe that biomimetic nanomaterials will be a promising and novel anticancer strategy in the future, and their wide application will certainly bring vitality to the field of tumor diagnosis and treatment. The combination of membrane and drug-loading nanomaterials embodies a highly efficient and target drug delivery system tailored to the tumor microenvironment, which broadens a new path of drug delivery for future cancer treatment. Meanwhile, it is also a perfect combination and application of biomedical nanomaterials, which is of great significance.


Subject(s)
Nanostructures , Neoplasms , Humans , Nanostructures/therapeutic use , Nanostructures/chemistry , Neoplasms/drug therapy , Neoplasms/pathology , Drug Delivery Systems , Drug Carriers/chemistry , Cell Membrane/pathology , Tumor Microenvironment
10.
Nat Rev Clin Oncol ; 20(1): 33-48, 2023 01.
Article in English | MEDLINE | ID: mdl-36307534

ABSTRACT

Traditional cancer therapeutics, such as chemotherapies, are often limited by their non-specific nature, causing harm to non-malignant tissues. Over the past several decades, nanomedicine researchers have sought to address this challenge by developing nanoscale platforms capable of more precisely delivering drug payloads. Cell membrane-coated nanoparticles (CNPs) are an emerging class of nanocarriers that have demonstrated considerable promise for biomedical applications. Consisting of a synthetic nanoparticulate core camouflaged by a layer of naturally derived cell membranes, CNPs are adept at operating within complex biological environments; depending on the type of cell membrane utilized, the resulting biomimetic nanoformulation is conferred with several properties typically associated with the source cell, including improved biocompatibility, immune evasion and tumour targeting. In comparison with traditional functionalization approaches, cell membrane coating provides a streamlined method for creating multifunctional and multi-antigenic nanoparticles. In this Review, we discuss the history and development of CNPs as well as how these platforms have been used for cancer therapy. The application of CNPs for drug delivery, phototherapy and immunotherapy will be described in detail. Translational efforts are currently under way and further research to address key areas of need will ultimately be required to facilitate the successful clinical adoption of CNPs.


Subject(s)
Nanoparticles , Neoplasms , Humans , Drug Delivery Systems/methods , Cell Membrane/metabolism , Cell Membrane/pathology , Neoplasms/therapy , Pharmaceutical Preparations , Nanoparticles/therapeutic use
11.
Cancer Immunol Immunother ; 72(3): 769-774, 2023 Mar.
Article in English | MEDLINE | ID: mdl-35988132

ABSTRACT

NK cells, especially FDA-approved NK-92 cells, could be used for TCR engineering owing to their specialized cytotoxicity against tumors, safety profile and potential use as an off-the-shelf cellular therapy. The TCR complex requires assembly of TCR- α/ ß chains with CD3 molecules (CD3δ, CD3γ, CD3ε, CD3ζ) to be correctly expressed at the cell membrane, and yet NK cells lack expression of these CD3 subunits besides CD3ζ. Since transmembrane regions of TCR α and ß chains are involved in TCR complex assembly, transmembrane regions of TCR replaced by CD28 transmembrane domain could result in the expression of TCR independent of its companion CD3 subunits. However, since the absence of CD3 signaling components can influence the transmission of TCR signals to NK cells, it is necessary to add the signaling molecules of NK cells followed by CD28 transmembrane domain. Both CD3ζ and DAP10 play an important role in the activation and cytotoxicity of NK cells; moreover, 2B4 and 4-1BB are the main costimulatory molecules in NK cells. Therefore, we designed a chimeric TCR that consisted of the extracellular domains of the TCR α and ß chains specific for NYESO-1 fused to the CD28 transmembrane domain followed by the 41BB and CD3ζ signaling domains as well as the 2B4 and DAP10 signaling domain, respectively. The chimeric TCR genetically engineered NK-92 cells exhibit antigen-specific recognition and lysis of tumor cells both in vitro and in vivo. In addition, TCR-28-2B10/BBζ can be feasibly expressed in primary NK cells and exhibit antigen-reactive recognition and effect function. The overall encouraging data highlight the value of NK-92 cells and primary NK cells engineered to express therapeutic chimeric TCR for adoptive immunotherapies.


Subject(s)
CD28 Antigens , Neoplasms , Humans , Killer Cells, Natural/metabolism , CD3 Complex/metabolism , Neoplasms/pathology , Receptors, Antigen, T-Cell, alpha-beta/metabolism , Cell Membrane/metabolism , Cell Membrane/pathology
12.
F1000Res ; 11: 245, 2022.
Article in English | MEDLINE | ID: mdl-35646332

ABSTRACT

Background: The loss of E-cadherin expression and the induction of N-cadherin are known as hallmarks of the epithelial-to-mesenchymal transition, an essential initial step in the process of metastasis in solid tumors. Although several studies have reported expressions of these cadherins in patients with multiple myeloma (MM), their clinical significance is unknown as MM cells are non-epithelial. Methods: In this study, we examined the expression of E- and N-cadherins by immunohistochemistry using bone marrow (BM) biopsy specimens from 31 newly diagnosed MM patients and in subsequent biopsy specimens from six of these. Results: Negative E-cadherin expression on BM myeloma cell membranes was significantly associated with the presence of soft-tissue masses arising from bone lesions and breaking through the cortical bone, referred to as extramedullary disease (EMD). Conclusions: Given the aggressive nature of EMD, our study suggests that screening for E-cadherin using BM immunohistochemistry is one measure that could predict the development of EMD in patients with MM.


Subject(s)
Multiple Myeloma , Humans , Bone Marrow/pathology , Cadherins , Epithelial-Mesenchymal Transition , Cell Membrane/metabolism , Cell Membrane/pathology
13.
Int J Mol Sci ; 23(11)2022 May 27.
Article in English | MEDLINE | ID: mdl-35682696

ABSTRACT

Identification of alternative attenuation targets of Mycobacterium tuberculosis (Mtb) is pivotal for designing new candidates for live attenuated anti-tuberculosis (TB) vaccines. In this context, the CtpF P-type ATPase of Mtb is an interesting target; specifically, this plasma membrane enzyme is involved in calcium transporting and response to oxidative stress. We found that a mutant of MtbH37Rv lacking ctpF expression (MtbΔctpF) displayed impaired proliferation in mouse alveolar macrophages (MH-S) during in vitro infection. Further, the levels of tumor necrosis factor and interferon-gamma in MH-S cells infected with MtbΔctpF were similar to those of cells infected with the parental strain, suggesting preservation of the immunogenic capacity. In addition, BALB/c mice infected with Mtb∆ctpF showed median survival times of 84 days, while mice infected with MtbH37Rv survived 59 days, suggesting reduced virulence of the mutant strain. Interestingly, the expression levels of ctpF in a mouse model of latent TB were significantly higher than in a mouse model of progressive TB, indicating that ctpF is involved in Mtb persistence in the dormancy state. Finally, the possibility of complementary mechanisms that counteract deficiencies in Ca2+ transport mediated by P-type ATPases is suggested. Altogether, our results demonstrate that CtpF could be a potential target for Mtb attenuation.


Subject(s)
Mycobacterium tuberculosis , Tuberculosis , Animals , Calcium , Calcium-Transporting ATPases , Cell Membrane/pathology , Mice , Tuberculosis/microbiology , Virulence/genetics
14.
Transpl Immunol ; 71: 101547, 2022 04.
Article in English | MEDLINE | ID: mdl-35121160

ABSTRACT

BACKGROUND: Eosinophilic gastroenteritis is a rare gastrointestinal disease that is characterized by diffuse or localized eosinophil infiltration in the gastrointestinal tract, and is accompanied by increased peripheral blood eosinophils. Herein, a case of plasma membrane lesion-type total intestinal eosinophil enteritis is reported. CASE PRESENTATION: We report on a 20-year-old male patient who was admitted to the hospital with "abdominal distension for 15 days". The infiltration of a large number of eosinophils was found by conducting an intestinal biopsy, routine ascites examination, blood routine, smear test, and a bone marrow puncture. A special feature of this patient was that a large number of eosinophils were found in the duodenum, small intestine, and colon. The final diagnosis was plasma membrane lesion type total intestinal eosinophilic enteritis. After four weeks of prednisone treatment, the symptoms disappeared completely and the entire intestinal mucosa was endoscopically observed as smooth. CONCLUSION: Clinical practitioners must pay attention to gastrointestinal endoscopy and biopsy pathology results for patients presenting with abdominal distention and ascites. Combined with an abnormal increase of eosinophils in ascites, bone marrow, and peripheral blood, clinical practitioners must be highly vigilant against plasma membrane lesion type total intestinal eosinophilic enteritis.


Subject(s)
Enteritis , Eosinophilia , Adult , Ascites/complications , Cell Membrane/pathology , Enteritis/complications , Enteritis/diagnosis , Enteritis/drug therapy , Eosinophilia/complications , Eosinophilia/pathology , Gastritis , Humans , Male , Young Adult
15.
Article in English | MEDLINE | ID: mdl-32865696

ABSTRACT

Ion channels are key regulators of cancer cell pathophysiology. They contribute to a variety of processes such as maintenance of cellular osmolarity and membrane potential, motility (via interactions with the cytoskeleton), invasion, signal transduction, transcriptional activity and cell cycle progression, leading to tumour progression and metastasis. Ion channels thus represent promising targets for cancer therapy. Ion channels are attractive targets because many of them are expressed at the plasma membrane and a broad range of existing inhibitors are already in clinical use for other indications. However, many of the ion channels identified in cancer cells are also active in healthy normal cells, so there is a risk that certain blockers may have off-target effects on normal physiological function. This review describes recent research advances into ion channel inhibitors as anticancer therapeutics. A growing body of evidence suggests that a range of existing and novel Na+, K+, Ca2+ and Cl- channel inhibitors may be effective for suppressing cancer cell proliferation, migration and invasion, as well as enhancing apoptosis, leading to suppression of tumour growth and metastasis, either alone or in combination with standard-of-care therapies. The majority of evidence to date is based on preclinical in vitro and in vivo studies, although there are several examples of ion channel-targeting strategies now reaching early phase clinical trials. Given the strong links between ion channel function and regulation of tumour growth, metastasis and chemotherapy resistance, it is likely that further work in this area will facilitate the development of new therapeutic approaches which will reach the clinic in the future.


Subject(s)
Neoplasms , Cell Membrane/metabolism , Cell Membrane/pathology , Cell Proliferation , Humans , Ion Channels , Neoplasms/pathology , Signal Transduction
16.
Neuropathol Appl Neurobiol ; 48(2): e12774, 2022 02.
Article in English | MEDLINE | ID: mdl-34811795

ABSTRACT

AIMS: Astrocytes adapt to acute acid stress. Intriguingly, cancer cells with astrocytic differentiation thrive even better in an acidic microenvironment. How changes in extracellular pH (pHe) are sensed and measured by the cell surface assemblies that first intercept the acid stress, and how this information is relayed downstream for an appropriate survival response remains largely uncharacterized. METHODS: In vitro cell-based studies were combined with an in vivo animal model to delineate the machinery involved in pH microenvironment sensing and generation of mechanoadaptive responses in normal and neoplastic astrocytes. The data was further validated on patient samples from acidosis driven ischaemia and astrocytic tumour tissues. RESULTS: We demonstrate that low pHe is perceived and interpreted by cells as mechanical stress. GM3 acts as a lipid-based pH sensor, and in low pHe, its highly protonated state generates plasma membrane deformation stress which activates the IRE1-sXBP1-SREBP2-ACSS2 response axis for cholesterol biosynthesis and surface trafficking. Enhanced surface cholesterol provides mechanical tenacity and prevents acid-mediated membrane hydrolysis, which would otherwise result in cell leakage and death. CONCLUSIONS: In summary, activating these lipids or the associated downstream machinery in acidosis-related neurodegeneration may prevent disease progression, while specifically suppressing this key mechanical 'sense-respond' axis should effectively target astrocytic tumour growth.


Subject(s)
Astrocytes/pathology , Astrocytoma/pathology , Stress, Mechanical , Tumor Microenvironment , Animals , Astrocytes/metabolism , Astrocytoma/metabolism , Cell Line, Tumor , Cell Membrane/metabolism , Cell Membrane/pathology , Humans , Hydrogen-Ion Concentration
17.
J Antibiot (Tokyo) ; 75(1): 29-39, 2022 01.
Article in English | MEDLINE | ID: mdl-34824374

ABSTRACT

Polymyxin B (PMB) is an essential antibiotic active against multidrug-resistant bacteria, such as multidrug-resistant Pseudomonas aeruginosa (MDRP). However, the clinical use of PMB is limited, because PMB causes serious side effects, such as nephrotoxicity and neurotoxicity, probably due to its cytotoxic activity. However, cytotoxic mechanisms of PMB are poorly understood. In this study, we found that macrophages are particularly sensitive to PMB, when compared with other types of cells, including fibroblasts and proximal tubule (PT) cells. Of note, PMB-induced necrosis of macrophages allowed passive release of high mobility group box 1 (HMGB1). Moreover, upon exposure of PMB to macrophages, the innate immune system mediated by the NLR family pyrin domain containing 3 (NLRP3) inflammasome that promotes the release of pro-inflammatory cytokines such as interleukin-1ß (IL-1ß) was stimulated. Interestingly, PMB-induced IL-1ß release occurred in the absence of the pore-forming protein gasdermin D (GSDMD), which supports the idea that PMB causes plasma membrane rupture accompanying necrosis. Emerging evidence has suggested that both HMGB1 and IL-1ß released from macrophages contribute to excessive inflammation that promote pathogenesis of various diseases, including nephrotoxicity and neurotoxicity. Therefore, these biochemical properties of PMB in macrophages may be associated with the induction of the adverse organ toxicity, which provides novel insights into the mechanisms of PMB-related side effects.


Subject(s)
Anti-Bacterial Agents/toxicity , Inflammation/chemically induced , Irritants/toxicity , Macrophages/drug effects , Polymyxin B/toxicity , Cell Line , Cell Membrane/pathology , Fibroblasts/drug effects , HMGB1 Protein/genetics , Humans , Immunity, Innate , Inflammasomes , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Kidney Tubules, Proximal/cytology , Kidney Tubules, Proximal/drug effects , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Necrosis , Phosphate-Binding Proteins/genetics , Phosphate-Binding Proteins/metabolism , Pore Forming Cytotoxic Proteins/genetics , Pore Forming Cytotoxic Proteins/metabolism
18.
Bioengineered ; 12(2): 12708-12721, 2021 12.
Article in English | MEDLINE | ID: mdl-34898368

ABSTRACT

Liver cancer is an aggressive malignancy with exhibits both high mortality and morbidity. The current treatment options are associated with several limitations, novel specific anti-cancer drugs are urgently needed to improve liver cancer treatment. In this study, a new peptide KK-64 was designed, and it showed strong cytotoxicity against liver cancer cells. To obtain the tumor targeting property, a plasmid that contains KK-64 DNA fragment and driven by human telomerase reverse transcriptase (hTERT) promoter was constructed. pcTERT-kk-64 plasmid was found to specifically inhibit the viability of liver cancer cells HepG2, induce substantial apoptosis as well as damage to the cell membranes, but had minimal effects toward normal liver HL-7702 cells. Furthermore, pcTERT-kk-64 plasmids was also noted to significantly attenuate migration and invasion of HepG2 cells. The anti-tumor effect of pcTERT-kk-64 plasmid was also observed in H22 cell-bearing mice, and it appeared to cause significant tumor regression, trigger tumor cell apoptosis, and infiltrate cytotoxicity T cells to the tumor tissues after plasmids injection. Thus, pcTERT-kk-64 plasmids showed both strong cytotoxicity and tumor selectivity in vitro and in tumor-bearing mice in liver cancer models.


Subject(s)
Cell Membrane/pathology , Genetic Therapy , Liver Neoplasms/therapy , Peptides/therapeutic use , Promoter Regions, Genetic , T-Lymphocytes/immunology , Telomerase/genetics , Animals , Apoptosis , Cell Death , Cell Line, Tumor , Cell Membrane/metabolism , Cell Movement/genetics , Cell Proliferation , Humans , Male , Mice, Inbred BALB C , Neoplasm Invasiveness , Peptides/chemistry , Plasmids/metabolism , Protein Structure, Secondary
19.
Microbiol Spectr ; 9(3): e0127821, 2021 12 22.
Article in English | MEDLINE | ID: mdl-34908430

ABSTRACT

Malaria parasites induce morphological and biochemical changes in the membranes of parasite-infected red blood cells (iRBCs) for propagation. Artemisinin combination therapies are the first-line antiplasmodials in countries of endemicity. However, the mechanism of action of artemisinin is unclear, and drug resistance decreases long-term efficacy. To understand whether artemisinin targets or interacts with iRBC membrane proteins, this study investigated the molecular changes caused by dihydroartemisinin (DHA), an artemisinin derivative, in Plasmodium falciparum 3D7 using a combined transcriptomic and membrane proteomic profiling approach. Optical microscopy and scanning electron microscopy showed that DHA can cause morphological variation in the iRBC membrane. We identified 125 differentially expressed membrane proteins, and functional analysis indicated structural molecule activity and protein export as key biological functions of the two omics studies. DHA treatment decreased the expression of var gene variants PF3D7_0415700 and PF3D7_0900100 dose-dependently. Western blotting and immunofluorescence analysis showed that DHA treatment downregulates the var gene encoding P. falciparum erythrocyte membrane protein-1 (pfEMP1). pfEMP1 knockout significantly increased artemisinin sensitivity. Results showed that pfEMP1 might be involved in the antimalarial mechanism of action of DHA and pfEMP1 or its regulated factors may be further exploited in antiparasitic drug design. The findings are beneficial for elucidating the potential effects of DHA on iRBC membrane proteins and developing new drugs targeting iRBC membrane. IMPORTANCE Malaria parasites induce morphological and biochemical changes in the membranes of parasite-infected red blood cells (iRBCs) for propagation, with artemisinin combination therapies as the first-line treatments. To understand whether artemisinin targets or interacts with iRBC membrane proteins, this study investigated the molecular changes caused by dihydroartemisinin (DHA), an artemisinin derivative, in Plasmodium falciparum 3D7 using a combined transcriptomic and membrane proteomic profiling approach. We found that DHA can cause morphological changes of iRBC membrane. Structural molecule activity and protein export are considered to be the key biological functions based on the two omics studies. pfEMP1 might be involved in the DHA mechanism of action. pfEMP1 or its regulated factors may be further exploited in antiparasitic drug design. The findings are beneficial for elucidating the potential effects of DHA on iRBC membrane proteins and developing new antimalarial drugs targeting iRBC membrane.


Subject(s)
Antimalarials/pharmacology , Artemisinins/pharmacology , Cell Membrane/pathology , Erythrocytes/parasitology , Membrane Proteins/metabolism , Plasmodium falciparum/drug effects , Erythrocytes/metabolism , Erythropoietin/genetics , Gene Expression/drug effects , Gene Expression Profiling , Microscopy, Electron, Scanning , Peptides, Cyclic/genetics , Plasmodium falciparum/genetics , Plasmodium falciparum/growth & development , Proteomics , Protozoan Proteins/biosynthesis , Transcriptome/genetics
20.
Molecules ; 26(19)2021 Sep 27.
Article in English | MEDLINE | ID: mdl-34641398

ABSTRACT

Due to the strong drug resistance of Pseudomonas aeruginosa (P. aeruginosa), the inhibition effects of conventional disinfectants and antibiotics are not obvious. Juglone extracted from discarded walnut husk, as a kind of plant-derived antimicrobial agent, has the advantages of naturalness, high efficiency, and low residue, with a potential role in the inhibition of P. aeruginosa. This study elucidated the inhibitory effect of juglone on the growth of plankton and the formation of P. aeruginosa biofilm. The results showed that juglone (35 µg/mL) had an irreversible inhibitory effect on P. aeruginosa colony formation (about 107 CFU/mL). The integrity and permeability of the cell membrane were effectively destroyed, accompanied by disorder of the membrane permeability, mass leakage of the cytoplasm, and ATP consumption. Further studies manifested that juglone could induce the abnormal accumulation of ROS in cells and block the formation of the cell membrane. In addition, RT-qPCR showed that juglone could effectively block the expression of five virulence genes and two genes involved in the production of extracellular polymers, thereby reducing the toxicity and infection of P. aeruginosa and preventing the production of extracellular polymers. This study can provide support for the innovation of antibacterial technology toward P. aeruginosa in food.


Subject(s)
Anti-Bacterial Agents/pharmacology , Bacterial Proteins/metabolism , Biofilms/growth & development , Cell Membrane/drug effects , Gene Expression Regulation, Bacterial/drug effects , Naphthoquinones/pharmacology , Pseudomonas aeruginosa/drug effects , Bacterial Proteins/genetics , Biofilms/drug effects , Cell Membrane/pathology , Cytotoxins/pharmacology , Polymers/metabolism , Pseudomonas aeruginosa/growth & development , Pseudomonas aeruginosa/metabolism , Quorum Sensing , Virulence
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