Materials that resist nonspecific protein adsorption are needed for many applications. However, few are able to achieve ultralow fouling in complex biological milieu. Zwitterionic polymers emerge as a class of highly effective ultralow fouling materials due to their superhydrophilicity, outperforming other hydrophilic materials such as poly(ethylene glycol). Unfortunately, there are only three major classes of zwitterionic materials based on poly(phosphorylcholine), poly(sulfobetaine), and poly(carboxybetaine) currently available. Inspired by trimethylamine N-oxide (TMAO), a zwitterionic osmolyte and the most effective protein stabilizer, we here report TMAO-derived zwitterionic polymers (PTMAO) as a new class of ultralow fouling biomaterials. The nonfouling properties of PTMAO were demonstrated under highly challenging conditions. The mechanism accounting for the extraordinary hydration of PTMAO was elucidated by molecular dynamics simulations. The discovery of PTMAO polymers demonstrates the power of molecular understanding in the design of new biomimetic materials and provides the biomaterials community with another class of nonfouling zwitterionic materials.
BackgroundInfection with pathogenic Leptospira species causes serious systemic inflammation in patients. Although a few leptospiral proinflammatory molecules have been identified, Leptospira likely encodes other unidentified strong inflammation stimulators. The pathogenic L. interrogans genome encodes numerous putative hemolysin genes. Since hemolysins from other bacteria can cause inflammatory reactions, we hypothesized that leptospiral hemolysins may function as proinflammatory stimulators that contribute to the strong inflammation associated with Leptospira infection.Methodology/Principal FindingsWe first used cytokine protein microarrays for systematic analysis of serum cytokine profiles in leptospirosis patients and leptospire-infected mice. We found that IL-1β, IL-6 and TNF-α were the main proinflammatory cytokines in the sera of both the patients and the mice. We then analyzed eight putative hemolysins in L. interrogans strain Lai. The results showed that five of them, Sph1, Sph2, Sph3, HlpA and TlyA were secreted and had hemolytic activity. More importantly, these five hemolysins induced the strong production of IL-1β, IL-6 and TNF-α in human and mouse macrophages (although a bit lower in the latter). Furthermore, blockade of TLR2 or TLR4 with either antibodies or inhibitors of the NF-κB or JNK signaling pathways significantly reduced the production of hemolysin-induced IL-1β, IL-6 and TNF-α. Macrophages isolated from TLR2-, TLR4-or double TLR2-and 4-deficient mice also confirmed that the leptospiral hemolysins that induce proinflammatory cytokines are both TLR2-and TLR4-dependent.Conclusions/SignificanceOur findings demonstrate that L. interrogans secretes many hemolysins that function as powerful inducers of proinflammatory cytokines through both TLR2-and TLR4-dependent JNK and NF-κB pathways.
Owing to the fast-paced growth and cross-infiltration of oncology, immunology and molecular biology, tumor immunotherapy technology represented by immune checkpoint blockade and chimeric antigen receptor (CAR) T cell therapy has lately made remarkable advancements. In comparison with traditional chemotherapy, immunotherapy has the potential to elicit a stronger sustained antitumor immune response in those patients who have advanced malignant malignancies. In spite of the advancements made, a significant number of clinical research works have validated that an extensive proportion of cancer patients still manifest insensitivity to immunotherapy, primarily because of the immunomodulatory interactions between tumor cells and the immunosuppressive tumor microenvironment (TME), together mediating the immune tolerance of tumors and accordingly impacting the positive response to immunotherapy. The intricate immunosuppressive networks formed by stromal cells, inflammatory cells, vasculature, extracellular matrix (ECM), and their secreted cytokines in the TME, play a pivotal role in tumor immune escape. Specific blocking of inhibition pathways in the TME is expected to effectively prevent immune escape and tolerance of tumor cells in addition to their metastasis, accordingly improving the antitumor immune response at various phases of tumor growth. Emerging nanoscale targeted drug carriers truly suit this specific requirement due to their specificity, biocompatibility, and convenience of production. This review emphasizes recent attempts to remodel the tumor immune microenvironment using novel nanoparticles, which include specifically eliminating immunosuppressive cells, reprogramming immune regulatory cells, promoting inflammatory cytokines and blocking immune checkpoints. Targeted remodeling of the immunosuppressive TME using well-designed and fabricated nanoparticles provides a promising strategy for improving the effectiveness of current immunotherapy and is greatly significant.
SummaryMammalian cell entry proteins (Mces) contribute to Mycobacterium tuberculosis virulence. A mce homologue has been identified in the Leptospira interrogans genome, but its function was unknown. We showed that the mce gene is expressed only by pathogenic Leptospira strains tested. Leptospiral mce mRNA and Mce protein levels increased during infection of macrophages. The ability to infect macrophages was significantly lower in a strain with the mce gene deleted (mce
Mesenchymal stem cell (MSC) transplantation has been shown to be beneficial in treating cerebral ischemia. However, such benefit is limited by the low survival of transplanted MSCs in an ischemic microenvironment. Previous studies showed that melatonin pretreatment can increase MSC survival in the ischemic kidney. However, whether it will improve MSC survival in cerebral ischemia is unknown. Our study examined the effect of melatonin pretreatment on MSCs under ischemia-related conditions in vitro and after transplantation into ischemic rat brain. Results showed that melatonin pretreatment greatly increased survival of MSCs in vitro and reduced their apoptosis after transplantation into ischemic brain. Melatonin-treated MSCs (MT-MSCs) further reduced brain infarction and improved neurobehavioral outcomes. Angiogenesis, neurogenesis, and the expression of vascular endothelial growth factor (VEGF) were greatly increased in the MT-MSC-treated rats. Melatonin treatment increased the level of p-ERK1/2 in MSCs, which can be blocked by the melatonin receptor antagonist luzindole. ERK phosphorylation inhibitor U0126 completely reversed the protective effects of melatonin, suggesting that melatonin improves MSC survival and function through activating the ERK1/2 signaling pathway. Thus, stem cells pretreated by melatonin may represent a feasible approach for improving the beneficial effects of stem cell therapy for cerebral ischemia.
Poly(ethylene glycol) (PEG) conjugation has been the gold standard to ameliorate the pharmacokinetic (PK) and immunological profiles of proteins. PEG polymer does become immunogenic once attached to proteins, evoking PEG-specific antibody (Ab) responses. The anti-PEG Abs could cause PEGylated biologic treatments to fail and even result in lethal adverse reactions. Thus the zwitterionic poly(carboxybetaine) (PCB) has been introduced as a PEG substitute for protein modification. Addressed herein is anti-polymer Ab induction by conjugating PEG and PCB polymers to a series of carrier proteins with escalating immunogenicity. Results indicate that titers of PEG-specific Abs were quantitatively correlated to the immunogenicity of carrier proteins, whereas the generation of PCB-specific Abs was minimal and insensitive to increased protein immunogenicity. This work provides insight into the immunological properties of PEG and PCB and has far-reaching implications for the development of polymer-protein conjugates.
Background and Purpose-Netrin-1 (NT-1) stimulates endothelial cell proliferation and migration in vitro and promotes focal neovascularization in the adult brain in vivo. This in vivo study in mice investigated the effect of NT-1 hyperexpression on focal angiogenesis and long-term functional outcome after transient middle cerebral artery occlusion (tMCAO). Methods-Adeno-associated viral vectors carrying either the NT-1 gene (AAV-NT-1) or GFP (AAV-GFP) were generated and injected into the brains of separate groups of 93 mice. Seven days later, tMCAO followed by 7-28 days of reperfusion were carried out. Histological outcomes and behavioral deficits were quantified 7-28 days after tMCAO. Small cerebral vessel network and angiogenesis were assessed 28 days after tMCAO, using synchrotron radiation microangiography and immunohistochemistry. Results-Western blot and immunohistochemistry showed that on the day of tMCAO, NT-1 hyperexpression had been achieved in both normal and ischemic hemispheres. Immunofluorescence imaging showed that NT-1 expression was primarily in neurons and astrocytes. Ischemia-induced infarction in the NT-1 hyperexpression group was attenuated in comparison to saline or AAV-GFP-treated groups (PϽ0.01). Similarly, neurological deficits were greatly improved in AAV-NT-1-treated mice compared with mice in saline or AAV-GFP-treated groups (PϽ0.05). In addition, angiogenesis was increased in AAV-NT-1-treated mice compared with the other 2 groups (PϽ0.05). In vivo synchrotron radiation microangiography 28 days after tMCAO revealed more branches in AAV-NT-1-treated mice than in other groups. Conclusions-AAV-NT-1 induced NT-1 hyperexpression before tMCAO reduced infarct size, enhanced neovascularization, and improved long-term functional recovery. (Stroke. 2012;43:838-843.)
Neural stem cells (NSCs) show therapeutic potential for ischemia in young-adult animals. However, the effect of aging on NSC therapy is largely unknown. In this work, NSCs were transplanted into aged (24-month-old) and young-adult (3-month-old) rats at 1 day after stroke. Infarct volume and neurobehavioral outcomes were examined. The number of differentiated NSCs was compared in aged and young-adult ischemic rats and angiogenesis and neurogenesis were also determined. We found that aged rats developed larger infarcts than young-adult rats after ischemia (Po0.05). The neurobehavioral outcome was also worse for aged rats comparing with young-adult rats. Brain infarction and neurologic deficits were attenuated after NSC transplantation in both aged and young-adult rats. The number of survived NSCs in aged rats was similar to that of the young-adult rats (P40.05) and most of them were differentiated into glial fibrillary acidic protein þ (GFAP þ ) cells. More importantly, angiogenesis and neurogenesis were greatly enhanced in both aged and young-adult rats after transplantation compared with phosphate-buffered saline (PBS) control (Po0.05), accompanied by increased expression of vascular endothelial growth factor (VEGF). Our results showed that NSC therapy reduced ischemic brain injury, along with increased angiogenesis and neurogenesis in aged rats, suggesting that aging-related microenvironment does not preclude a beneficial response to NSCs transplantation during cerebral ischemia.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.