Dendritic cells (DCs) are specialized immune sentinels that play key role in maintaining immune homeostasis by efficiently regulating the delicate balance between protective immunity and tolerance to ...self. Although DCs respond to maturation signals present in the surrounding milieu, multiple layers of suppression also co-exist that reduce the infringement of tolerance against self-antigens. These tolerance inducing properties of DCs are governed by their origin and a range of other factors including distribution, cytokines, growth factors, and transcriptional programing, that collectively impart suppressive functions to these cells. DCs directing tolerance secrete anti-inflammatory cytokines and induce naïve T cells or B cells to differentiate into regulatory T cells (Tregs) or B cells. In this review, we provide a detailed outlook on the molecular mechanisms that induce functional specialization to govern central or peripheral tolerance. The tolerance-inducing nature of DCs can be exploited to overcome autoimmunity and rejection in graft transplantation.
•Mesoporous silica-coated superparamagnetic manganese ferrite nanoparticles were synthesized.•Nanoparticles combined targeting, imaging and therapeutic ability in a single entity.•Drug loaded ...nanoparticles exhibited cytotoxicity to cancer cells.•Nanoparticles performed as superior MRI contrast agent for cancer cells.
Multifunctional mesoporous silica-coated superparamagnetic manganese ferrite (MnFe2O4) nanoparticles (M-MSN) were synthesized and evaluated for targeted drug delivery and magnetic resonance imaging (MRI) applications. MnFe2O4 nanoparticles were prepared by solvothermal route and were silica-coated by surface silylation using sol–gel reactions. Subsequently, silylation was done using (3-aminopropyl)triethoxysilane in presence of a surfactant (CTAB), followed by selective etching of the surfactant molecules that resulted in amine-functionalized superparamagnetic nanoparticles (NH2-MSN). Further modification of the surface of the NH2-MSN with targeting (folate) or fluorescent (RITC) molecules resulted in M-MSN. The formation of the M-MSN was proved by several characterization techniques viz. XRD, XPS, HRTEM, FESEM, VSM, BET surface area measurement, FTIR, and UV–Vis spectroscopy. The M-MSN were loaded with anticancer drug Doxorubicin and the efficacy of the DOX loaded M-MSN was evaluated through in vitro cytotoxicity, fluorescence microscopy, and apoptosis studies. The in vivo biocompatibility of the M-MSN was demonstrated in a mice-model system. Moreover, the M-MSN also acted as superior MRI contrast agent owing to a high magnetization value as well as superparamagnetic behavior at room temperature. These folate-conjugated nanoparticles (FA-MSN) exhibited stronger T2-weighted MRI contrast towards HeLa cells as compared to the nanoparticles without folate conjugation, justifying their potential importance in MRI based diagnosis of cancer. Such M-MSN with a magnetic core required for MRI imaging, a porous shell for carrying drug molecules, a targeting moeity for cancer cell specificity and a fluorescent molecule for imaging, all integrated into a single system, may potentially serve as an excellent material in biomedical applications.
Targeted and efficient delivery of therapeutics to tumor cells is one of the key issues in cancer therapy. In the present work, we report a temperature and pH dual responsive core–shell nanoparticles ...comprising smart polymer shell coated on magnetic nanoparticles as an anticancer drug carrier and cancer cell-specific targeting agent. Magnetite nanoparticles (MNPs), prepared by a simple coprecipitation method, was surface modified by introducing amine groups using 3-aminopropyltriethoxysilane. Dual-responsive poly(N-isopropylacrylamide)-block-poly(acrylic acid) copolymer, synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization, was then attached to the amine-functionalized MNPs via EDC/NHS method. Further, to accomplish cancer-specific targeting properties, folic acid was tethered to the surface of the nanoparticles. Thereafter, rhodamine B isothiocyanate was conjugated to endow fluorescent property to the MNPs required for cellular imaging applications. The nanoparticles were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), selected area electron diffraction (SAED), field emission scanning electron microscopy (FESEM), energy-dispersive X-ray spectroscopy (EDX), thermogravimetric analysis (TGA), zeta potential, vibrating sample magnetometer (VSM), X-ray photoelectron spectroscopy (XPS) measurements, and FTIR, UV–vis spectral analysis. Doxorubicin (DOX), an anticancer drug used for the present study, was loaded into the nanoparticles and its release behavior was subsequently studied. Result showed a sustained release of DOX preferentially at the desired lysosomal pH and temperature condition. The biological activity of the DOX-loaded MNPs was studied by MTT assay, fluorescence microscopy, and apoptosis. Intracellular-uptake studies revealed preferential uptake of these nanoparticles into cancer cells (HeLa cells) compared to normal fibroblast cells (L929 cells). The in vitro apoptosis study revealed that the DOX-loaded nanoparticles caused significant death to the HeLa cells. These nanoparticles were capable of target specific release of the loaded drug in response to pH and temperature and hence may serve as a potential drug carrier for in vivo applications.
We report for the first time the use of perylene-3-ylmethanol fluorescent organic nanoparticles as a drug delivery system. In the present system, perylene-3-ylmethanol nanoparticles performed four ...important roles: (i) “nanocarriers” for drug delivery; (ii) “phototriggers” for the drug release; (iii) fluorescent chromophores for cell imaging; and (iv) detectors for real time-monitoring of drug release. In vitro biological studies revealed that the newly developed perylene-3-ylmethanol nanoparticles exhibit good biocompatibility and cellular uptake as well as efficient photoregulated anticancer drug release ability. Such fluorescent organic nanoparticles may open up new perspectives for designing a new class of promising photoresponsive nanocarriers for drug delivery.
•A β-glucan (PS) was isolated from the mushroom Russula albonigra (Krombh.) Fr.•Its structure was established by chemical and 1D/2D NMR studies.•This molecule showed immunostimulatory properties in ...vitro.•It also showed potent antioxidant activities.
A water soluble β-glucan (PS) with an average molecular weight ∼1.95×105Da was isolated from the alkaline extract of ectomycorrhizal edible mushroom, Russula albonigra (Krombh.) Fr. and found to consist of terminal, (1→3)-, (1→6)-, and (1→3,6)-linked β-d-glucopyranosyl moieties in a ratio of nearly 1:2:2:1. The structure of this PS was elucidated on the basis of total hydrolysis, methylation analysis, Smith degradation, partial hydrolysis, and 1D/2D NMR experiments. On the basis of these experiments, the repeating unit of the PS was found to contain a backbone of three (1→6)-β-d-glucopyranosyl residues, one of which was branched at O-3 position with the side chain consisting of two (1→3)-β-d-glucopyranosyl and a terminal β-d-glucopyranosyl residue. This PS showed in vitro macrophage activation by NO production as well as splenocytes and thymocytes proliferation. Moreover, it also exhibited potent antioxidant activities.
There is a need for better classification and understanding of tumor-infiltrating lymphocytes (TILs). Here, we applied advanced functional genomics to interrogate 9,000 human tumors and multiple ...single-cell sequencing sets using benchmarked T cell states, comprehensive T cell differentiation trajectories, human and mouse vaccine responses, and other human TILs. Compared with other T cell states, enrichment of T memory/resident memory programs was observed across solid tumors. Trajectory analysis of single-cell melanoma CD8+ TILs also identified a high fraction of memory/resident memory-scoring TILs in anti-PD-1 responders, which expanded post therapy. In contrast, TILs scoring highly for early T cell activation, but not exhaustion, associated with non-response. Late/persistent, but not early activation signatures, prognosticate melanoma survival, and co-express with dendritic cell and IFN-γ response programs. These data identify an activation-like state associated to poor response and suggest successful memory conversion, above resuscitation of exhaustion, is an under-appreciated aspect of successful anti-tumoral immunity.
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•Improved global TIL classification methods are required to deconvolve cell states•αPD-1 non-responder TILs and dysfunctional TILs score for T activation, not exhaustion•αPD-1 response and patient survival associates with late T cell memory/TRM scoring•Persistent programs co-express with DC maturation and IFN-γ response programs
Jaiswal et al. highlight the need for improved tumor-infiltrating lymphocyte (TIL) classification by showing that current transcriptome assignments may misclassify early activated/effector TILs as exhausted. The study surveys 9,000 solid tumors, multiple single-cell RNA sequencing sets, mouse and human models, and scoring methods to reclassify TILs and associate melanoma survival to T cell memory/resident memory.
Homeostatic programs balance immune protection and self-tolerance. Such mechanisms likely impact autoimmunity and tumor formation, respectively. How homeostasis is maintained and impacts tumor ...surveillance is unknown. Here, we find that different immune mononuclear phagocytes share a conserved steady-state program during differentiation and entry into healthy tissue. IFNγ is necessary and sufficient to induce this program, revealing a key instructive role. Remarkably, homeostatic and IFNγ-dependent programs enrich across primary human tumors, including melanoma, and stratify survival. Single-cell RNA sequencing (RNA-seq) reveals enrichment of homeostatic modules in monocytes and DCs from human metastatic melanoma. Suppressor-of-cytokine-2 (SOCS2) protein, a conserved program transcript, is expressed by mononuclear phagocytes infiltrating primary melanoma and is induced by IFNγ. SOCS2 limits adaptive anti-tumoral immunity and DC-based priming of T cells in vivo, indicating a critical regulatory role. These findings link immune homeostasis to key determinants of anti-tumoral immunity and escape, revealing co-opting of tissue-specific immune development in the tumor microenvironment.
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•Immune phagocytes share a conserved program during differentiation and tissue entry•IFNγ is a critical instructive cue in the steady state•IFNγ and tissue programming are co-opted across cancers and include SOCS2•SOCS2 is a critical determinant of tumor-immune surveillance in dendritic cells
Tumors exploit physiological mechanisms that are in place to keep tissue homeostasis in order to escape the surveillance of the immune system.
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► Preparation of silver nanoparticles through greener route. ► Anticancerous but non-toxic to normal cell. ► Promising antibacterial efficacy to both gram positive and negative ...species. ► Promoting earthworm proliferation and growth. ► Environmentally benign, bioactive nanoparticles with potential future applications.
Poly(ethylene glycol) stabilized colloidal silver nanoparticles were prepared using the reductive potency of the aqueous extract of Thuja occidentalis leaves under ambient conditions. The nanoparticles were well dispersed within a narrow size spectrum (7–14nm) and displayed characteristic surface plasmon resonance peak at around 420nm and Bragg's reflection planes of fcc structure. MTT assay revealed the dose-dependent cytocompatibility and toxicity of the nanoparticles with the L929 normal cell line. On the other hand, the antiproliferative action of the nanoparticles was evaluated on HeLa cell (cancerous cells) line. Fluorescence and phase contrast microscopic imaging indicated the appearance of multinucleate stages with aggregation and nuclear membrane disruption of the HeLa cells post treatment with the nanoparticles. The interaction at the prokaryotic level was also assessed via differential antibacterial efficacy against Staphylococcus aureus (MTCC 3160) and Escherichia coli (MTCC 40). Under these perspectives, it is also necessary to observe the environmental impact of the prepared silver nanoparticles. Hence, the dose dependent toxicity of silver nanoparticles was evaluated upon the earthworm species Eisenia fetida. Neither the survival nor the reproduction was affected by the addition of silver nanoparticles up to 1000ppm. Thus these ‘green’ silver nanoparticles have promising potential as future materials.
► Glucans isolated from P. ostreatus mycelia have a high mol. wt. of ∼2.7×106Da. ► Glucose, mannose and fucose moieties with β and α linkage form its basic framework. ► Lectin array signify glucose, ...mannose and fucose residues in terminals and interior. ► The heteroglucan folded into a triple helical conformation. ► Antitumor activity was associated with immune cell activation on glucan treatment.
Glucans isolated from various mushroom and mycelia sources are interestingly being studied nowadays as a potent therapeutic agent. The present work was focused on the isolation, characterization and immunomodulatory study of a novel water soluble glucan from the pure mycelia of Pleurotus ostreatus. The extracted glucan was found to have a high molecular weight of ∼2.7×106Da and mainly comprised of glucose, mannose and fucose in a ratio of 3:2:1 with both β and α linkages. Presence of terminal or interior glucose, mannose and fucose residues was also revealed using a high throughput miniaturized platform of lectin microarray. The heteroglucan folded into a triple helical conformation and exhibited enhanced immune cell activation and anti-tumor potential in tumor bearing mice model. Thus, potential biological functions incorporated in these glucan molecules acts in accord with its structural property and exploration of such structure–function relationship will unveil its diverse mechanism of action.
The present study delves into a combined bio‐nano‐macromolecular approach for bone tissue engineering. This approach relies on the properties of an ideal scaffold material imbued with all the ...chemical premises required for fostering cellular growth and differentiation. A tannic acid based water dispersible hyperbranched polyurethane is fabricated with bio‐nanohybrids of carbon dot and four different peptides (viz. SVVYGLR, PRGDSGYRGDS, IPP, and CGGKVGKACCVPTKLSPISVLYK) to impart target specific in vivo bone healing ability. This polymeric bio‐nanocomposite is blended with 10 wt% of gelatin and examined as a non‐invasive delivery vehicle. In vitro assessment of the developed polymeric system reveals good osteoblast adhesion, proliferation, and differentiation. Aided by this panel of peptides, the polymeric bio‐nanocomposite exhibits in vivo ectopic bone formation ability. The study on in vivo mineralization and vascularization reveals the occurrence of calcification and blood vessel formation. Thus, the study demonstrates carbon dot/peptide functionalized hyperbranched polyurethane gel for bone tissue engineering application.
Water dispersible hyperbranched polyurethane is conjugated with bio‐nano‐hybrid of carbon dot and RGD sequenced peptides to obtain a target specific multifunctional system with excellent in vitro and in vivo osteogenic activity.
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