Exosome-encapsulated ncRNAs: Emerging yin and yang of tumor hallmarks.

Tumorigenesis is a multifaceted process, where multiple physiological traits serving as cancer's distinctive characteristics are acquired. "Hallmarks of cancer" is a set of cognitive abilities acquired by human cells that are pivotal to their tumor-forming potential. With limited or no protein-coding ability, non-coding RNAs (ncRNAs) interact with their target molecules and yield significant regulatory effects on several cell cycle processes. They play a "yin" and "yang" role, thereby functioning both as oncogenic and tumor suppressor and considered important in the management of various types of cancer entities. ncRNAs serve as important post-transcriptional and translational regulators of not only unrestricted expansion and metastasis of tumor cells but also of various biological processes, such as genomic mutation, DNA damage, immune escape, and metabolic disorder. Dynamical attributes such as increased proliferative signaling, migration, invasion, and epithelial-mesenchymal transition are considered to be significant determinants of tumor malignancy, metastatic dissemination, and therapeutic resistance. Furthermore, these biological attributes engage tumor cells with immune cells within the tumor microenvironment to promote tumor formation. We elaborate the interaction of ncRNAs with various factors in order to regulate cancer intra/intercellular signaling in a specific tumor microenvironment, which facilitates the cancer cells in acquiring malignant hallmarks. Exosomes represent a means of intercellular communication and participate in the maintenance of the tumor hallmarks, adding depth to the intricate, multifactorial character of malignant neoplasia. To summarize, ncRNAs have a profound impact on tumors, affecting their microcirculation, invasiveness, altered metabolism, microenvironment, and the capacity to modify the host immunological environment. Though the significance of ncRNAs in crosstalk between the tumor and its microenvironment is being extensively explored, we intend to review the hallmarks in the light of exosome-derived non-coding RNAs and their impact on the tumor microenvironment.

Immunotherapy With 5, 15-DPP Mediates Macrophage M1 Polarization and Modulates Subsequent Mycobacterium tuberculosis Infectivity in rBCG30 Immunized Mice.

Tuberculosis (TB) is a significant and continuing problem worldwide, with a death toll of around 1.5 million human lives annually. BCG, the only vaccine against TB, offers a varied degree of protection among human subjects in different regions and races of the world. The majority of the population living near the tropics carries a varying degree of tolerance against BCG due to the widespread prevalence of non-tuberculous mycobacteria (NTM). Interestingly, ≈90% of the Mycobacterium tuberculosis (Mtb) infected population restrain the bacilli on its own, which strengthens the notion of empowering the host immune system to advance the protective efficacy of existing mycobacterial vaccines. In general, Mtb modulates IL-10/STAT3 signaling to skew host mononuclear phagocytes toward an alternatively activated, anti-inflammatory state that helps it thrive against hostile immune advances. We hypothesized that modulating the IL-10/STAT3 driven anti-inflammatory effects in mononuclear cells may improve the prophylactic ability of TB vaccines. This study investigated the immunotherapeutic ability of a porphyrin based small molecule inhibitor of IL-10/STAT3 axis, 5, 15-diphenyl porphyrin (DPP), in improving anti-TB immunity offered by second generation recombinant BCG30 (rBCG30-ARMF-II®) vaccine in mice. The DPP therapy potentiated vaccine induced anti-TB immunity by down-modulating anti-inflammatory responses, while simultaneously up-regulating pro-inflammatory immune effector responses in the immunized host. The employed DPP based immunotherapy led to the predominant activation/proliferation of pro-inflammatory monocytes/macrophages/DCs, the concerted expansion of CD4+/CD8+ effector and central memory T cells, alongside balanced Th17 and Treg cell amplification, and conferred augmented resistance to aerosol Mtb challenge in rBCG30 immunized BALB/c mice.

Corrigendum: Leishmania-Specific Promiscuous Membrane Protein Tubulin Folding Cofactor D Divulges Th1/Th2 Polarization in the Host via ERK-1/2 and p38 MAPK Signaling Cascade.

[This corrects the article DOI: 10.3389/fimmu.2020.00817.].

Leishmania-Specific Promiscuous Membrane Protein Tubulin Folding Cofactor D Divulges Th1/Th2 Polarization in the Host via ERK-1/2 and p38 MAPK Signaling Cascade.

Visceral leishmaniasis (VL)-related mortality and morbidity imposes a great deal of health concern across the globe. The existing anti-leishmanial drug regimen generally fails to eliminate newly emerging resistant isolates of this dreadful parasite. In such circumstances, the development of a prophylactic strategy to impart protection against the disease is likely to take center stage. In order to develop a promising prophylactic vaccine, it is desirable to identify an adequately potential vaccine candidate. In silico analysis of Leishmania tubulin folding cofactor D protein predicted its potential to activate both B- and T-cell repertoires. Furthermore, the ELISA employing anti-peptide27 (a segment of tubulin folding cofactor D) antibody revealed its proficiency in VL diagnosis and treatment monitoring. The peptide27 and its cocktail with another Leishmania peptide (peptide23) prompted the up-regulation of pro-inflammatory cytokines, such as IFN-γ, TNF-α, IL-2, IL-17, etc., and the down-regulation of immune-regulatory cytokines, such as IL-10, in the immunized BALB/c mice. Coherent to the consequence of peptide-specific humoral immune response, peptide cocktail-based immunization ensued in the predominant amplification of pathogen-specific IgG2a over the IgG1 isotype, up-regulated proliferation of T lymphocytes, and enhanced production of nitric oxide, reactive oxygen species, etc. We also established that the peptide cocktail modulated host MAPK signaling to favor the amplification of Th1-dominated immune response in the host. The peptide cocktail mediated the activation of the host immune armory, which was eventually translated into a significant decline in parasitic load in the visceral organs of experimental animals challenged with Leishmania donovani.

Hydroxyapatite Nanoparticles Fortified Xanthan Gum-Chitosan Based Polyelectrolyte Complex Scaffolds for Supporting the Osteo-Friendly Environment.

Nanoparticle-reinforced polymer-based scaffolding matrices as artificial bone-implant materials are potential suitors for bone regenerative medicine as they simulate the native bone. In the present work, a series of bioinspired, osteoconductive tricomposite scaffolds made up of nano-hydroxyapatite (NHA) embedded xanthan gum-chitosan (XAN-CHI) polyelectrolyte complex (PEC) are explored for their bone-regeneration potential. The Fourier transform infrared spectroscopy studies confirmed complex formation between XAN and CHI and showed strong interactions between the NHA and PEC matrix. The X-ray diffraction studies indicated regulation of the nanocomposite (NC) scaffold crystallinity by the physical cues of the PEC matrix. Further results exhibited that the XAN-CHI/NHA5 scaffold, with a 50/50 (polymer/NHA) ratio, has optimized porous structure, appropriate compressive properties, and sufficient swelling ability with slower degradation rates, which are far better than those of CHI/NHA and other XAN-CHI/NHA NC scaffolds. The simulated body fluid studies showed XAN-CHI/NHA5 generated apatite-like surface structures of a Ca/P ratio ∼1.66. Also, the in vitro cell-material interaction studies with MG-63 cells revealed that relative to the CHI/NHA NC scaffold, the cellular viability, attachment, and proliferation were better on XAN-CHI/NHA scaffold surfaces, with XAN-CHI/NHA5 specimens exhibiting an effective increment in cell spreading capacity compared to XAN-CHI/NHA4 and XAN-CHI/NHA6 specimens. The presence of an osteo-friendly environment is also indicated by enhanced alkaline phosphatase expression and protein adsorption ability. The higher expression of extracellular matrix proteins, such as osteocalcin and osteopontin, finally validated the induction of differentiation of MG-63 cells by tricomposite scaffolds. In summary, this study demonstrates that the formation of PEC between XAN and CHI and incorporation of NHA in XAN-CHI PEC developed tricomposite scaffolds with robust potential for use in bone regeneration applications.

Corrigendum: Selective Targeting of 4SO4-N-Acetyl-Galactosamine Functionalized Mycobacterium tuberculosis Protein Loaded Chitosan Nanoparticle to Macrophages: Correlation With Activation of Immune System.

[This corrects the article DOI: 10.3389/fmicb.2018.02469.].

Bio-mediated synthesis of 5-FU based nanoparticles employing orange fruit juice: a novel drug delivery system to treat skin fibrosarcoma in model animals.

Nano-sized drug delivery systems (NDDS) have been widely exploited to achieve targeted delivery of pharmaco-materials. Traditional pharmaceutical approaches, implied in the synthesis of nano-formulations, are obscure owing to the incompatible physico-chemical properties of the core drug as well as some other factors crucial in development of NDDS. Infact, most of the existing methods used in development of NDDS rely on usage of additives or excipients, a special class of chemicals. Barring few exceptions, the usage of synthetic excipients ought to be curtailed because of several associated undesirable features. Such issues necessitate strategies that lead to development of the synthetic excipient free drug delivery system. Plant based extracts have great potential to induce synthesis of nano-sized particles. Considering this fact, here we propose a prototype employing orange fruit juice (OJ) to facilitate bio-mediated synthesis of nano-sized supra-molecular assemblies of 5-fluorouracil (5-FU), a potent anticancer drug. The as-synthesized 5-FU Nanoparticles (NPs) retained the anti-neoplastic efficacy of the parent compound and induced apoptosis in cancer cells. The novel 5-FU NPs formulation demonstrated enhanced efficacy against DMBA induced experimental fibrosarcoma in the mouse model when compared to the micro-sized crystals of parent 5-FU drug.

Selective Targeting of 4SO4-N-Acetyl-Galactosamine Functionalized Mycobacterium tuberculosis Protein Loaded Chitosan Nanoparticle to Macrophages: Correlation With Activation of Immune System.

In the present study, we investigated potential of chitosan-based nanoparticles (CNPs) to deliver loaded therapeutic molecules to pathogen harboring macrophages. We fabricated stable CNPs employing ionic cross-linking method and evaluated their potential to target RAW 264.7 cells. The physicochemical characterization of as-synthesized CNPs was determined using electron microscopy, infrared microscopy and zeta potential measurement. Next, cellular uptake and intracellular localization studies of CNPs were followed in living RAW264.7 cells using confocal microscopy. We found that both Acr-1 loaded (CNP-A) and 4-SO4-GalNAc ligand harboring (CNP-L) chitosan nanoparticle experience increased cellular uptake by Mycobacterium smegmatis infected RAW cells. Following cellular digestion in model macrophage cell line (RAW), CNPs provide an increased immune response. Further, 4-SO4-GalNAc bearing CNP-L exhibits high binding affinity as well as antibacterial efficacy toward M. smegmatis. The data of the present study suggest that CNP-based nanoparticle offer a promising delivery strategy to target infected macrophages for prevention and eradication of intracellular pathogens such as M. smegmatis.

Amyloid form of ovalbumin evokes native antigen-specific immune response in the host: prospective immuno-prophylactic potential.

Amyloids are highly organized protein aggregates that arise from inappropriately folded versions of proteins or polypeptides under both physiological as well as simulated ambiences. Once thought to be irreversible assemblies, amyloids have begun to expose their more dynamic and reversible attributes depending upon the intrinsic properties of the precursor protein/peptide and experimental conditions such as temperature, pressure, structural modifications in proteins, or presence of chemicals in the reaction mixture. It has been repeatedly proposed that amyloids undergo transformation to the bioactive peptide/protein forms under specific conditions. In the present study, amyloids assembled from the model protein ovalbumin (OVA) were found to release the precursor protein in a slow and steady manner over an extended time period. Interestingly, the released OVA from amyloid depot was found to exhibit biophysical characteristics of native protein and reacted with native-OVA specific monoclonal as well as polyclonal antibodies. Moreover, antibodies generated upon immunization of OVA amyloidal aggregates or fibrils were found to recognize the native form of OVA. The study suggests that amyloids may act as depots for the native form of the protein and therefore can be exploited as vaccine candidates, where slow antigen release over extended time periods is a pre-requisite for the development of desired immune response.