Key Regulatory miRNAs and their Interplay with Mechanosensing and Mechanotransduction Signaling Pathways in Breast Cancer Progression.

According to the WHO, breast cancer is the most common cancer in women worldwide. Identification of underlying mechanisms in breast cancer progression is the main concerns of researches. The mechanical forces within the tumor microenvironment, in addition to biochemical stimuli such as different growth factors and cytokines, activate signaling cascades, resulting in various changes in cancer cell physiology. Cancer cell proliferation, invasiveness, migration, and, even, resistance to cancer therapeutic agents are changed due to activation of mechanotransduction signaling. The mechanotransduction signaling is frequently dysregulated in breast cancer, indicating its important role in cancer cell features. So far, a variety of experimental investigations have been conducted to determine the main regulators of the mechanotransduction signaling. Currently, the role of miRNAs has been well-defined in the cancer process through advances in molecular-based approaches. miRNAs are small groups of RNAs (∼22 nucleotides) that contribute to various biological events in cells. The central role of miRNAs in the regulation of various mediators involved in the mechanotransduction signaling has been well clarified over the last decade. Unbalanced expression of miRNAs is associated with different pathologic conditions. Overexpression and downregulation of certain miRNAs were found to be along with dysregulation of mechanotransduction signaling effectors. This study aimed to critically review the role of miRNAs in the regulation of mediators involved in the mechanosensing pathways and clarify how the cross-talk between miRNAs and their targets affect the cell behavior and physiology of breast cancer cells.

How hypoxia regulate exosomes in ischemic diseases and cancer microenvironment?

Exosomes, as natural occurring vesicles, play highly important roles in the behavior and fate of ischemic diseases and different tumors. Secretion, composition, and function of exosomes are remarkably influenced by hypoxia in ischemic diseases and tumor microenvironment. Exosomes secreted from hypoxic cells affect development, growth, angiogenesis, and progression in ischemic diseases and tumors through a variety of signaling pathways. In this review article, we discuss how hypoxia affects the quantity and quality of exosomes, and review the mechanisms by which hypoxic cell-derived exosomes regulate ischemic cell behaviors in both cancerous and noncancerous cells.

Emerging roles of exosomal miRNAs in breast cancer drug resistance.

Breast cancer (BC), as a heterogeneous disease, is considered as one of the most common malignancies in women worldwide. The resistance of BC cells to therapeutic agents has remained a big challenge in the treatment of BC patients. Some factors such as cytokines, exosomes, and soluble receptors were recognized as crucial agents involved in the development of drug resistance. However, the exact mechanisms underlying the drug resistance is still unknown. There is growing evidence to support the emerging roles of exosomes, especially exosomal miRNAs, in tumor initiation, angiogenesis, proliferation, migration, invasion, metastasis, and drug resistance. Therefore, identification of BC-specific exosomal miRNAs and their underlying mechanisms would be helpful to define sensitivity to therapeutic drugs and establish an appropriate therapeutic strategy. This review focuses mainly on the roles of exosomal miRNAs and their associated mechanisms in the resistance of BC cells to therapeutic agents, as well as critically examines the potential of these macromolecules as a treatment biomarker in BC patients.

Bordetella pertussis antigens encapsulated into N-trimethyl chitosan nanoparticulate systems as a novel intranasal pertussis vaccine.

The mucosal immune system serves as the first line of defense against Bordetella pertussis. Intranasal vaccination, due to its potential to induce systemic and mucosal immune responses, appears to prevent the initial adherence and colonization of the bacteria at the first point of contact. In the present study, two B. pertussis antigens, pertussis Toxoid (PTd) and Filamentous hemagglutinin (FHA), which play a very significant role in virulence and protection against pertussis, were encapsulate into N-trimethyl chitosan (TMC) nanoparticulate systems. After preparation of TMC nanoparticles (NPs), the NPs were characterized and their ability to induce efficient immune responses against B. pertussis was studied in a mouse model. Our findings showed that PTd + FHA-loaded TMC NPs have strong ability to induce IL-4, IL-17, IFN-γ, IgG, and IgA in the mouse model. Results from this study suggest that nasal administration of the PTd + FHA-loaded TMC NPs induced not only a systemic immune response but also a local mucosal response, which may improve the efficacy of pertussis prevention through respiratory tract transmission.

Nasal vaccination with r4M2e.HSP70c antigen encapsulated into N-trimethyl chitosan (TMC) nanoparticulate systems: Preparation and immunogenicity in a mouse model.

In this study, the potential of N-trimethyl chitosan (TMC) nanoparticles as a carrier system for the nasal delivery of the r4M2e.HSP70c, as an M2e-based universal recombinant influenza virus vaccine candidate, was investigated in mice. The anti-M2e specific cellular and humoral immune responses were assessed and the protective efficacy against a 90% lethal dose (LD90) of influenza A/PR/8/34 (H1N1) in a mice model was evaluated. Our results showed that the intranasal immunization of mice with r4M2e.HSP70c+TMC rather than the control groups, r4M2e+TMC, r4M2e and PBS (Phosphate buffer saline), significantly elevated both longevity and serum level of the total M2e-specific IgG antibody with a significant shift in the IgG2a/IgG1 ratio toward IgG2a, induced a Th1 skewed humoral and cellular immune responses, increased IFN-γ, IgG, and IgA in the bronchoalveolar lavage fluid (BALF), and promoted the proliferation of peripheral blood lymphocytes with lower morbidity and mortality rate against viral challenge. In conclusion, based on evidence to our finding, nasal vaccination with r4M2e.HSP70c antigen encapsulated into N-Trimethyl Chitosan (TMC) nanoparticulate system showed to induce a long lasting M2e-specific humoral and cellular immune responses and also provided full protection against a 90% lethal dose (LD90) of the influenza virus A/PR/8/34 (H1N1). It seems, protective immunity following intranasal administration of r4M2e could be resulted by the cooperation of both adjuvants, TMC and HSP70c.

Evaluation of Factors Influencing Antibody Reduction for Development of Antibody Drug Conjugates

Background: Reduction/alkylation is one of the leading strategies for the development of antibody drug conjugates (ADCs). Precise control of the reduction process would not only yield a defined number of free thiols per antibody but also result in development of more homogenous conjugates. Methods: In the present study, we investigated the effect of various dithiothreitol (DTT) concentrations, temperature conditions, and DTT exposure times on antibody reduction. After antibody reduction, the Ellman's test and SDS-PAGE analysis were used to evaluate free thiols produced and confirm the reduction process, respectively. Results: DTT concentration seems to be a potential factor in the reduction process. Concentrations of 0.1, 1, 5, 10, 20, 50, and 100 mM DTT at 37°C for 30 minutes resulted in approximately 0.4, 1.2, 5.4, 7, 8, 8, and 8 thiols per antibody, respectively. Conclusion: Optimized site-specific conjugation can provide better process control and reproducibility for the development of disulfide-based ADCs.

Development of an effective delivery system for intranasal immunization against Mycobacterium tuberculosis ESAT-6 antigen.

Introduction The early secreted antigenic target 6-kDa protein (ESAT-6) plays an important role in immune protection against Tuberculosis. Owing to its great potential to increase immune response, chitosan can be considered as a suitable biodegradable polymer for intranasal administration. Methods The physiochemical properties of the nanoparticle were measured in vitro. Two weeks after the last intranasal administration, blood samples were collected and specific IgG, IFN-gama, and IL-4 levels were measured by ELISA. Results Chitosan nanoparticles containing ESAT-6 demonstrated stronger ability to induce IFN-gama, IL-4, and IgG antibody level than the control groups. Conclusion Administration of chitosan nanoparticles can be a suitable method to induce more appropriate immune responses against low inherent immunogenic tuberculosis proteins through intranasal routs.