Deregulation of interferon-gamma receptor 1 expression and its implications for lung adenocarcinoma progression.

Interferon-gamma (IFN-γ) plays a dual role in cancer; it is both a pro- and an antitumorigenic cytokine, depending on the type of cancer. The deregulation of the IFN-γ canonic pathway is associated with several disorders, including vulnerability to viral infections, inflammation, and cancer progression. In particular, the interplay between lung adenocarcinoma (LUAD) and viral infections appears to exist in association with the deregulation of IFN-γ signaling. In this mini-review, we investigated the status of the IFN-γ signaling pathway and the expression level of its components in LUAD. Interestingly, a reduction in IFNGR1 expression seems to be associated with LUAD progression, affecting defenses against viruses such as severe acute respiratory syndrome coronavirus 2. In addition, alterations in the expression of IFNGR1 may inhibit the antiproliferative action of IFN-γ signaling in LUAD.

Protein ISGylation: a posttranslational modification with implications for malignant neoplasms.

Interferon (IFN)-stimulated gene 15 (ISG15) is a member of the ubiquitin-like (UBL) protein family that can modify specific proteins via a catalytic process called ISGylation. This posttranslational modification can modulate the stability of the ISGylated proteins and protein-protein interactions. Some proteins modified by ISG15 have been identified in malignant neoplasms, suggesting the functional relevance of ISGylation in cancer. This review discusses the ISGylated proteins reported in malignant neoplasms that suggest the potential of ISG15 as a biomarker and therapeutic target in cancer.

Interferon-stimulated gene 15 and ISGylation are upregulated in glioblastoma.

Interferon stimulated gene 15 (ISG15) encodes a 15-kDa ubiquitin-like protein that acts as a posttranslational modifier of target proteins via ISGylation, a catalytic process similar to ubiquitination. Protein ISGylation is associated with the modulation of protein stability and protein-protein interactions. Furthermore, non-conjugated ISG15 (free ISG15) is secreted to act as a cytokine-like protein in some cellular contexts. The expression of ISG15 in some cancer types is dysregulated, but its expression status in glioblastoma, a malignant brain tumor highly aggressive and invasive, requires more studies. To explore the potential of ISG15 as a biomarker for glioblastoma, we first evaluated the ISG15 levels in glioblastoma cell lines and the effect of IFN-γ treatment on protein levels and localization of ISG15. In addition, we analyzed the ISG15 levels in glioblastoma samples compared to healthy brain tissue. Our results indicate that ISG15 levels are increased in glioblastoma and are upregulated in response to IFN-γ stimulus, suggesting that ISG15 and ISGylation may play a central role in glioblastoma progression. Thus, ISG15/ISGyaltion may be useful as biomarkers of this type of malignant brain tumors.

Implications of the Immune Polymorphisms of the Host and the Genetic Variability of SARS-CoV-2 in the Development of COVID-19.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for the current pandemic affecting almost all countries in the world. SARS-CoV-2 is the agent responsible for coronavirus disease 19 (COVID-19), which has claimed millions of lives around the world. In most patients, SARS-CoV-2 infection does not cause clinical signs. However, some infected people develop symptoms, which include loss of smell or taste, fever, dry cough, headache, severe pneumonia, as well as coagulation disorders. The aim of this work is to report genetic factors of SARS-CoV-2 and host-associated to severe COVID-19, placing special emphasis on the viral entry and molecules of the immune system involved with viral infection. Besides this, we analyze SARS-CoV-2 variants and their structural characteristics related to the binding to polymorphic angiotensin-converting enzyme type 2 (ACE2). Additionally, we also review other polymorphisms as well as some epigenetic factors involved in the immunopathogenesis of COVID-19. These factors and viral variability could explain the increment of infection rate and/or in the development of severe COVID-19.

Protein degradation-associated mechanisms that are affected in Alzheimer´s disease.

Alzheimer's disease (AD) is the most common type of dementia associated with age-related neurodegeneration. Alteration of several molecular mechanisms has been correlated with the progression of AD. In recent years, dysregulation of proteostasis-associated pathways has emerged as a potential risk factor for neurodegenerative diseases. This review investigated the ubiquitin-proteasome system, lysosome-associated degradation, endoplasmic-reticulum-associated degradation, and the formation of advanced glycation end products. These pathways involved in proteostasis have been reported to be altered in AD, suggesting that their study may be critical for identifying new biomarkers and target molecules for AD.

Estrogenic hormones receptors in Alzheimer's disease.

Estrogens are hormones that play a critical role during development and growth for the adequate functioning of the reproductive system of women, as well as for maintaining bones, metabolism, and cognition. During menopause, the levels of estrogens are decreased, altering their signaling mediated by their intracellular receptors such as estrogen receptor alpha and beta (ERα and ERß), and G protein-coupled estrogen receptor (GPER). In the brain, the reduction of molecular pathways mediated by estrogenic receptors seems to favor the progression of Alzheimer's disease (AD) in postmenopausal women. In this review, we investigate the participation of estrogen receptors in AD in women during aging.

An artificial virus-like triblock protein shows low in vivo humoral immune response and high stability.

The use of viral vectors for in vivo gene therapy can be severely limited by their immunogenicity. Non-viral vectors may represent an alternative, however, reports analyzing their immunogenicity are still lacking. Here, we studied the humoral immune response in a murine model triggered by artificial virus-like particles (AVLPs) carrying plasmid or antisense DNA. The AVLPs were assembled using a family of modular proteins based on bioinspired collagen-like and silk-like sequences that produce virus-like particles. We compared our AVLPs against an Adeno Associated Virus 1 (AAV), a widely used viral vector for in vivo gene delivery that has been approved by the FDA and EMA for gene therapy. We found that a 1000-fold higher mass of AVLPs than AAV are necessary to obtain similar specific antibody titters. Furthermore, we studied the stability of AVLPs against relevant biological reagents such as heparin and fetal bovine serum to ensure nucleic acid protection in biological media. Our study demonstrates that the AVLPs are stable in physiological conditions and can overcome safety limitations such as immunogenicity. The scarce humoral immunogenicity and high stability found with AVLPs suggest that they have potential to be used as stealth non-viral gene delivery systems for in vivo studies or gene therapy.

SARS-CoV-2 Vaccines Based on the Spike Glycoprotein and Implications of New Viral Variants.

Coronavirus 19 Disease (COVID-19) originating in the province of Wuhan, China in 2019, is caused by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), whose infection in humans causes mild or severe clinical manifestations that mainly affect the respiratory system. So far, the COVID-19 has caused more than 2 million deaths worldwide. SARS-CoV-2 contains the Spike (S) glycoprotein on its surface, which is the main target for current vaccine development because antibodies directed against this protein can neutralize the infection. Companies and academic institutions have developed vaccines based on the S glycoprotein, as well as its antigenic domains and epitopes, which have been proven effective in generating neutralizing antibodies. However, the emergence of new SARS-CoV-2 variants could affect the effectiveness of vaccines. Here, we review the different types of vaccines designed and developed against SARS-CoV-2, placing emphasis on whether they are based on the complete S glycoprotein, its antigenic domains such as the receptor-binding domain (RBD) or short epitopes within the S glycoprotein. We also review and discuss the possible effectiveness of these vaccines against emerging SARS-CoV-2 variants.

Cellular Senescence and ApoE4: Their Repercussions in Alzheimer's Disease.

Alzheimer's Disease (AD) is characterized by progressive memory loss due to neurodegeneration that occurs mainly during aging. The accumulation of senescent cells has been related to aging. Furthermore, the expression of the variant ApoE ε4 is a critical risk factor for AD. Some events that occur in senescence, such as the secretion of pro-inflammatory molecules, and metabolic and epigenetic changes, in addition to the detection of ApoE4, may accelerate the progression of AD. Here, we discuss the implications of cellular senescence and the ApoE variants in AD. Molecular studies of these risk factors for AD may hence be pivotal to define new biomarkers and novel therapeutic strategies for this neurodegenerative pathology.

Proteolysis-targeting chimeras and their implications in breast cancer.

Breast cancer (BC) is a highly heterogeneous neoplasm of the mammary tissue, causing the deaths of a large number of women worldwide. Nearly 70% and 20% of BC cases are estrogen receptor alpha positive (ERα+) and human epidermal growth factor receptor 2-positive (HER2+), respectively; therefore, ER and HER2 targeted therapies have been employed in BC treatment. However, resistance to these therapies has been reported, indicating a need for developing novel therapeutic strategies. Proteolysis-targeting chimeras (PROTACs) are new, promising therapeutic tools designed with a bimodular structure: one module allows specific binding to target proteins, and the other module allows efficient degradation of these target proteins. In this paper, PROTACs and their potential in controlling the progression of ERα and HER2+ BC are discussed.

Epigenetic basis of Alzheimer disease.

Alzheimer disease (AD) is the primary form of dementia that occurs spontaneously in older adults. Interestingly, the epigenetic profile of the cells forming the central nervous system changes during aging and may contribute to the progression of some neurodegenerative diseases such as AD. In this review, we present general insights into relevant epigenetic mechanisms and their relationship with aging and AD. The data suggest that some epigenetic changes during aging could be utilized as biomarkers and target molecules for the prevention and control of AD.

Interaction Between Virus-Like Particles (VLPs) and Pattern Recognition Receptors (PRRs) From Dendritic Cells (DCs): Toward Better Engineering of VLPs.

Virus-like particles (VLPs) have been shown to be strong activators of dendritic cells (DCs). DCs are the most potent antigen presenting cells (APCs) and their activation prompts the priming of immunity mediators based on B and T cells. The first step for the activation of DCs is the binding of VLPs to pattern recognition receptors (PRRs) on the surface of DCs, followed by VLP internalization. Like wild-type viruses, VLPs use specific PRRs from the DC; however, these recognition interactions between VLPs and PRRs from DCs have not been thoroughly reviewed. In this review, we focused on the interaction between proteins that form VLPs and PRRs from DCs. Several proteins that form VLP contain glycosylations that allow the direct interaction with PRRs sensing carbohydrates, prompting DC maturation and leading to the development of strong adaptive immune responses. We also discussed how the knowledge of the molecular interaction between VLPs and PRRs from DCs can lead to the smart design of VLPs, whether based on the fusion of foreign epitopes or their chemical conjugation, as well as other modifications that have been shown to induce a stronger adaptive immune response and protection against infectious pathogens of importance in human and veterinary medicine. Finally, we address the use of VLPs as tools against cancer and allergic diseases.

A self-aggregating peptide: implications for the development of thermostable vaccine candidates.

BACKGROUND: The use of biomaterials has been expanded to improve the characteristics of vaccines. Recently we have identified that the peptide PH(1-110) from polyhedrin self-aggregates and incorporates foreign proteins to form particles. We have proposed that this peptide can be used as an antigen carrying system for vaccines. However, the immune response generated by the antigen fused to the peptide has not been fully characterized. In addition, the adjuvant effect and thermostability of the particles has not been evaluated. RESULTS: In the present study we demonstrate the use of a system developed to generate nano and microparticles carrying as a fusion protein peptides or proteins of interest to be used as vaccines. These particles are purified easily by centrifugation. Immunization of animals with the particles in the absence of adjuvant result in a robust and long-lasting immune response. Proteins contained inside the particles are maintained for over 1 year at ambient temperature, preserving their immunological properties. CONCLUSION: The rapid and efficient production of the particles in addition to the robust immune response they generate position this system as an excellent method for the rapid response against emerging diseases. The thermostability conferred by the particle system facilitates the distribution of the vaccines in developing countries or areas with no electricity.

Incorporation of ORF2 from Porcine Circovirus Type 2(PCV2) into genetically encoded nanoparticles as a novel vaccine using a self-aggregating peptide.

Porcine Circovirus Type 2 (PCV2) is one of the most important pathogens in pigs around the world. PCV2 is a non-enveloped virus and its capsid is formed by a single protein known as open reading frame 2 (ORF2). The aim of this study was to evaluate the antigenicity and immunogenicity of genetically-encoded protein nanoparticles (NPs) containing ORF2 from PCV2 fused to the first 110 amino acids of the N-terminus of polyhedrin from the insect virus Autographa californica nucleopolyhedrovirus (PH(1 -1 1 0)). Our group has previously described that some polyhedrin fragments self-aggregate forming polyhedra-like particles. We identified a self-aggregating signal within the first 110 amino acids from polyhedrin (PH(1 -1 1 0)). Fusing the ORF2 from PCV2 to the carboxyl terminus from PH(1 -1 1 0) results in the formation of NPs which incorporate the antigen of interest. Using this system we synthesized NPs containing PH(1 -1 1 0) fused to ORF2 (PH(1 -1 1 0)PCV2) and purify them to immunize pigs and evaluate the humoral immune response generated by these NPs comparing them to a commercially available vaccine. Pigs immunized with PH(1 -1 1 0)PCV2 NPs produced antibodies against ORF2 from PCV2 as indicated by western blot and ELISA analysis. Antibodies obtained with PH(1 -1 1 0)PCV2 NPs were comparable to those obtained using a commercial PCV2 vaccine. These antibodies neutralized the infection of a recombinant PCV2 expressing the green fluorescent protein (GFP). These results together suggest that the self-aggregating peptide PH(1 -1 1 0) can be used for the synthesis of subunit vaccines against PCV2.

Induction of adaptive immune response by self-aggregating peptides.

INTRODUCTION: Recently, subunit vaccines are replacing some of the traditional vaccines because they offer a higher margin of safety. However, generally subunit vaccines have low antigenicity. Adjuvants are used in vaccine formulations to increase their immunogenicity, but current research suggests that adjuvants could induce serious side effects in susceptible individuals; therefore, the improvement of antigens and adjuvants is important. AREAS COVERED: Here we reviewed some self-aggregating peptides (SAPs) used as antigen delivery systems. SAPs are based on a short sequence of amino acids, which have self-aggregating properties, inducing self-interaction among peptide molecules by means of non-covalent interactions to generate nanoparticles (NPs). EXPERT COMMENTARY: SAPs increase the immunogenicity of fused/conjugated antigens because they can interact with antigen-presenting cells and induce adaptive immunity based on both humoral and cellular responses. As an example, we report an antigen delivery system based on SAPs forming NPs. These NPs are synthesized using a recombinant baculovirus. We fused the green fluorescent protein to the first 110 amino acids of polyhedrin protein from Autographa californica nucleopolyhedrovirus, which has self-aggregating properties. We showed that these NPs prompt high antibody levels without inducing inflammation, similarly to some SAPs reported here.