Kelli Monteiro da Costa

Cancer cells are characterized by metabolic reprogramming, which enables their survival in of-ten inhospitable conditions. A very well-documented example that has gained attraction in re-cent years and is already considered a hallmark of transformed cells is the reprogramming of carbohydrate metabolism. Such a feature, in association with the differential expression of en-zymes involved in the biosynthesis of glycoconjugates, generically known as glycosyltransfer-ases, contributes to the expression of structurally atypical glycans when compared to those ex-pressed in healthy tissues. The latest studies have demonstrated that glycophenotypic alterations are capable of modulating multifactorial events essential for the development and/or progres-sion of the disease. Herein, we will address the importance of glycobiology in modern medi-cine, focusing on the ability of unusual/truncated O-linked glycans to modulate two complex and essential phenomena for cancer progression: the acquisition of the multidrug resistance (MDR) phenotype and the activation of molecular pathways associated with the epithelial–mesenchymal transition (EMT) process, an event deeply linked with cancer metastasis.

Multidrug resistance (MDR) and induction of metastasis are some of the puzzles encountered during cancer chemotherapy. The MDR phenotype is associated with overexpression of ABC transporters, involved in drug efflux. Metastasis originates from the epithelial-mesenchymal transition (EMT), in which cells acquire a migratory phenotype, invading new tissues. ABC transporters’ role during EMT is still elusive, though cells undergoing EMT exhibit enhanced ABCB1 expression. We demonstrated increased ABCB1 expression but no change in activity after TGF-β-induced EMT in A549 cells. Moreover, ABCB1 inhibition by verapamil increased snail and fibronectin expression, an event associated with upregulation of ABCB1, evidencing coincident cell signaling pathways leading to ABCB1 and EMT-related markers transcription, rather than a direct effect of transport. Additionally, for the first time, increased ABCC1 expression and activity was observed after EMT, and use of ABCC1 inhibitors partially inhibited EMT-marker snail, although increased ABCC1 function translated into collateral sensibility to daunorubicin. More investigations must be done to evaluate the real benefits that the gain of ABC transporters might have on the process of metastasis. Considering ABCC1 is involved in the stress response, affecting intracellular GSH content and drug detoxification, this transporter could be used as a therapeutic target in cancer cells undergoing EMT.

In this article, we discuss the main aspects regarding the recognition of cell surface glycoconjugates and the immunomodulation of responses against the progression of certain pathologies, such as cancer and infectious diseases. In the first part, we talk about different aspects of glycoconjugates and delve deeper into the importance of N-glycans in cancer immunotherapy. Then, we describe two important lectin families that have been very well studied in the last 20 years. Examples include the sialic acid-binding immunoglobulin (Ig)-like lectins (siglecs), and galectins. Finally, we discuss a topic that needs to be better addressed in the field of glycoimmunology: the impact of oncofetal antigens on the cells of the immune system. New findings in this area are of great importance for advancement, especially in the field of oncology, since it is already known that cellular interactions mediated by carbohydrate–carbohydrate and/or carbohydrate proteins are able to modulate the progression of different types of cancer in events that compromise the functionality of the immune responses.

Cancer and parasitic diseases, such as leishmaniasis and Chagas disease, share similarities that allow the co-development of new antiproliferative agents as a strategy to quickly track the discovery of new drugs. This strategy is especially interesting regarding tropical neglected diseases, for which chemotherapeutic alternatives are extremely outdated. We designed a series of (E)-3-aryl-5-(2-aryl-vinyl)-1,2,4-oxadiazoles based on the reported antiparasitic and anticancer activities of structurally related compounds. The synthesis of such compounds led to the development of a new, fast, and efficient strategy for the construction of a 1,2,4-oxadiazole ring on a silica-supported system under microwave irradiation. One hit compound (23) was identified during the in vitro evaluation against drug-sensitive and drug-resistant chronic myeloid leukemia cell lines (EC₅₀ values ranging from 5.5 to 13.2 µM), Trypanosoma cruzi amastigotes (EC₅₀ = 2.9 µM) and Leishmania amazonensis promastigotes (EC₅₀ = 12.2 µM) and amastigotes (EC₅₀ = 13.5 µM). In silico studies indicate a correlation between the in vitro activity and the interaction with tubulin at the colchicine binding site. Furthermore, ADMET in silico predictions indicate that the compounds possess a high druggability potential due to their physicochemical, pharmacokinetic, and toxicity profiles, and for hit 23, it was identified by multiple spectroscopic approaches that this compound binds with human serum albumin (HSA) via a spontaneous ground-state association with a moderate affinity driven by entropically and enthalpically energies into subdomain IIA (site I) without significantly perturbing the secondary content of the protein.

Human trypanosomiasis affects nearly eight million people worldwide, causing great economic and social impact, mainly in endemic areas. T. cruzi and T. brucei are protozoan parasites that present efficient mechanisms of immune system evasion, leading to disease chronification. Currently, there is no vaccine, and chemotherapy is effective only in the absence of severe clinical manifestations. Nevertheless, resistant phenotypes to chemotherapy have been described in protozoan parasites, associated with cross-resistance to other chemically unrelated drugs. Multidrug resistance is multifactorial, involving: (i) drug entry, (ii) activation, (iii) metabolism and (iv) efflux pathways. In this context, ABC transporters, initially discovered in resistant tumor cells, have drawn attention in protozoan parasites, owing to their ability to decrease drug accumulation, thus mitigating their toxic effects. The discovery of these transporters in the Trypanosomatidae family started in the 1990s; however, few members were described and functionally characterized. This review contains a brief history of the main ABC transporters involved in resistance that propelled their investigation in Trypanosoma species, the main efflux modulators, as well as ABC genes described in T. cruzi and T. brucei according to the nomenclature HUGO. We hope to convey the importance that ABC transporters play in parasite physiology and chemotherapy resistance.

Fungal infections are the most common secondary infections in debilitated individuals in a state of chronic disease or immunosuppression. Despite this, most fungal infections are neglected, mainly due to the lower frequency of their more severe clinical forms in immunocompetent individuals with a healthy background. However, over the past few years, several cases of severe fungal infections in healthy individuals have provoked a change in the epidemiological dynamics of fungal infections around the world, both due to recurrent outbreaks in previously infrequent regions and the greater emergence of more pathogenic fungal variants affecting healthy individuals, such as in the Cryptococcus genus. Therefore, before the arrival of a scenario of prevalent severe fungal infections, it is necessary to assess more carefully what are the real reasons for the increased incidence of fungal infection globally. What are the factors that are currently contributing to this new possible epidemiological dynamic? Could these be of a structural nature? Herein, we propose a discussion based on the importance of the virulence factors of glycoconjugate composition in the adaptation of pathogenic fungal species into the current scenario of increasing severity of these infections.

Cancer development and progression is associated with aberrant changes in cellular glycosylation. Cells expressing altered glycan-structures are recognized by cells of the immune system, favoring the induction of inhibitory immune processes which subsequently promote tumor growth and spreading. Here, we discuss about the importance of glycobiology in modern medicine, taking into account the impact of altered glycan structures expressed in cancer cells as potential glycobiomarkers of disease, as well as on cancer development and progression.

Chagas’ disease is caused by the protozoanTrypanosoma cruzi, described in the early 20^thcentury by the Brazilian physician Dr. Carlos Chagas. There was a great amount of research devoted to diagnosis, treatment and prevention of the disease. One of the most important discoveries made since then, impacting the understanding of how the parasite interacts with the host’s immune system, was the description oftrans-sialidase. It is an unique enzyme, capable of masking the parasite’s presence from the host, while at the same time dampening the activation of CD8+ T cells, the most important components of the immune response. Since the description of Chagas’ disease in 1909, extensive research has identified important events in the disease in order to understand the biochemical mechanism that modulatesT. cruzi-host cell interactions and the ability of the parasite to ensure its survival. The importance of thetrans-sialidase enzyme brought life to many studies for the design of diagnostic tests, drugs and vaccines. While many groups have been prolific, such efforts have encountered problems, among them: the fact that whileT. cruzihave many genes that are unique to the parasite, it relies on multiple copies of them and the difficulty in providing epitopes that result in effective and robust immune responses. In this review, we aim to convey the importance oftrans-sialidase as well as to provide a history, including the initial failures and the most promising successes in the chasing of a working vaccine for a disease that is endemic in many tropical countries, including Brazil.

The pathology associated with COVID-19 infection is progressively being revealed. Recent postmortem assessments have revealed acute airway inflammation as well as diffuse alveolar damage, which bears resemblance to severe acute respiratory syndromes induced by both SARS-CoV and MERS-CoV infections. Although recent papers have highlighted some neuropathologies associated with COVID-19 infection, little is known about this topic of great importance in the area of public health. Here, we discuss how neuroinflammation related to COVID-19 could be triggered by direct viral neuroinvasion and/or cytokine release over the course of the infection.

Coronavirus disease 2019 (COVID-19) can progress to severe pneumonia with respiratory failure and is aggravated by the deregulation of the immune system causing an excessive inflammation including the cytokine storm. Since 2019, several studies regarding the interplay between autoimmune diseases and COVID-19 infections is increasing all over the world. In addition, thanks to new scientific findings, we actually know better why certain conditions are considered a higher risk in both situations. There are instances when having an autoimmune disease increases susceptibility to COVID-19 complications, such as when autoantibodies capable of neutralizing type I IFN are present, and other situations in which having COVID-19 infection precedes the appearance of various autoimmune and autoinflammatory diseases, including multisystem inflammatory syndrome in children (MIS-C), Guillain-Barré syndrome, and Autoimmune haemolytic anaemia (AIHA), thus, adding to the growing mystery surrounding the SARS-CoV-2 virus and raising questions about the nature of its link with autoimmune and autoinflammatory sequelae. Herein, we discuss the role of host and virus genetics and some possible immunological mechanisms that might lead to the disease aggravation.