Expert Reviews in Molecular Medicine最新文献

Background: Glioblastoma multiforme (GBM) is the most prevalent primary brain tumour, with an incidence of 2 per 100,000. The standard clinical treatments do not sufficiently target cell migration and invasion, leading to recurrence after surgical resection and resistance after chemotherapy and radiotherapy. Pre-clinical studies are being conducted to construct artificial substrates that can mimic the tumour microenvironment (TME) to prevent GBM cells from migrating along their primary route through blood vessels and white matter tracts. Alongside, targeted therapies using anti-migratory or ‘migrastatic’ drugs are also being developed. This study aimed to review the therapeutic translational strategies emerging from the study of the GBM microenvironment and anti-migratory drugs.

Methods: A systematic literature search was carried out using search key terms and synonyms. Full-paper screening was performed based on specific inclusion and exclusion criteria.

Results: From the systems interrogated, the ‘Nanofibre’ assay is suitable to simulate white matter tracts, while hydrogel-based invasion assays and GBM cerebral organoid (GLICO) mimic the brain extracellular matrix. Inhibitors with anti-migratory activity found in this study are active involving distinct molecular mechanisms and have been tested on cell migration assays.

Conclusion: Overall, we have analysed therapeutic strategies emerging from an artificial GBM TME approach and from the identification of anti-migratory inhibitors. Both carry potential to improve treatment options to prevent tumour dissemination and spread for GBM.

Background: Leishmaniasis, Chagas disease (CD), and Human African Trypanosomiasis (HAT) are neglected tropical diseases in humans caused by intracellular parasites from the class Kinetoplastida. Leishmaniasis is one infectious disease that exhibits sex-bias not explained solely by behavioral or cultural differences. However, HAT and CD have less well documented and understood sex-related differences, either due to a lack of differences or insufficient research and reporting.

Methods: This paper reviews the rate of disease and disease severity among male and females infected with CD, HAT, and leishmaniasis. We further review the specific immune response to each pathogen and potential sex-based mechanisms which could impact immune responses and disease outcomes.

Results: These mechanisms include sex hormone modulation of the immune response, sex-related genetic differences, and socio-cultural factors impacting risky behaviors in men and women. The mechanistic differences in immune response among sexes and pathogens provide important insights and identification of areas for further research.

Conclusions: This information can aid in future development of inclusive, targeted, safe, and effective treatments and control measures for these neglected diseases and other infectious diseases.

Despite the emergence of the first human papillomavirus vaccine, the incidence of cervical cancer is still responsible for more than 350,000 deaths yearly. Over the past decade, ecto-5'-nucleotidase (CD73/5'-NT) and extracellular adenosine (ADO) signalling has been the subject of many investigations to target cancer progression. In general, the adenosinergic axis has been linked to tumourigenic effects. However, CD73 can play contradictory effects, probably dependent on the tumour type, tumour microenvironment and tumour stage, thus being in some circumstances, inversely related to tumour progression. We herein reviewed the pathophysiological function of CD73 in cervical cancer and performed in silico analysis of the main components of the adenosinergic signalling in human tissues of cervical cancer compared to non-tumour cervix tissue. Our data showed that the NT5E gene, that encoded CD73, is hypermethylated, leading to a decreased CD73 expression in cervical cancer cells compared to normal cells. Consequently, the high availability of ADO cytoplasmatic/extracellular leads to its conversion to AMP by ADK, culminating in global hypermethylation. Therefore, epigenetic modulation may reveal a new role for CD73 in cervical cancer.

Tuberculosis (TB) is one of the deadliest infectious diseases globally, ranking as 13th leading cause of mortality and morbidity. According to the Global Tuberculosis Report 2022, TB claimed the lives of 1.6 million people worldwide in 2021. Among the casualties, 1 870 000 individuals with HIV co-infections contributed to 6.7% of the total fatalities, accounting TB as the second most lethal infectious disease following COVID-19. In the quest to identify biomarkers for disease progression and anti-TB therapy, microRNAs (miRNAs) have gained attention due to their precise regulatory role in gene expression in disease stages and their ability to distinguish latent and active TB, enabling the development of early TB prognostic signatures. miRNAs are stable in biological fluids and therefore will be useful for non-invasive and broad sample collection. However, their inherent lack of specificity and experimental variations may lead to false-positive outcomes. These limitations can be overcome by integrating standard protocols with machine learning, presenting a novel tool for TB diagnostics and therapeutics. This review summarizes, discusses and highlights the potential of miRNAs as a biomarker, particularly their differential expression at disease stages. The review assesses the advantages and obstacles associated with miRNA-based diagnostic biomarkers in pulmonary TB and facilitates rapid, point-of-care testing.

Glycosylation modifications of proteins and glycan hydrolysis are critical for protein function in biological processes. Aberrations in glycosylation enzymes are linked to lysosomal storage disorders (LSDs), immune interactions, congenital disorders and tumour progression. Mannosidase alpha class 2B member 1 (MAN2B1) is a lysosomal hydrolase from the α-mannosidase family. Dysfunction of MAN2B1 has been implicated as causative factors in mannosidosis, a lysosomal storage disorder characterised by cognitive impairment, hearing loss and immune system and skeletal anomalies. Despite decades of research, its role in pathogenic infections, autoimmune conditions, cancers and neurodegenerative pathologies is highly ambiguous. Future studies are required to shed more light on the intricate functioning of MAN2B1. To this end, we review the biological functions, expression patterns, enzymatic roles and potential implications of MAN2B1 across various cell types and disease contexts. Additionally, the novel insights presented in this review may aid in understanding the role of MAN2B1 in immune cells, thereby paving the way for targeted therapeutic interventions in immune-related disorders.

Human neurodevelopment is a complex process vulnerable to disruptions, particularly during the prenatal period. Maternal viral infections represent a significant environmental factor contributing to a spectrum of congenital defects with profound and enduring impacts on affected offspring. The advent of induced pluripotent stem cell (iPSC)-derived three-dimensional (3D) human brain organoids has revolutionised our ability to model prenatal viral infections and associated neurodevelopmental disorders. Notably, human brain organoids provide a distinct advantage over traditional animal models, whose brain structures and developmental processes differ markedly from those of humans. These organoids offer a sophisticated platform for investigating viral pathogenesis, infection mechanisms and potential therapeutic interventions, as demonstrated by their pivotal role during the 2016 Zika virus outbreak. This review critically examines the utilisation of brain organoids in elucidating the mechanisms of TORCH viral infections, their impact on human brain development and contribution to associated neurodevelopmental disorders.