Expert Reviews in Molecular Medicine最新文献

Target deconvolution can help understand how compounds exert therapeutic effects and can accelerate drug discovery by helping optimise safety and efficacy, revealing mechanisms of action, anticipate off-target effects and identifying opportunities for therapeutic expansion. Chemoproteomics, a combination of chemical biology with mass spectrometry has transformed target deconvolution. This review discusses modification-free chemoproteomic approaches that leverage the change in protein thermodynamics induced by small molecule ligand binding. Unlike modification-based methods relying on enriching specific protein targets, these approaches offer proteome-wide evaluations, driven by advancements in mass spectrometry sensitivity, increasing proteome coverage and quantitation methods. Advances in methods based on denaturation/precipitation by thermal or chemical denaturation, or by protease degradation are evaluated, emphasising the evolving landscape of chemoproteomics and its potential impact on future drug-development strategies.

Glioblastoma IDH wild type (GBM) is a very aggressive brain tumour, characterised by an infiltrative growth pattern and by a prominent neoangiogenesis. Its prognosis is unfortunately dismal, and the median overall survival of GBM patients is short (15 months). Clinical management is based on bulk tumour removal and standard chemoradiation with the alkylating drug temozolomide, but the tumour invariably recurs leading to patient's death. Clinical options for GBM patients remained unaltered for almost two decades until the encouraging results obtained by the phase II REGOMA trial allowed the introduction of the multikinase inhibitor regorafenib as a preferred regimen in relapsed GBM treatment by the National Comprehensive Cancer Network (NCCN) 2020 Guideline. Regorafenib, a sorafenib derivative, targets kinases associated with angiogenesis (VEGFR 1-3), as well as oncogenesis (c-KIT, RET, FGFR) and stromal kinases (FGFR, PDGFR-b). It was already approved for metastatic colorectal cancers and hepatocellular carcinomas. The aim of the present review is to focus on both the molecular and clinical knowledge collected in these first three years of regorafenib use in GBM.

Epigenetic modifications, such as DNA methylation, are enzymatically regulated processes that directly impact gene expression patterns. In early life, they are central to developmental programming and have also been implicated in regulating inflammatory responses. Research into the role of epigenetics in neonatal health is limited, but there is a growing body of literature related to the role of DNA methylation patterns and diseases of prematurity, such as the intestinal disease necrotizing enterocolitis (NEC). NEC is a severe intestinal inflammatory disease, but the key factors that precede disease development remain to be determined. This knowledge gap has led to a failure to design effective targeted therapies and identify specific biomarkers of disease. Recent literature has identified altered DNA methylation patterns in the stool and intestinal tissue of neonates with NEC. These findings provide the foundation for a new avenue in NEC research. In this review, we will provide a general overview of DNA methylation and then specifically discuss the recent literature related to methylation patterns in neonates with NEC. We will also discuss how DNA methylation is used as a biomarker for other disease states and how, with further research, methylation patterns may serve as potential biomarkers for NEC.

Deubiquitinases are a group of proteins that identify and digest monoubiquitin chains or polyubiquitin chains attached to substrate proteins, preventing the substrate protein from being degraded by the ubiquitin-proteasome system. Deubiquitinases regulate cellular autophagy, metabolism and oxidative stress by acting on different substrate proteins. Recent studies have revealed that deubiquitinases act as a critical regulator in various cardiac diseases, and control the onset and progression of cardiac disease through a board range of mechanism. This review summarizes the function of different deubiquitinases in cardiac disease, including cardiac hypertrophy, myocardial infarction and diabetes mellitus-related cardiac disease. Besides, this review briefly recapitulates the role of deubiquitinases modulators in cardiac disease, providing the potential therapeutic targets in the future.

The host immune system status remains an unresolved mystery among several malignancies. An immune-compromised state or smart immune-surveillance tactics orchestrated by cancer cells are the primary cause of cancer invasion and metastasis. Taking a closer look at the tumour-immune microenvironment, a complex network and crosstalk between infiltrating immune cells and cancer cells mediated by cytokines, chemokines, exosomal mediators and shed ligands are present. Cytokines such as interleukins can influence all components of the tumour microenvironment (TME), consequently promoting or suppressing tumour invasion based on their secreting source. Interleukin-10 (IL-10) is an interlocked cytokine that has been associated with several types of malignancies and proved to have paradoxical effects. IL-10 has multiple functions on cellular and non-cellular components within the TME. In this review, the authors shed the light on the regulatory role of IL-10 in the TME of several malignant contexts. Moreover, detailed epigenomic and pharmacogenomic approaches for the regulation of IL-10 were presented and discussed.

In vitro fertilization (IVF) and embryo transfer and intracytoplasmic sperm injection (ICSI) have allowed millions of infertile couples to achieve pregnancy. As an essential part of IVF/ICSI enabling the retrieval of a high number of oocytes in one cycle, controlled ovarian stimulation (COS) treatment mainly composes of the standard long gonadotrophin-releasing hormone agonist (GnRH-a) protocol and the gonadotrophin-releasing hormone antagonist (GnRH-ant) protocol. However, the effectiveness of GnRH-ant protocol is still debated because of inconsistent conclusions and insufficient subgroup analyses. This systematic review and meta-analysis included a total of 52 studies, encompassing 5193 participants in the GnRH-ant group and 4757 in the GnRH-a group. The findings of this study revealed that the GnRH-ant protocol is comparable with the long GnRH-a protocol when considering live birth as the primary outcome, and it is a favourable protocol with evidence reducing the incidence of ovarian hyperstimulation syndrome in women undergoing IVF/ICSI, especially in women with polycystic ovary syndrome. Further research is needed to compare the subsequent cumulative live birth rate between the two protocols among the general and poor ovarian response patients since those patients have a lower clinical pregnancy rate, fewer oocytes retrieved or fewer high-grade embryos in the GnRH-ant protocol.

Manipulation of T cells has revolutionized cancer immunotherapy. Notably, the use of T cells carrying engineered T cell receptors (TCR-T) offers a favourable therapeutic pathway, particularly in the treatment of solid tumours. However, major challenges such as limited clinical response efficacy, off-target effects and tumour immunosuppressive microenvironment have hindered the clinical translation of this approach. In this review, we mainly want to guide TCR-T investigators on several major issues they face in the treatment of solid tumours after obtaining specific TCR sequences: (1) whether we have to undergo affinity maturation or not, and what parameter we should use as a criterion for being more effective. (2) What modifications can be added to counteract the tumour inhibitory microenvironment to make our specific T cells to be more effective and what is the safety profile of such modifications? (3) What are the new forms and possibilities for TCR-T cell therapy in the future?

Negative pressure wound therapy (NPWT) has significantly advanced wound care and continues to find new applications. Its effects at a molecular level however, remain a subject of debate. The aim of this systematic review is to summarize the current evidence regarding the molecular mechanisms of action of NPWT. Medline, Embase, EBSCO databases and clinical trial registries were searched from inception to January 2023. Clinical studies, animal models or in-vitro studies that quantitatively or semi-quantitatively evaluated the influence of NPWT on growth factors, cytokine or gene-expression in the circulation or wound-bed were included. Risk of Bias assessment was performed using the RoBANS tool for non-randomized studies, the COCHRANE's Risk of Bias 2(ROB-2) tool for randomized clinical studies, OHAT tool for in-vitro studies or the SYRCLE tool for animal model studies. A descriptive summary was collated and the aggregated data is presented as a narrative synthesis. This review included 19 clinical studies, 11 animal studies and 3 in-vitro studies. The effects of NPWT on 43 biomarkers and 17 gene expressions were studied across included studies. NPWT stimulates modulation of numerous local and circulating cytokines and growth factor expressions to promote an anti-inflammatory profile. This is most likely achieved by downregulation of TNFα, upregulation of VEGF, TGF-β and fibronectin.