EXCLI Journal最新文献

Polyphenols are naturally occurring compounds that can be found in plant-based foods, including fruits, vegetables, nuts, seeds, herbs, spices, and beverages, the use of which has been linked to enhanced brain health and cognitive function. These natural molecules are broadly classified into two main groups: flavonoids and non-flavonoid polyphenols, the latter including phenolic acids, stilbenes, and tannins. Flavonoids are primarily known for their potent antioxidant properties, which help neutralize harmful reactive oxygen species (ROS) in the brain, thereby reducing oxidative stress, a key contributor to neurodegenerative diseases. In addition to their antioxidant effects, flavonoids have been shown to modulate inflammation, enhance neuronal survival, and support neurogenesis, all of which are critical for maintaining cognitive function. Phenolic acids possess strong antioxidant properties and are believed to protect brain cells from oxidative damage. Neuroprotective effects of these molecules can also depend on their ability to modulate signaling pathways associated with inflammation and neuronal apoptosis. Among polyphenols, hydroxycinnamic acids such as caffeic acid have been shown to enhance blood-brain barrier permeability, which may increase the delivery of other protective compounds to the brain. Another compound of interest is represented by resveratrol, a stilbene extensively studied for its potential neuroprotective properties related to its ability to activate the sirtuin pathway, a molecular signaling pathway involved in cellular stress response and aging. Lignans, on the other hand, have shown promise in reducing neuroinflammation and oxidative stress, which could help slow the progression of neurodegenerative diseases and cognitive decline. Polyphenols belonging to different subclasses, such as flavonoids, phenolic acids, stilbenes, and lignans, exert neuroprotective effects by regulating microglial activation, suppressing pro-inflammatory cytokines, and mitigating oxidative stress. These compounds act through multiple signaling pathways, including NF-κB, MAPK, and Nrf2, and they may also influence genetic regulation of inflammation and immune responses at brain level. Despite their potential for brain health and cognitive function, polyphenols are often characterized by low bioavailability, something that deserves attention when considering their therapeutic potential. Future translational studies are needed to better understand the right dosage, the overall diet, the correct target population, as well as ideal formulations allowing to overcome bioavailability limitations. See also the graphical abstract(Fig. 1).

Berberine (BBR) is a plant-derived alkaloid that has been traditionally used in Chinese medicine to treat diarrhea. In recent years, accumulating evidence has highlighted its broad therapeutic potential across multiple organ systems. This review systematically examines the pharmacological mechanisms and therapeutic applications of BBR in cancer, as well as in digestive, metabolic, cardiovascular, and neurological diseases. The effects of BBR on endogenous factors-such as energy metabolism, immune responses, cellular homeostasis, and gene expression-are discussed, along with its regulation of cellular functions and inflammatory responses. In addition, we explore BBR's actions on exogenous factors, particularly the gut microbiota. The review also summarizes emerging molecular targets of BBR and addresses current clinical applications, as well as novel strategies to improve its low oral bioavailability. By integrating findings from basic, translational, and clinical research, this review provides a comprehensive overview of BBR's therapeutic potential and supports its integration into modern medical practice. See also the graphical abstract(Fig. 1).

Metabolic syndrome (MetS), is a non-communicable disorder caused by impaired management and storage of energy, primarily associated with unhealthy diets, sedentary lifestyles and stress. It is diagnosed when any three of the following conditions are observed, obesity (primary factor), hyperglycemia, low HDL, hypertriglyceridemia, and hypertension (ATP III guidelines). MetS affects approximately 14-34 % of the global population, highlighting significant public health concern. If left untreated, it leads to the development of other serious metabolic diseases like atherosclerosis, diabetes, PCOS, NAFLD, NASH, thyroid, cancer, sleep disturbance, osteoarthritis, anxiety, and depression. Despite ongoing research, no first-line drug currently exists for the comprehensive management of MetS. Its multifactorial nature often requires lifelong polytherapy with lifestyle intervention, raising concern over chronic drug use, drug-drug interactions, increasing morbidity and mortality. Therefore, there is a need highlighting the requirement of a single and targeted pharmacotherapy which offers a safer and more specific therapeutic approach. This review aims to identify and analyse ten key molecular targets in managing the pathogenesis of Metabolic Syndrome (MetS). These targets can further pave the way for a targeted and safer approach in the treatment of MetS. See also the graphical abstract(Fig. 1).

Sepsis remains a global health problem that causes millions of deaths each year. A rapid and accurate diagnosis is highly desired to allow a rapid use of appropriate antibiotics. A better understanding of the associated pathophysiology has been achieved these recent years. The initial appropriate immune response to infection evolves towards an overwhelmed inflammatory response involving both pro- and anti-inflammatory players that act concomitantly. It also includes cell deaths and cellular dysfunctions of leukocytes, endothelial cells and epithelial cells, associated with mitochondrial dysfunction. These dysregulations are responsible for organ impairment and alteration of immune status of circulating leukocytes. In contrast, within the tissues, an over-activation exists as illustrated by transcriptomic analyses of organs of patients deceased of sepsis, and revealed by the presence of a macrophage activation syndrome within the bone marrow. Despite progresses in understanding the mechanisms underlying sepsis and despite successful therapies in animal models, no real new therapies have emerged these recent decades. This failure may reflect the yin yang aspect of the same players of the host response such as fever, release of cytokines, or coagulation which can display both a beneficial or a detrimental role. Great hopes are now expected from precision medicine, based on patients' endotypes which should help to decipher the patient's sub-groups who could benefit from the different treatments, or to define some appropriate time windows for a given treatment. See also the graphical abstract(Fig. 1).

This study investigated the therapeutic impact of dual immune checkpoint inhibition targeting TIGIT and VISTA in non-small cell lung cancer (NSCLC). Current monotherapies have failed to produce consistent and durable responses owing to tumor heterogeneity and immune evasion. By evaluating the biological and immunomodulatory roles of TIGIT and VISTA, this study provides a rationale for their simultaneous blockade. Preclinical models have shown that this dual strategy not only revitalizes T-cell function but also alters the suppressive tumor microenvironment, leading to improved antitumor immunity in mice. Preliminary clinical data suggest potential survival benefits; however, the long-term outcomes and resistance dynamics remain uncertain. These findings suggest a paradigm shift toward precision-designed, multi-target immunotherapies. Future studies should integrate molecular profiling, adaptive clinical trial designs, and follow-up models to optimize patient selection and sustain therapeutic benefits. See also the graphical abstract(Fig. 1).

Cancer is a multifactorial disease with cellular proliferative molecular networks and immune evasion properties. The well-known cancer intra- and inter-tumoral heterogeneity presents a notable limitation of the current histological and diagnostic techniques. Thus, biasing the risk of invasiveness and restricting its broader application in oncology in prognostic, survival, and treatment response differences between patients. Monolayer cell cultures have been a consistent in vitro model in cancer research throughout time. However, this system fails to replicate the complex pathogenesis of this disease, as key mechanisms underlying initiation, metastasis, drug resistance, and recurrence remain poorly understood. 3D culture models are presented as the most suitable model to better reflect the patient's tumor development. Some methods to introduce the third dimension into cell cultures is by promoting cell-cell interactions to give 3D cell structures, using scaffolds to promote growth beyond monolayers and introducing microfluidic platforms to the system. The present review provides an overview of different techniques to develop 3D culture models in oncology, the advantages compared between monolayer cell cultures, their applications, limitations, and applicability in oncology research. See also the graphical abstract(Fig. 1).

Breast cancer (BC), characterised by its diverse subtypes and molecular heterogeneity, remains a major challenge in oncology. Despite advances in chemotherapy, such as doxorubicin (Dox), limitations persist due to toxicity and drug resistance. Pigment epithelium-derived factor (PEDF) is a multifunctional protein with unique anti-tumour properties. The aim here was to elucidate metabolic reprogramming in human BC cell lines using a metabolomics approach. Untargeted gas chromatography-quadrupole mass spectrometry (GC/Q-MS) was employed to identify the metabolic alterations in BC cell lines MCF-7 (ER-positive) and MDA-MB-231 (TNBC) following treatment with PEDF, Dox, and their combination (Dox+PEDF) in comparison to untreated controls. Statistical models were employed using a combination of multivariate and univariate analyses, including partial least squares discriminant analysis (PLS-DA) and one-way ANOVA, applied by MetaboAnalyst and SIMCA software. To address the potential for multiple-testing errors, false discovery rate (FDR)-adjusted p-values were calculated to ensure robust statistical reliability. The overall analysis revealed significant metabolic alterations across the treatment groups, with distinct patterns emerging in carbohydrate, lipid, and amino acid metabolisms. In MCF-7 cells, PEDF combined with Dox significantly decreased cystine levels and modulated aspartic acid and lipid-related metabolites, indicating potential shifts in redox homeostasis and membrane composition. In MDA-MB-231 cells, the combination treatment significantly reduced glucose-6-phosphate and lactate levels, suggesting remodeling of glycolytic flux and redox balance. Furthermore, the combination of PEDF and Dox influenced amino acid and lipid metabolism. Pathway enrichment and correlation analyses revealed significant perturbations in glutathione metabolism, energy pathways, and lipid signaling, with notable differences between the two cell lines. Combining Dox and PEDF induced coordinated changes in metabolic networks, suggesting synergistic and antagonistic mechanisms that impact multiple biochemical pathways. These findings underline the importance of combining PEDF with chemotherapy to improve treatment outcomes in BC. See also the graphical abstract(Fig. 1).