Frontiers in bioscience (Landmark edition)最新文献

Cardiovascular complications claim the lives of up to 70% of patients with diabetes mellitus (DM). The mechanisms increasing cardiovascular risk in DM remain to be fully understood and successfully addressed. Nonetheless, there is increasing evidence in the scientific literature of the participation of platelets in the cardiovascular complications of DM. Multiple reports describe the hyperactivity of platelets in DM and their participation in inflammatory responses. The understanding of the mechanisms underlying the contribution of platelets to cardiovascular pathologies in DM will help the development of targeted therapeutic strategies able to reduce cardiovascular risk in these patients. In this literature review, we summarise our current understanding of the molecular mechanisms leading to the contribution of platelets to cardiovascular risk in DM. Both platelet haemostatic activity leading to thrombus formation and their participation to inflammatory processes are stimulated by the biochemical conditions associated with DM. We also present evidence on how DM affect the efficacy of existing therapeutic treatments for thrombosis and, by converse, how antidiabetic drugs may affect platelet function and the haemostasis/thrombosis balance. Taken together, the growing evidence of the different and unexpected roles of platelets in the progression of DM provides a strong rationale for the design of cardiovascular drugs targeting specifically platelets, their pro-inflammatory activity and their activation mechanisms in this disease. Overall, this article provides an important up-to-date overview of the pathophysiological alterations of platelets in DM, which need to be taken into account for the effective management of cardiovascular health in this disease.

Cardiovascular disease (CVD) is the most prevalent cause of mortality and morbidity in the Western world. A common underlying hallmark of CVD is the plaque-associated arterial thickening, termed atherosclerosis. Although the molecular mechanisms underlying the aetiology of atherosclerosis remain unknown, it is clear that both its development and progression are associated with significant changes in the pattern of DNA methylation within the vascular cell wall. The endothelium is the major regulator of vascular homeostasis, and endothelial cell dysfunction (ED) is considered an early marker for atherosclerosis. Thus, it is speculated that changes in DNA methylation within endothelial cells may, in part, be causal in ED, leading to atherosclerosis and CVD generally. This review will evaluate the extensive evidence that environmental risk factors, known to be associated with atherosclerosis, such as diabetes, metabolic disorder, smoking, hypertension and hypercholesterolaemia etc. can affect the methylome of the endothelium and consequently act to alter gene transcription and function. Further, the potential mechanisms whereby such risk factors might impact upon the activities and/or specificities of the epigenetic writers and erasers which determine the methylome [the DNA methyl transferases (DNMTs) and Ten Eleven translocases (TETs)] are considered here. Notably, the TET proteins are members of the 2-oxoglutarate-dependent dioxygenase superfamily which require molecular oxygen (O₂) and α-ketoglutarate (α-KG) as substrates and iron-2⁺ (Fe II) as a cofactor. This renders their activities subject to modulation by hypoxia, metabolic flux and cellular redox. The potential significance of this, with respect to the impact of modifiable risk factors upon the activities of the TETs and the methylome of the endothelium is discussed.

Background: Rheumatic heart disease (RHD), which is caused mainly by Group A Streptococcus, leads to fibrotic damage to heart valves. Recently, endothelial‒mesenchymal transition (EndMT), in which activin plays an important role, has been shown to be an important factor in RHD valvular injury. However, the mechanism of activin activity and EndMT in RHD valvular injury is not clear.

Methods: Our study was divided into two parts: in vivo and in vitro. We constructed a small interfering RNA (ACVR2A-siRNA) by silencing activin receptor type IIA (ACVR2A) and an adeno-associated virus (AAV-ACVR2A) containing a sequence that silenced ACVR2A. The EndMT cell model was established via human umbilical vein endothelial cells (HUVECs), and the RHD animal model was established via female Lewis rats. ACVR2A-siRNA and AAV-ACVR2A were used in the above experiments.

Results: EndMT occurred in the valvular tissues of RHD rats, and activin and its associated intranuclear transcription factors were also activated during this process, with inflammatory infiltration and fibrotic damage also occurring in the valvular tissues. After inhibition of ACVR2A, EndMT in valvular tissues was also inhibited, and inflammatory infiltration and fibrosis were reduced. Endothelial cell experiments suggested that mesenchymal transition could be stimulated by activin and that inhibition of ACVR2A attenuated mesenchymal transition.

Conclusions: Activin plays an important role in signal transduction during EndMT after activation, and inhibition of ACVR2A may attenuate RHD valvular damage by mediating EndMT. Targeting ACVR2A may be a therapeutic strategy to alleviate RHD valvular injury.

Background: We investigated chitosan's protective effects against tertiary butylhydroquinone (TBHQ)-induced toxicity in adult male rats, focusing on cognitive functions and oxidative stress in the brain, liver, and kidneys.

Methods: Rats were divided into four groups (n = 8/group): (1) Control, (2) Chitosan only, (3) TBHQ only, and (4) Chitosan + TBHQ.

Results: TBHQ exposure led to significant cognitive impairments and increased oxidative stress, marked by elevated malondialdehyde (MDA) and decreased superoxide dismutase (SOD) and glutathione (GSH) levels. Behavioral tests, including the Morris Water Maze (MWM) as well as Passive Avoidance Learning (PAL) tasks, confirmed memory and learning deficits in the TBHQ group. Histopathological analysis showed damage in the brain, liver, and kidney tissues of TBHQ-exposed rats. Chitosan treatment significantly mitigated these effects, reducing oxidative stress markers and preserving tissue integrity. These findings suggest that chitosan's antioxidant properties may provide a therapeutic benefit against TBHQ-induced neurotoxicity and organ damage.

Conclusions: These findings suggest that chitosan exerts potent neuroprotective effects, potentially through its antioxidant and anti-inflammatory properties, and could serve as a therapeutic agent against TBHQ-induced toxicity.

Multiple sclerosis (MS) is a chronic autoimmune disorder marked by neuroinflammation, demyelination, and neuronal damage. Recent advancements highlight a novel interaction between iron-dependent cell death, known as ferroptosis, and gut microbiota, which may significantly influences the pathophysiology of MS. Ferroptosis, driven by lipid peroxidation and tightly linked to iron metabolism, is a pivotal contributor to the oxidative stress observed in MS. Concurrently, the gut microbiota, known to affect systemic immunity and neurological health, emerges as an important regulator of iron homeostasis and inflammatory responses, thereby influencing ferroptotic pathways. This review investigates how gut microbiota dysbiosis and ferroptosis impact MS, emphasizing their potential as therapeutic targets. Through an integrated examination of mechanistic pathways and clinical evidence, we discuss how targeting these interactions could lead to novel interventions that not only modulate disease progression but also offer personalized treatment strategies based on gut microbiota profiling. This synthesis aims at deepening insights into the microbial contributions to ferroptosis and their implications in MS, setting the stage for future research and therapeutic exploration.

Background: Spatial-temporal control of mRNA translation in dendrites is important for synaptic plasticity. In response to pre-synaptic stimuli, local mRNA translation can be rapidly triggered near stimulated synapses to supply the necessary proteins for synapse maturation or elimination, and 3' untranslated regions (UTRs) are responsible for proper localization of mRNAs in dendrites. Although FISH is a robust technique for analyzing RNA localization in fixed neurons, live-cell imaging of RNA dynamics remains challenging.

Methods: In this study, we optimized existing RNA visualization techniques (MS2-tagging and microinjection of fluorescently-labeled mRNAs) to observe novel behaviors of dendritic mRNAs.

Results: We found that the signal-to-noise ratio (SNR) of MS2-tagged mRNAs was greatly improved by maximizing the ratio of the MS2-RNA to MS2 coat protein-fluorescent protein (MCP-FP) constructs, as well as by the choice of promoter. Our observations also showed that directly fluorescently labeled mRNAs result in brighter granules compared to other methods. Importantly, we visualized the dynamic movement of co-labeled mRNA/protein complexes in dendrites and within dendritic spines. In addition, we observed the simultaneous movement of three distinct mRNAs within a single neuron. Surprisingly, we observed splitting of these complexes within dendritic spines.

Conclusions: Using highly optimized RNA-labeling methods for live-cell imaging, one can now visualize the dynamics of multiple RNA / protein complexes within the context of diverse cellular events. Newly observed RNA movements in dendrites and synapses may shed light on the complexities of spatio-temporal control of gene expression in neurons.

Background: Regulatory T-cells (Tregs) play a crucial role in maintaining immune homeostasis, but their dynamics are altered in a subset of people living with Human Immunodeficiency Virus (HIV) known as immunological non-responders (INRs). INRs fail to reconstitute CD4⁺ T-cell counts despite viral suppression. This study aimed to examine Treg dysregulation in INRs, comparing them to immunological responders (IRs) and healthy controls (HCs).

Methods: The study included 40 INRs, 42 IRs, and 23 HCs. Peripheral blood mononuclear cells were isolated and analyzed by flow cytometry. Conventional CD4⁺ T-cells (Tconvs) were identified as CD25^-/loFOXP3^- cells, while Tregs were identified as CD25⁺CD127^loFOXP3⁺ CD4⁺ T-cells. Cells were further divided into naive, central memory, effector memory, and effector memory cells re-expressing CD45RA (TEMRA) subsets. Activated/cycling cells were identified as CD71⁺ and quiescent cells were CD71^-. Mitochondrial mass and transmembrane potential were measured using MitoTracker Green and MitoTracker Orange dyes, respectively. Statistical comparisons were made using the Kruskal-Wallis test with Dunn's post-hoc analysis and Mann-Whitney U-test.

Results: INRs exhibited the highest frequencies of activated/cycling CD4⁺ T-cells. The proportion of activated/cycling cells was higher in Tregs compared to Tconvs in all groups. Cycling rates of Tregs and Tconvs were correlated, suggesting Tregs help control Tconv proliferation. Despite high overall Treg frequencies in INRs, they showed a Treg deficiency in activated/cycling CD4⁺ T-cells, specifically in naive and central memory subsets, causing an imbalance in the Tconv/Treg ratio. This deficiency was hidden by increased Treg frequencies in quiescent effector memory CD4⁺ T-cells. Activated/cycling naive and memory Tregs from INRs had normal forkhead box P3 (FOXP3) and CD25 expression, but activated/cycling memory Tregs showed decreased ability to regulate mitochondrial transmembrane potential, indicating impaired mitochondrial fitness. These mitochondrial abnormalities were similar to those observed in memory conventional T-cells.

Conclusions: The complex Treg dysregulation in immunological non-responders involves quantitative and functional alterations, including a Treg deficiency within activated/cycling naive and central memory CD4⁺ T-cells, impaired mitochondrial fitness of activated/cycling memory Tregs, and functional disorders of the parent conventional T-lymphocytes. These findings underscore the need for a nuanced understanding of Treg dynamics in suboptimal CD4⁺ T-cell reconstitution during HIV-infection.

Objective: Ca²⁺ overload of muscle fibers is one of the factors that secondarily aggravate the development of Duchenne muscular dystrophy (DMD). The purpose of this study is to evaluate the effects of the Ca²⁺ channel modulator 2-aminoethoxydiphenyl borate (APB) on skeletal muscle pathology in dystrophin-deficient mdx mice.

Methods: Mice were randomly divided into six groups: wild type (WT), WT+3 mg/kg APB, WT+10 mg/kg APB, mdx, mdx+3 mg/kg APB, mdx+10 mg/kg APB. APB was administered intraperitoneally daily for 28 days. Finally, we assessed the grip strength and hanging time of mice, the histology and ultrastructure of the quadriceps, as well as the parameters reflecting quadricep mitochondrial function.

Results: 3 mg/kg APB was shown to reduce creatine kinase activity in the serum, intensity of degeneration and the level of fibrosis in the quadriceps of mdx mice, and improved tissue ultrastructure. However, this effect of APB was not sufficient to improve grip strength and hanging time of mdx mice. The effect of 3 mg/kg APB may be due to improve Ca²⁺ homeostasis in skeletal muscles, as evidenced by a trend toward decreased Ca²⁺ overload of quadricep mitochondria. High dose of APB (10 mg/kg body weight) showed less pronounced effect on the pathological phenotype of mdx mice. Moreover, 10 mg/kg APB disrupted the ultrastructure of the quadriceps and caused a decrease in grip strength in WT mice.

Conclusions: APB is able to improve the phenotype in mdx mouse DMD model. However, the effect of APB is quite limited, which may be due to its multitargeting of Ca²⁺ channels in the membranes of muscle fibers and intracellular organelles, differentially expressed in DMD.